degenerative joint disease research paper

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Review Article
• Open access
• Published: 17 January 2017

Osteoarthritis: toward a comprehensive understanding of pathological mechanism

• Di Chen 1 ,
• Jie Shen 2 ,
• Weiwei Zhao 1 , 3 ,
• Tingyu Wang 4 ,
• Lin Han 5 ,
• John L Hamilton 1 &
• Hee-Jeong Im 1  

Bone Research volume  5 , Article number:  16044 ( 2017 ) Cite this article

41k Accesses

728 Citations

27 Altmetric

Metrics details

• Pathogenesis

Osteoarthritis (OA) is the most common degenerative joint disease and a major cause of pain and disability in adult individuals. The etiology of OA includes joint injury, obesity, aging, and heredity. However, the detailed molecular mechanisms of OA initiation and progression remain poorly understood and, currently, there are no interventions available to restore degraded cartilage or decelerate disease progression. The diathrodial joint is a complicated organ and its function is to bear weight, perform physical activity and exhibit a joint-specific range of motion during movement. During OA development, the entire joint organ is affected, including articular cartilage, subchondral bone, synovial tissue and meniscus. A full understanding of the pathological mechanism of OA development relies on the discovery of the interplaying mechanisms among different OA symptoms, including articular cartilage degradation, osteophyte formation, subchondral sclerosis and synovial hyperplasia, and the signaling pathway(s) controlling these pathological processes.

Similar content being viewed by others

Osteoarthritis: pathogenic signaling pathways and therapeutic targets

Synovial inflammation in osteoarthritis progression

Structural changes in the collagen network of joint tissues in late stages of murine OA

Introduction.

Osteoarthritis (OA) is the most common degenerative joint disease, affecting more than 25% of the population over 18 years-old. Pathological changes seen in OA joints include progressive loss and destruction of articular cartilage, thickening of the subchondral bone, formation of osteophytes, variable degrees of inflammation of the synovium, degeneration of ligaments and menisci of the knee and hypertrophy of the joint capsule. 1 The etiology of OA is multi-factorial and includes joint injury, obesity, aging, and heredity. 1 – 5 Because the molecular mechanisms involved in OA initiation and progression remain poorly understood, there are no current interventions to restore degraded cartilage or decelerate disease progression. Studies using genetic mouse models suggest that growth factors, including transforming growth factor-β (TGF-β), Wnt3a and Indian hedgehog, and signaling molecules, such as Smad3, β-catenin and HIF-2α, 6 – 10 are involved in OA development. One feature common to several OA animal models is the upregulation of Runx2. 7 , 8 , 11 – 13 Runx2 is a key transcription factor directly regulating the transcription of genes encoding matrix degradation enzymes in articular chondrocytes. 14 – 17 In this review article, we will discuss the etiology of OA, the available mouse models for OA research and current techniques used in OA studies. In addition, we will also summarize the recent progress on elucidating the molecular mechanisms of OA pain. Our goal is to provide readers a comprehensive coverage on OA research approaches and the most up-to-date progress on understanding the molecular mechanism of OA development.

OA is the most prevalent joint disease associated with pain and disability. It has been forecast that 25% of the adult population, or more than 50 million people in the US, will be affected by this disease by the year 2020 and that OA will be a major cause of morbidity and physical limitation among individuals over the age of 40. 18 , 19 Major clinical symptoms include chronic pain, joint instability, stiffness and radiographic joint space narrowing. 20 Although OA primarily affects the elderly, sports-related traumatic injuries at all ages can lead to post-traumatic OA. Currently, apart from pain management and end stage surgical intervention, there are no effective therapeutic treatments for OA. Thus, there is an unmet clinical need for studies of the etiology and alternative treatments for OA. In recent years, studies using the surgically induced destabilization of the medial meniscus (DMM) model and tissue or cells from human patients demonstrated that genetic, mechanical, and environmental factors are associated with the development of OA. At the cellular and molecular level, OA is characterized by the alteration of the healthy homeostatic state toward a catabolic state.

One of the most common risk factors for OA is age. A majority of people over the age of 65 were diagnosed with radiographic changes in one or more joints. 21 – 25 In addition to cartilage, aging affects other joint tissues, including synovium, subchondral bone and muscle, which is thought to contribute to changes in joint loading. Studies using articular chondrocytes and other cells suggest that aging cells show elevated oxidative stress that promotes cell senescence and alters mitochondrial function. 26 – 29 In a rare form of OA, Kashin-Back disease, disease progression was associated with mitochondrial dysfunction and cell death. 30 Another hallmark of aging chondrocytes is reduced repair response, partially due to alteration of the receptor expression pattern. In chondrocytes from aged and OA cartilage, the ratio of TGF-β receptor ALK1 to ALK5 was increased, leading to down-regulation of the TGF-β pathway and shift from matrix synthesis activity to catabolic matrix metalloproteinase (MMP) expression. 31 , 32 Recent studies also indicate that methylation of the entire genomic DNA displayed a different signature pattern in aging cells. 33 , 34 Genome-wide sequencing of OA patients also confirmed that this epigenetic alteration occurred in OA chondrocytes, 35 – 37 partially due to changes in expression of Dnmts (methylation) and Tets (de-methylation) enzymes. 38 – 40

In recent years, obesity has become a worldwide epidemic characterized by an increased body composition of adipose tissue. The association between obesity and OA has long been recognized. 41 , 42 Patients with obesity develop OA earlier and have more severe symptoms, higher risk for infection and more technical difficulties for total joint replacement surgery. In addition to increased biomechanical loading on the knee joint, obesity is thought to contribute to low-grade systemic inflammation through secretion of adipose tissue-derived cytokines, called adipokines. 43 – 45 Specifically, levels of pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) were elevated 46 – 50 in high-fat diet-induced mouse obesity models 51 – 54 and in obese patients. 55 – 57 These inflammatory factors may trigger the nuclear factor-κB (NF-κB) signaling pathway to stimulate an articular chondrocyte catabolic process and lead to extracellular matrix (ECM) degradation through the upregulation of MMPs. 58 – 60

Sport injury

Knee injury is the major cause of OA in young adults, increasing the risk for OA more than four times. Recent clinical reports showed that 41%–51% of participants with previous knee injuries have radiographic signs of knee OA in later years. 61 Cartilage tissue tear, joint dislocation and ligament strains and tears are the most common injuries seen clinically that may lead to OA. Trauma-related sport injuries can cause bone, cartilage, ligament, and meniscus damage, all of which can negatively affect joint stabilization. 62 – 66 Signs of inflammation observed in both patients with traumatic knee OA and in mouse injury models include increased cytokine and chemokine production, synovial tissue expansion, inflammatory cell infiltration, and NF-κB pathway activation. 67

Inflammation

It has been established that the chronic low-grade inflammation found in OA contributes to disease development and progression. During OA progression, the entire synovial joint, including cartilage, subchondral bone, and synovium, are involved in the inflammation process. 68 In aging and diabetic patients, conventional inflammatory factors, such as IL-1β and TNF-α, as well as chemokines, were reported to contribute to the systemic inflammation that leads to activation of NF-κB signaling in both synovial cells and chondrocytes. Innate inflammatory signals were also involved in OA pathogenesis, including damage associated molecular patterns (DAMPs), alarmins (S100A8 and S100A9) and complement. 69 – 71 DAMPs and alarmins were reported to be abundant in OA joints, signaling through either toll-like receptors (TLR) or the canonical NF-κB pathway to modulate the expression of MMPs and a disintegrin and metalloprotease with thrombospondin motif (ADAMTS) in chondrocytes. 72 – 76 Complement can be activated in OA chondrocytes and synovial cells by DAMPs, ECM fragments and dead-cell debris. 77 , 78 Recent studies further clarified that systemic inflammation can re-program chondrocytes through inflammatory mediators toward hypertrophic differentiation and catabolic responses through the NF-κB pathway, 9 , 10 , 79 the ZIP8/Zn + /MTF1 axis, 80 and autophagy mechanisms. 81 – 85 Indeed, the recent Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of OA and control samples provide evidence that inflammation signals contribute to OA pathogenesis through cytokine-induced mitogen-activated protein (MAP) kinases, NF-κB activation, and oxidative phosphorylation. 86

Genetic predisposition

An inherited predisposition to OA has been known for many years from family-based studies. 87 – 89 Although the genetics of OA are complex, the genetic contribution to OA is highly significant. Over the past decade, the roles of genes and signaling pathways in OA pathogenesis have been demonstrated by ex vivo studies using tissues derived from OA patients and in vivo studies using surgically induced OA animal models and genetic mouse models. For example, alterations in TGF-β, Wnt/β-catenin, Indian Hedgehog (Ihh), Notch and fibroblast growth factor (FGF) pathways have been shown to contribute to OA development and progression by primarily inducing catabolic responses in chondrocytes. 8 , 90 – 95 Such responses converge on Hif2α , Runx2 , and inflammatory mediators that lead to cartilage ECM degradation through the increased expression of MMPs and ADAMTS activity. 80 , 96 – 99 Recent studies of genome-wide association screens (GWAS) that have been performed on large numbers of OA and control populations throughout the world have confirmed over 80 gene mutations or single-nucleotide polymorphisms (SNPs) involved in OA pathogenesis. Some of the genes are important structural and ECM-related factors ( Col2a1 , Col9a1 , and Col11a1 ), and critical signaling molecules in the Wnt ( Sfrp3 ), bone morphogenetic protein (BMP) ( Gdf5 ), and TGF-β ( Smad3 ) signaling pathways; most of these genes have been previously implicated in OA or articular cartilage and joint maintenance by studies using mouse models of induced genetic alteration- or surgically induced OA. 100 – 106 A recent arcOGEN Consortium genome-wide screen study 107 identified new SNPs in several genes, including GNL3, ASTN2, and CHST11. These findings need to be verified by further studies.

Mouse models for OA research

DMM was developed 10 years ago and is a well established surgical OA model in mice and rats. It is widely used to study OA initiation and progression in combination with transgenic mouse models and aging and obesity models. DMM surgery was performed by transection of the medial meniscotibial ligament (MMTL). 26 , 27 Briefly, following the initial incision, the joint capsule on the medial side was incised using scissors to expose either the intercondylar region or the MMTL, which anchors the medial meniscus (MM) to the tibial plateau. The MMTL was visualized under a dissection microscope and the MMTL was cut using micro-surgical scissors, releasing the ligament from the tibia plateau thus destabilizing the medial meniscus. Closure of the joint capsule and skin was with a continuous 8–0 tapered Vicryl suture. As a control for DMM studies, sham surgery was performed by only exposing the medial side of knee joint capsule. Because of the medial displacement of the meniscus tissue, greater stress occurred on the posterior femur and central tibia, especially on the medial side. 108 Histology demonstrated the severity of OA lesions at 4-weeks post-surgery with fibrillation of the cartilage surface. Cartilage destruction and subchondral bone sclerosis developed 8 weeks post-surgery and osteophyte formation was seen 12-weeks post- surgery. 98 , 109 – 111

Aging model

As a degenerative disease, OA always occurs in elderly populations; thus, aging is a major risk factor for the most common form in humans, spontaneous OA. Several laboratory animals develop spontaneous OA, which approximates the stages of human OA progression. These animal models are valuable tools for studying natural OA pathogenesis. 112 , 113 The most commonly used inbred strain of laboratory mouse is C57/BL6; these mice usually develop knee OA at about 17 months of age. 112 The STR/ort mouse is one strain that easily develops spontaneous OA. It requires 12–20 weeks for STR/ort mice to develop articular cartilage destruction. 114 – 116 This may be partially due to their heavier body weight compared with other mouse strains. Given the background genetic consistency, although aging OA models have many advantages, it normally requires at least one year for mice to model the disease. Therefore, surgically induced OA models 107 , 117 and genetic mouse models are preferred in recent decades for their relatively fast induction for use as aging models for the study of OA lesions.

In addition to the mouse, the Dunkin Hartley guinea pig provides an aging model widely used to study OA development. 118 The Dunkin Hartley guinea pig can develop a spontaneous, age-related OA phenotype within 3 months. The severity of OA lesions increases with age, and moderate to severe OA is observable in 18-month-old animals. Histological analysis demonstrated that the spontaneous OA progression in Dunkin Hartley guinea pig resembles that of humans. Thus, the Dunkin Hartley guinea pig is a useful animal to study the pathogenesis and evaluation of potential treatments for human OA.

Obesity model

It has become evident that obesity contributes to a variety of musculoskeletal diseases, particularly OA, because of inflammatory and metabolic responses. 119 Together with surgically induced injury and genetic models, mouse obesity models are widely used to explore the mechanisms of obesity-induced OA. The obese mouse model is induced by a high-fat diet, in which 60% of calories are derived from fat as opposed to the normal 13%. 120 The entire joint tissue, but especially synovium tissue, is affected by the high-fat diet. A synovial inflammation phenotype has been independently reported by different laboratories. 54 An elevated systemic inflammation was observed in obese mice following DMM surgery. Serum levels of pro-inflammatory factors, including interleukin-12p70, 54 interleukin-6, TNFα and several other chemokines, were increased, suggesting a role for obesity in the development of post-traumatic OA (PTOA).

Genetic mouse models

Genetic mouse models have recently become widely used to investigate the cellular and molecular mechanisms of OA development. Based on the GWAS studies of human patients, mutant mouse strains were generated carrying either mutant genes or SNPS. For example, Del1 +/- mice carried a mutation in the collagen II gene. Both Del1 +/- mice and Col9a1 −/− mice developed spontaneous OA. 121 Because cartilage functions as a skeletal architect, conventional gene deletion approaches have the drawback of causing embryonic lethality or severe skeletal deformation. To overcome embryonic lethality and bypass the limits of constitutive gene knockout (KO), inducible conditional KO technology has been widely used. This usually combines Cre-loxP gene targeting with tamoxifen-induced nuclear translocation of CreER fusion protein driven by tissue-specific promoters. The Col2a1-Cre ERT2 , Agc1-Cre ERT2 and Prg4-Cre ERT2 transgenic mice 122 – 124 have become powerful tools for targeting joint tissue to study the mechanism of OA development. Based on the gene expression pattern, both Col2a1 and Agc1 can efficiently target chondrocytes in the growth plate cartilage, articular cartilage and temporomandibular joint. Because Agc1 is expressed more robustly than Col2a1 in adult cartilage tissue, Agc1 is expected to better target chondrocytes in adult mice. 123 In addition to chondrocytes, Agc1 were also reported to target nucleus pulposus tissue in the intervertebral disc. 123 Prg4 only targets the superficial layer of articular chondrocytes. 124 It needs to be emphasized that all of these genetic tools are used to address the importance of cartilage tissue in OA development. Additional CreER transgenic mice need to be developed to efficiently target subchondral bone, synovial tissue and meniscus.

Using these transgenic mice, specific genes have been studied in chondrocyte-specific experiments to dissect their role in OA. In vivo studies employing mutant mice suggest that pathways involving (i) receptor ligands, such as TGF-β1, Wnt3a, and Indian hedgehog, (ii) signaling molecules, such as Smads, β-catenin, Runx2 and HIF-2α and, (iii) peptidases, such as MMP13 and ADAMTS4/5, have some degree of involvement in OA development. Table 1 summarizes the mutant lines available for OA study.

TGF-β and its downstream molecules have important roles in OA pathogenesis. Mutations of Smad3 , a central molecule in TGF-β signaling, have been found in patients with early-onset OA. 131 – 133 It has been known for years that TGF-β promotes mesenchymal progenitor cell differentiation and matrix protein synthesis and inhibits chondrocyte hypertrophy. TGF-β signaling may play differential roles in joint tissues during OA development. For example, global deletion of Smad3 causes chondrocyte hypertrophy and OA-like articular cartilage damage. 6 The deletion of Tgfbr2 , encoding for type II TGF-β receptor, 91 or Smad3 12 in articular chondrocytes also led to an OA-like phenotype. In contrast, the activation of TGF-β signaling in mesenchymal progenitor cells of subchondral bone also caused OA-like lesions. 134 These findings suggest that TGF-β signaling may have differential roles in various joint tissues 135 and that therapeutic interventions targeting TGF-β signaling may require a tissue-specific approach.

Techniques for OA studies

In vitro studies, in vitro articular chondrocyte isolation and culture.

To investigate signaling mechanisms in articular cartilage, primary human articular chondrocytes will be obtained from surgically discarded cartilage tissues. Briefly, full-thickness sections of cartilage are excised from the subchondral bone. The cartilage pieces will be digested for about 15 h using a digestion buffer. The isolated cells will be then collected and filtered to remove undigested tissue and debris, and washed with Hanks' buffered salt solution. The cells will be then re-suspended in chondrocyte basal medium and plated in high density monolayer cultures as shown in Table 2 . 136 , 137 Human articular chondrocytes can also be cultured in three dimensions. Briefly, 4×10 6 freshly isolated human articular chondrocytes will be re-suspended in alginate solution and the cell suspension is added drop-wise into 102 mmol·L −1 CaCl 2 to form beads. After washing the beads with 0.15 mol·L −1 NaCl and basal medium, the chondrocytes encapsulated in alginate beads will be cultured in three dimensions with basal medium. 138 , 139

In vitro human articular cartilage explant culture

Osteochondral tissues from radiographically and anatomically normal joints will be obtained from patients with different surgeries, such as oncologic surgical procedures, meniscal tear repair or total knee joint replacement. The collected osteochondral tissues will be first washed with sterile phosphate-buffered saline (PBS). Fresh cartilage samples will be harvested from the femoral condyle using a 6 mm diameter biopunch. The cartilage explants will be cultured in chondrocyte basal medium. 140

Histology/histomorphometry

Knee cartilage samples to be used for histological and histomorphometric analyses will be fixed in 10% neutral buffered formalin (NBF), decalcified in 14% EDTA for 10 days and embedded in paraffin. The paraffin-embedded samples will be cut into 5 μm sections and stained with Alcian blue/Hematoxylin-Orange G (ABH) or Safranin O/Fast green to determine changes in architectures of cartilage, bone, and synovial tissues throughout OA progression. Quantitative histomorphometric analyses of ABH-stained sections can be performed using a Visiopharm analysis system. 141 Using this system, high resolution digital images of histology slides can be obtained. Cartilage thickness will be measured from the middle of the femoral and tibial condyles. Cartilage area will be traced from both articular cartilage surfaces. The tidemark will be used to delineate the upper and deep zone of articular cartilage. 91 , 93

OARSI score system

Several scoring systems have been developed to semi-quantify the severity of OA lesions of the knee. A scoring system recommended by the Osteoarthritis Research Society International (OARSI) society is based on continuous histological staining of the knee joint. A 0–6 subjective scoring system, as shown in Table 3 , is applied to all four quadrants through multiple step sections of the joint. Sagittal sections obtained every 80 μm across the medial femoral-tibial joint will be used to determine the maximal and cumulative scores. 142

Nanoindentation

It is necessary to understand changes in mechanical properties of OA cartilage across multiple length scales because they directly reflect cartilage functional changes during degradation. 143 Atomic force microscopy (AFM)-based nanoindentation is well-suited for evaluating changes at a nm-to-μm scale that is comparable to the sizes of matrix molecules and cells. 144 For AFM-nanoindentation measurement, a microspherical or a pyramidal tip is programmed to indent the sample tissues, cells or tissue sections to a pre-set force or depth. An effective indentation modulus can be calculated by fitting the loading portion of each indentation force versus depth curve to the elastic Hertz model. 145 The use of nanoindentation over the past decade has uncovered many new aspects of cartilage structure-mechanics relationships and OA pathomechanics. Highlights among these include micromechanical anisotropy and heterogeneity of healthy and OA cartilage 146 or meniscus, 147 cartilage weakening in spontaneous 148 , 149 and post-traumatic 150 – 152 OA, mechanics of individual chondrocytes, 151 , 153 and quality evaluation of engineered neo-tissues. 154 – 156

Notably, AFM-nanoindentation has made it possible to study the mechanical properties of murine cartilage. Previously, the ~100 μm thickness of murine cartilage prevented such attempts. Because in vivo OA studies are largely dependent on murine models, 157 nanoindentation provides a critical bridge across two crucial fields of OA research: biology and biomechanics. The benefit of nanoindentation for murine model studies has been demonstrated by a number of recent studies. For example, cartilage in mice lacking collagen IX ( Col9a1 −/− ) 148 showed abnormally higher moduli, while those lacking lubricin ( Prg4 −/− ) 158 or chondroadherin ( Chad −/− ) 159 showed lower moduli. Col9a1 −/− and Prg4 −/− mice also developed macroscopic signs of OA, 148 , 158 underscoring the high correlation between abnormalities in cartilage biomechanics and OA. Li et al. also recently demonstrated the applicability of nanoindentation to the murine meniscus. 160 Further applications of nanoindentation to clinically relevant OA models, such as the DMM model, 110 hold the potential of assessing OA as an entire joint disease through biomechanical symptoms in multiple murine synovial tissues.

Two other recent technological advances provide paths to further in-depth studies. First, Wilusz et al. 161 stained cartilage cryosections with immunofluorescence antibodies of the pericellular matrix signature molecules, type VI collagen and perlecan. 162 Using immunofluorescence guidance, nanoindentation was used to delineate the mechanical behavior of cartilage pericellular matrix and ECM, 161 – 163 and to reveal the role of type VI collagen in each matrix by employing Col6 −/− mice. 164 Therefore, it is now possible to directly examine the relationships across micro-domains between biochemical content and biomechanical properties of cartilage, 161 meniscus 165 or other synovial tissues in situ . Second, Nia et al. 166 converted the AFM to a high-bandwidth nanorheometer. This tool enabled separation of the fluid flow-driven poroelasticity and macromolecular frictional intrinsic viscoelasticity that govern cartilage energy-dissipative mechanics. 166 – 168 Hydraulic permeability, the property that regulates poroelasticity, was found to be mainly determined by aggrecan rather than collagen 169 and to change more drastically than modulus upon depletion of aggrecan. 166 , 170 This new tool provides a comprehensive approach beyond the scope of elastic modulus for assessing cartilage functional changes in OA.

Molecules mediating OA pain

The perception of OA pain is a complex and dynamic process involving structural and biochemical alterations at the joint as well as in the peripheral and central nervous systems. While there have been extensive studies of mediators of OA joint degeneration, only recently have studies begun to characterize biochemical influences on and in the peripheral and central nervous systems in OA. In this regard, OA appears to show similarities and differences with other conditions causing pain. 171 , 172 There are a wide variety of signaling pathways linked to joint destruction and/or pain. In this section we will discuss three emerging and highly relevant pathways that provide insight into the mechanisms underlying OA pain.

Chemotactic cytokine ligand 2/chemokine (C–C motif) receptor 2

Chemotactic cytokine ligand 2 (CCL2), also known as monocyte chemoattractant protein 1 (MCP-1), is well-known to mediate the migration and infiltration of monocytes and macrophages by signaling through chemokine (C–C motif) receptor 2 (CCR2). 173 In arthritis, CCL2 promotes inflammation of the joint. 174 Evidence also suggests that CCL2 is an important mediator of neuroinflammation. 175 , 176 In neuropathic pain, CCL2 expression is increased in microglia and in sensory neurons in the dorsal root ganglia (DRGs), where CCL2 can be further transported and released into central spinal nerve terminals. Increased CCL2/CCR2 signaling has been correlated with direct excitability of nociceptive neurons and microglial activation, leading to persistent hyperalgesia and allodynia. 177 , 178

In a DMM mouse OA model, CCL2 and CCR2 levels were elevated in DRGs at 8 weeks post surgery, correlating with increased OA-associated pain behaviors. Increased CCL2 and CCR2 levels in the DRG were thought to mediate pro-nociceptive effects both by increasing sensory neuron excitability through CCL2/CCR2 signaling directly in DRG sensory neurons and through CCL2/CCR2-mediated recruitment of macrophages in the DRG. Compared with wild-type mice, Ccr2 -null mice showed reduced pain behaviors following DMM with similar levels of joint damage. 179 Although CCR2 antagonists are currently being assessed in clinical studies, no clinical studies have targeted CCL2 or CCR2 in OA pain. 180

Nerve growth factor/tropomyosin receptor kinase A

In both clinical and animal studies, the targeted inhibition of nerve growth factor (NGF) and inhibition of its cognate receptor, tropomyosin receptor kinase A (TrkA), reduced OA pain. Clinically, the systemic administration of NGF caused persistent whole-body muscle hyperalgesia in healthy human subjects, 174 , 177 while anti-NGF antibody, tanezumab, therapy significantly reduced OA pain. 181 – 184 There are a number of potential mechanisms through which NGF mediates pain. Over-expressed NGF in peripheral tissues can bind directly to TrkA at sensory neuron nerve terminals and be retrogradely transported to the DRG. There it stimulates sensory neurons to activate mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling. 185 The activation of the NGF-MAPK/ERK axis upregulates the expression of pain-related molecules, including transient receptor potential cation channel subfamily V member I (TRPV1), substance P, calcitonin gene-related peptide (CGRP), brain-derived neurotrophic factor (BDNF), and nociceptor-specific ion channels, such as Ca v 3.2, 3.3, and Na v 1.8. 186 – 188

In addition to direct signaling of sensory neurons, NGF promotes algesic effects by targeting other cell types. For example, NGF/TrkA signaling occurs in mast cells, triggering release of pro-inflammatory and pain mediators, including histamine and prostaglandins, in addition to NGF. 186 , 189 NGF signaling is upregulated by pro-inflammatory mediators, and NGF promotes leukocyte chemotaxis and vascular permeability, further stimulating inflammation. 190 – 192 NGF/TrkA signaling further promotes angiogenesis and nerve growth. The process of angiogenesis is not only inflammatory, but also serves as a track for nerve growth into the joint. 193

Given the high efficacy of targeting NGF in a clinical study on reducing OA pain, it is of great interest to further define NGF/TrkA pain signaling mechanisms and to find additional therapeutic targets in this pathway. Recent evidence indicates that loss of PKCδ signaling significantly increases both NGF and TrkA in the DRG and synovium, is associated with increased MAPK/ERK signaling at the innervating DRGs, and is associated with OA hyperalgesia. 194 However, in recent clinical studies, a small population of patients treated with systemic anti-NGF therapy exhibited rapid progression of OA and were more prone to bone fractures. 195 Considering the analgesic effects by anti-NGF therapy on OA-associated pain, understanding of the precise roles of the NGF/TrkA pathway in different joint tissues in OA and OA-associated pain is of great interest.

The use of Adamts5 KO mice and therapeutic treatment with anti-ADAMTS5 antibody in wild-type mice produce inhibition of ADAMTS5 signaling/expression in the DMM model, resulting in reduction of both joint degeneration and pain. 98 , 196 , 197 ADAMTS5 is a major aggrecanase, and because aggrecan is a major component of the proteoglycans in cartilage that provides compressive resistance, ADAMTS5 is thought to be a critical mediator of cartilage degeneration during the development of OA. 198 Although variations in pain signaling can be independent from the degree of joint degeneration, the use of Adamts5 KO mice and direct inhibition of joint degeneration with anti-ADAMTS5 antibody may provide insight into how joint degeneration produces OA pain. For example, hyalectan fragments generated by ADAMTS5 have been suggested to directly stimulate nociceptive neurons as well as glial activation, promoting increased pain perception. 196 , 199 Furthermore, inhibition of ADAMTS5 following DMM resulted in reduced levels of CCL2 in DRG neurons, thus suggesting a role for CCL2 in OA-specific pain. 197

Pain-related behavior tests

Pain is the most common reason patients seek medical treatment and is a major indication for joint replacement surgery. 200 , 201 Therefore, evaluating pain in pre-clinical animal models is of critical importance to better understand mechanisms of and to develop treatments for OA pain. The evaluation of OA pain in animals involves indirect and direct measures.

Recognizing pain as a clinical sign and quantitatively assessing pain intensity are essential in research for effective OA pain management. Rodent animal models are routinely used for basic and pre-clinical studies because of the relatively low cost of animal maintenance, the abundance of historical data for comparison, and smaller amounts of drugs required for experimental studies. For pain measurements, rodents have advantages over other small animal models, such as rabbits, which present challenges to obtain a pain response and are immobile if startled by an unfamiliar observer. Mice are usually used for the development of genetically engineered strains to enable molecular understanding of OA progression and pain in vivo . 202 Larger animals, including dogs, sheep, goats, and horses are also sometimes used for modeling OA pain. 202 , 203

A wide range of direct and indirect measures of pain are used in small animal models of OA. Indirect and/or direct measures of pain include static or dynamic weight bearing, foot posture, gait analysis, spontaneous activity, as well as sensitivity to mechanical allodynia, mechanical hyperalgesia, and thermal, and cold stimuli. 202 , 203 Among indirect tests involving pain-evoked behaviors, mechanical stimuli may be the most correlated with OA pain. A commonly used measure of indirect pain is the von Frey test for mechanical allodynia using filaments to assess referred pain. 186 , 194 , 196 , 202 , 204 Direct mechanical hyperalgesia is performed using an analgesymeter for paw pressure pain threshold. Additional direct measures of OA pain include the hind limb withdrawal test, vocalization evoked by knee compression on the affected knee, the struggle reaction to knee extension, and ambulation and rearing spontaneous movements. 194 , 202 , 203 Weight-bearing and gait analyses may have important translational relevance for assessing OA pain because these tests are also used to assess clinical OA pain. 203 However, obtaining clear pain responses from weight bearing or gait is challenging when using the unilateral DMM mouse model because the nature of OA pain is a dull pain unlike that of, for example, sharp inflammatory pain.

In large animals, pain behavior testing is more challenging and there is no consensus for the best method of evaluating pain. 202 However, dogs, the most commonly used large animal, have been suggested to provide the best predictive modeling for OA pain translated into the clinical setting. 205 Methods used for assessing pain in large animals are restricted to assessing degree of lameness, gait analysis, and subjective rating scales, which assess descriptors of pain similar to those of humans.

Overall, there is a wide range of pain-behavior tests for small and large animal models. Although no animal model or pain behavior test perfectly translates to OA-associated pain in patients, these tests yield a valuable understanding of the mechanisms of OA pain and allow assessment of treatments for relief from OA-associated pain. Rodents will continue to be widely used for basic OA pain research, but large animals continue to be important because of their greater potential for modeling clinical OA pain.

Future perspective

Although significant progress has been made in OA research in recent years, very little is yet known about the molecular mechanisms of OA initiation and progression. OA is a heterogeneous disease caused by multiple factors. One important potential factor for OA development is Runx2, which is upregulated in several OA mouse models and in cartilage samples derived from patients with OA disease. 7 , 8 , 11 , 13 , 91 Key questions that need to be addressed are: (1) Is Runx2 a central molecule mediating OA development in joint tissue?; and (2) Could manipulation of Runx2 expression be used to treat OA disease? OA is a disease affecting the entire joint, including articular cartilage, subchondral bone, synovial tissues and menisci. In which of these joint tissues OA damage first occurs during disease initiation is currently unknown; this is important because it is directly related to OA treatment. In addition, the interplaying mechanisms among different OA symptoms, such as articular cartilage degradation, osteophyte formation, subchondral sclerosis and synovial hyperplasia, await clarification. The understanding of the molecular mechanisms underlying these issues will accelerate the development of novel therapeutic strategies for OA.

Loeser RF, Goldring SR, Scanzello CR et al. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum 2012; 64 : 1697–1707.

Article   PubMed   PubMed Central   Google Scholar  

Felson DT . Clinical practice. Osteoarthritis of the knee. N Engl J Med 2006; 354 : 841–848.

Article   CAS   PubMed   Google Scholar  

Goldring MB, Goldring SR . Osteoarthritis. J Cell Physiol 2007; 213 : 626–634.

Krasnokutsky S, Samuels J, Abramson SB . Osteoarthritis in 2007. Bull NYU Hosp Jt Dis 2007; 65 : 222–228.

PubMed   Google Scholar  

Loeser RF . Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis Cartilage 2009; 17 : 971–979.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Yang X, Chen L, Xu X et al. TGF-β/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol 2001; 153 : 35–46.

Zhu M, Tang D, Wu Q et al. Activation of β-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult β-catenin conditional activation mice. J Bone Miner Res 2009; 24 : 12–21.

Lin AC, Seeto BL, Bartoszko JM et al. Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 2009; 15 : 1421–1425.

Saito T, Fukai A, Mabuchi A et al. Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development. Nat Med 2010; 16 : 678–686.

Yang S, Kim J, Ryu JH et al. Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med 2010; 16 : 687–693.

Kamekura S, Kawasaki Y, Hoshi K et al. Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheum 2006; 54 : 2462–2470.

Chen CG, Thuillier D, Chin EN et al. Chondrocyte-intrinsic Smad3 represses Runx2-inducible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis. Arthritis Rheum 2012; 64 : 3278–3289.

Hirata M, Kugimiya F, Fukai A et al. C/EBPβ and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2α as the inducer in chondrocytes. Hum Mol Genet 2012; 21 : 1111–1123.

Pei Y, Harvey A, Yu XP et al. Differential regulation of cytokine-induced MMP1 and MMP13 expression by p38 kinase inhibitors in human chondrosarcoma cells: potential role of Runx2 in mediating p38 effects. Osteoarthritis Cartilage 2006; 14 : 749–758.

Article   PubMed   Google Scholar  

Thirunavukkarasu K, Pei Y, Wei T . Characterization of the human ADAMTS-5 (aggrecanase-2) gene promoter. Mol Biol Rep 2007; 34 : 225–231.

Tetsunaga T, Nishida K, Furumatsu T et al. Regulation of mechanical stress-induced MMP13 and ADAMTS5 expression by Runx2 transcriptional factor in SW1353 chondrocyte-like cells. Osteoarthritis Cartilage 2011; 19 : 222–232.

Wang M, Tang D, Shu B et al. Conditional activation of β-catenin signaling in mice leads to severe defects in intervertebral disc tissue. Arthritis Rheum 2012; 64 : 2611–2623.

Helmick CG, Felson DT, Lawrence RC et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum 2008; 58 : 15–25.

Lawrence RC, Felson DT, Helmick CG et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008; 58 : 26–35.

Felson DT . Osteoarthritis of the knee. N Engl J Med 2006; 354 : 841–848.

Felson DT, Naimark A, Anderson J et al. The prevalence of knee osteoarthritis in the elderly. The Framingham Osteoarthritis Study. Arthritis Rheum 1987; 30 : 914–918.

Jordan JM, Helmick CG, Renner JB et al. Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project. J Rheumatol 2007; 34 : 172–180.

Dillon CF, Rasch EK, Gu Q et al. Prevalence of knee osteoarthritis in the United States: arthritis data from the Third National Health and Nutrition Examination Survey 1991-94. J Rheumatol 2006; 33 : 2271–2279.

van Saase JL, van Romunde LK, Cats A et al. Epidemiology of osteoarthritis: Zoetermeer survey. Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations. Ann Rheum Dis 1989; 48 : 271–280.

Andrianakos AA, Kontelis LK, Karamitsos DG et al. Prevalence of symptomatic knee, hand, and hip osteoarthritis in Greece. The ESORDIG study. J Rheumatol 2006; 33 : 2507–2513.

Loeser RF . Aging and osteoarthritis. Curr Opin Rheumatol 2011; 23 : 492–496.

Kim J, Xu M, Xo R et al. Mitochondrial DNA damage is involved in apoptosis caused by pro-inflammatory cytokines in human OA chondrocytes. Osteoarthritis Cartilage 2010; 18 : 424–432.

Goodwin W, McCabe D, Sauter E et al. Rotenone prevents impact-induced chondrocyte death. J Orthop Res 2010; 28 : 1057–1063.

CAS   PubMed   PubMed Central   Google Scholar  

Naik E, Dixit VM . Mitochondrial reactive oxygen species drive proinflammatory cytokine production. J Exp Med 2011; 208 : 417–420.

Liu JT, Guo X, Ma WJ et al. Mitochondrial function is altered in articular chondrocytes of an endemic osteoarthritis, Kashin-Beck disease. Osteoarthritis Cartilage 2010; 18 : 1218–1226.

Blaney Davidson EN, Remst DF, Vitters EL et al. Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. J Immunol 2009; 182 : 7937–7945.

van der Kraan PM, Blaney Davidson EN, van den Berg WB . A role for age-related changes in TGF-β signaling in aberrant chondrocyte differentiation and osteoarthritis. Arthritis Res Ther 2010; 12 : 201–209.

Article   PubMed   PubMed Central   CAS   Google Scholar  

Richardson B . Impact of aging on DNA methylation. Ageing Res Rev 2003; 2 : 245–261.

Christensen BC, Houseman EA, Marsit CJ et al. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 2009; 5 : e1000602.

Fernandez-Tajes J, Soto-Hermida A, Vazquez-Mosquera ME et al. Genome-wide DNA methylation analysis of articular chondrocytes reveals a cluster of osteoarthritic patients. Ann Rheum Dis 2014; 73 : 668–677.

Jeffries MA, Donica M, Baker LW et al. Genome-wide DNA methylation study identifies significant epigenomic changes in osteoarthritic cartilage. Arthritis Rheumatol 2014; 66 : 2804–2815.

den Hollander W, Ramos YF, Bos SD et al. Knee and hip articular cartilage have distinct epigenomic landscapes: implications for future cartilage regeneration approaches. Ann Rheum Dis 2014; 73 : 2208–2212.

Haseeb A, Makki MS, Haqqi TM . Modulation of ten-eleven translocation 1 (TET1), Isocitrate Dehydrogenase (IDH) expression, alpha-Ketoglutarate (alpha-KG), and DNA hydroxymethylation levels by interleukin-1beta in primary human chondrocytes. J Biol Chem 2014; 289 : 6877–6885.

Taylor SE, Smeriglio P, Dhulipala L et al. A global increase in 5-hydroxymethylcytosine levels marks osteoarthritic chondrocytes. Arthritis Rheumatol 2014; 66 : 90–100.

Taylor SE, Li YH, Wong WH et al. Genome-wide mapping of DNA hydroxymethylation in osteoarthritic chondrocytes. Arthritis Rheumatol 2015; 67 : 2129–2140.

Felson DT, Anderson JJ, Naimark A et al. Obesity and knee osteoarthritis. The Framingham Study. Ann Intern Med 1988; 109 : 18–24.

Anandacoomarasamy A, Caterson I, Sambrook P et al. The impact of obesity on the musculoskeletal system. Int J Obes (Lond) 2008; 32 : 211–222.

Article   CAS   Google Scholar  

Conde J, Scotece M, Gomez R et al. Adipokines and osteoarthritis: novel molecules involved in the pathogenesis and progression of disease. Arthritis 2011; 2011 : 203901.

Das UN . Is obesity an inflammatory condition? Nutrition 2001; 17 : 953–966.

Fain JN . Release of inflammatory mediators by human adipose tissue is enhanced in obesity and primarily by the nonfat cells: a review. Mediators Inflamm 2010; 2010 : 513948.

Bunout D, Munoz C, Lopez M et al. Interleukin 1 and tumor necrosis factor in obese alcoholics compared with normal-weight patients. Am J Clin Nutr 1996; 63 : 373–376.

Visser M . Higher levels of inflammation in obese children. Nutrition 2001; 17 : 480–481.

Aygun AD, Gungor S, Ustundag B et al. Proinflammatory cytokines and leptin are increased in serum of prepubertal obese children. Mediators Inflamm 2005; 2005 : 180–183.

Pou KM, Massaro JM, Hoffmann U et al. Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study. Circulation 2007; 116 : 1234–1241.

Straczkowski M, Dzienis-Straczkowska S, Stepien A et al. Plasma interleukin-8 concentrations are increased in obese subjects and related to fat mass and tumor necrosis factor-alpha system. J Clin Endocrinol Metab 2002; 87 : 4602–4606.

Zhou Q, Leeman SE, Amar S . Signaling mechanisms in the restoration of impaired immune function due to diet-induced obesity. Proc Natl Acad Sci U S A 2011; 108 : 2867–2872.

Neels JG, Badeanlou L, Hester KD et al. Keratinocyte-derived chemokine in obesity: expression, regulation, and role in adipose macrophage infiltration and glucose homeostasis. J Biol Chem 2009; 284 : 20692–20698.

Brown ML, Yukata K, Farnsworth CW et al. Delayed fracture healing and increased callus adiposity in a C57BL/6 J murine model of obesity-associated type 2 diabetes mellitus. PLoS One 2014; 9 : e99656.

Louer CR, Furman BD, Huebner JL et al. Diet-induced obesity significantly increases the severity of posttraumatic arthritis in mice. Arthritis Rheum 2012; 64 : 3220–3230.

Stehouwer CD, Gall MA, Twisk JW et al. Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death. Diabetes 2002; 51 : 1157–1165.

Duncan BB, Schmidt MI, Pankow JS et al. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes 2003; 52 : 1799–1805.

Wellen KE, Hotamisligil GS . Inflammation, stress, and diabetes. J Clin Invest 2005; 115 : 1111–1119.

Kapoor M, Martel-Pelletier J, Lajeunesse D et al. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 2011; 7 : 33–42.

Fernandes JC, Martel-Pelletier J, Pelletier JP . The role of cytokines in osteoarthritis pathophysiology. Biorheology 2002; 39 : 237–246.

CAS   PubMed   Google Scholar  

Martel-Pelletier J, Alaaeddine N, Pelletier JP . Cytokines and their role in the pathophysiology of osteoarthritis. Front Biosci 1999; 4 : D694–D703.

Roos EM . Joint injury causes knee osteoarthritis in young adults. Curr Opin Rheumatol 2005; 17 : 195–200.

Radin EL . Who gets osteoarthritis and why? J Rheumatol Suppl , 2004; 70 : 10–15.

Andriacchi TP, Mundermann A, Smith RL et al. A framework for the in vivo pathomechanics of osteoarthritis at the knee. Ann Biomed Eng 2004; 32 : 447–457.

Miyazaki T, Wada M, Kawahara H et al. Dynamic load at baseline can predict radiographic disease progression in medial compartment knee osteoarthritis. Ann Rheum Dis 2002; 61 : 617–622.

Fridén T, Sommerlath K, Egund N et al. Instability after anterior cruciate ligament rupture. Measurements of sagittal laxity compared in 11 cases. Acta Orthop Scand 1992; 63 : 593–598.

Sernert N, Kartus JT Jr, Ejerhed L et al. Right and left knee laxity measurements: a prospective study of patients with anterior cruciate ligament injuries and normal control subjects. Arthroscopy 2004; 20 : 564–571.

Lieberthal J, Sambamurthy N, Scanzello CR . Inflammation in joint injury and post-traumatic osteoarthritis. Osteoarthritis Cartilage 2015; 23 : 1825–1834.

Malfait AM . Osteoarthritis year in review 2015: biology. Osteoarthritis Cartilage 2016; 24 : 21–26.

van Lent PL, Blom AB, Schelbergen RF et al. Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis. Arthritis Rheum 2012; 64 : 1466–1476.

Schelbergen RF, van Dalen S, ter Huurne M et al. Treatment efficacy of adipose-derived stem cells in experimental osteoarthritis is driven by high synovial activation and reflected by S100A8/A9 serum levels. Osteoarthritis Cartilage 2014; 22 : 1158–1166.

Nasi S, Ea HK, Chobaz V et al. Dispensable role of myeloid differentiation primary response gene 88 (MyD88) and MyD88-dependent toll-like receptors (TLRs) in a murine model of osteoarthritis. Joint Bone Spine 2014; 81 : 320–324.

Liu-Bryan R, Terkeltaub R . The growing array of innate inflammatory ignition switches in osteoarthritis. Arthritis Rheum 2012; 64 : 2055–2058.

Schelbergen RF, Blom AB, van den Bosch MH et al. Alarmins S100A8 and S100A9 elicit a catabolic effect in human osteoarthritic chondrocytes that is dependent on Toll-like receptor 4. Arthritis Rheum 2012; 64 : 1477–1487.

Zreiqat H, Belluoccio D, Smith MM et al. S100A8 and S100A9 in experimental osteoarthritis. Arthritis Res Ther 2010; 12 : R16.

Cecil DL, Appleton CT, Polewski MD et al. The pattern recognition receptor CD36 is a chondrocyte hypertrophy marker associated with suppression of catabolic responses and promotion of repair responses to inflammatory stimuli. J Immunol 2009; 182 : 5024–5031.

Jin C, Frayssinet P, Pelker R et al. NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy. Proc Natl Acad Sci U S A 2011; 108 : 14867–14872.

Wang Q, Rozelle AL, Lepus CM et al. Identification of a central role for complement in osteoarthritis. Nat Med 2011; 17 : 1674–1679.

Lepus CM, Song JJ, Wang Q et al. Brief report: carboxypeptidase B serves as a protective mediator in osteoarthritis. Arthritis Rheumatol 2014; 66 : 101–106.

Pap T, Bertrand J . Syndecans in cartilage breakdown and synovial inflammation. Nat Rev Rheumatol 2013; 9 : 43–55.

Kim JH, Jeon J, Shin M et al. Regulation of the catabolic cascade in osteoarthritis by the zinc-ZIP8-MTF1 axis. Cell 2014; 156 : 730–743.

Kroemer G . Autophagy: a druggable process that is deregulated in aging and human disease. J Clin Invest 2015; 125 : 1–4.

Lopez-Otin C, Blasco MA, Partridge L et al. The hallmarks of aging. Cell 2013; 153 : 1194–1217.

Carames B, Olmer M, Kiosses WB et al. The relationship of autophagy defects to cartilage damage during joint aging in a mouse model. Arthritis Rheumatol 2015; 67 : 1568–1576.

Vasheghani F, Zhang Y, Li YH et al. PPARγ deficiency results in severe, accelerated osteoarthritis associated with aberrant mTOR signalling in the articular cartilage. Ann Rheum Dis 2015; 74 : 569–578.

Takayama K, Kawakami Y, Kobayashi M et al. Local intra-articular injection of rapamycin delays articular cartilage degeneration in a murine model of osteoarthritis. Arthritis Res Ther 2014; 16 : 482–491.

Li ZC, Xiao J, Peng JL et al. Functional annotation of rheumatoid arthritis and osteoarthritis associated genes by integrative genome-wide gene expression profiling analysis. PLoS One 2014; 9 : e85784.

Spector TD, Cicuttini F, Baker J et al. Genetic influences on osteoarthritis in women: a twin study. BMJ 1996; 312 : 940–943.

Felson DT, Couropmitree NN, Chaisson CE et al. Evidence for a Mendelian gene in a segregation analysis of generalized radiographic osteoarthritis: the Framingham Study. Arthritis Rheum 1998; 41 : 1064–1071.

Loughlin J, Mustafa Z, Smith A et al. Linkage analysis of chromosome 2q in osteoarthritis. Rheumatology 2000; 39 : 377–381.

Serra R, Johnson M, Filvaroff EH et al. Expression of a truncated, kinase-defective TGF-beta type II receptor in mouse skeletal tissue promotes terminal chondrocyte differentiation and osteoarthritis. J Cell Biol 1997; 139 : 541–552.

Shen J, Li J, Wang B et al. Deletion of the transforming growth factor beta receptor type II gene in articular chondrocytes leads to a progressive osteoarthritis-like phenotype in mice. Arthritis Rheum 2013; 65 : 3107–3119.

Wang M, Tang D, Shu B et al. Conditional activation of beta-catenin signaling in mice leads to severe defects in intervertebral disc tissue. Arthritis Rheum 2012; 64 : 2611–2623.

Mirando AJ, Liu Z, Moore T et al. RBP-Jkappa-dependent Notch signaling is required for murine articular cartilage and joint maintenance. Arthritis Rheum 2013; 65 : 2623–2633.

Lories RJ, Corr M, Lane NE . To Wnt or not to Wnt: the bone and joint health dilemma. Nat Rev Rheumatol 2013; 9 : 328–339.

Sassi N, Laadhar L, Allouche M et al. WNT signaling and chondrocytes: from cell fate determination to osteoarthritis physiopathology. J Recept Signal Transduct Res 2014; 34 : 73–80.

Hirata M, Kugimiya F, Fukai A et al. C/EBPbeta and RUNX2 cooperate to degrade cartilage with MMP-13 as the target and HIF-2alpha as the inducer in chondrocytes. Hum Mol Genet 2012; 21 : 1111–1123.

Little CB, Barai A, Burkhardt D et al. Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum 2009; 60 : 3723–3733.

Glasson SS, Askew R, Sheppard B et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 2005; 434 : 644–648.

Barnholtz-Sloan JS, Severson RK, Stanton B et al. Pediatric brain tumors in non-Hispanics, Hispanics, African Americans and Asians: differences in survival after diagnosis. Cancer Causes Control 2005; 16 : 587–592.

Loughlin J, Dowling B, Chapman K et al. Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc Natl Acad Sci U S A 2004; 101 : 9757–9762.

Bijsterbosch J, Kloppenburg M, Reijnierse M et al. Association study of candidate genes for the progression of hand osteoarthritis. Osteoarthritis Cartilage 2013; 21 : 565–569.

Valdes AM, Spector TD, Tamm A et al. Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum 2010; 62 : 2347–2352.

Rodriguez RR, Seegmiller RE, Stark MR et al. A type XI collagen mutation leads to increased degradation of type II collagen in articular cartilage. Osteoarthritis Cartilage 2004; 12 : 314–320.

Jeong C, Lee JY, Kim J et al. Novel COL9A3 mutation in a family diagnosed with multiple epiphyseal dysplasia: a case report. BMC Musculoskelet Disord 2014; 15 : 371.

Carlson KM, Yamaga KM, Reinker KA et al. Precocious osteoarthritis in a family with recurrent COL2A1 mutation. J Rheumatol 2006; 33 : 1133–1136.

Zhang R, Yao J, Xu P et al. A comprehensive meta-analysis of association between genetic variants of GDF5 and osteoarthritis of the knee, hip and hand. Inflamm Res 2015; 64 : 405–414.

arcOGEN Consortium and arcOGEN Collabortors. Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study. Lancet 2012; 380 : 815–823.

Glasson SS, Blanchet TJ, Morris EA . The surgical destabilization of the medial meniscus (DMM) model of osteoarthritis in the 129/SvEv mouse. Osteoarthritis Cartilage 2007; 15 : 1061–1069.

Glasson SS, Askew R, Sheppard B et al. Characterization of and osteoarthritis susceptibility in ADAMTS-4-knockout mice. Arthritis Rheum 2004; 50 : 2547–2558.

Welch ID, Cowan MF, Beier F et al. The retinoic acid binding protein CRABP2 is increased in murine models of degenerative joint disease. Arthritis Res Ther 2009; 11 : R14.

Ma HL, Blanchet TJ, Peluso D et al. Osteoarthritis severity is sex dependent in a surgical mouse model. Osteoarthritis Cartilage 2007; 15 : 695–700.

Wilhelmi G, Faust R . Suitability of the C57 black mouse as an experimental animal for the study of skeletal changes due to ageing, with special reference to osteo-arthrosis and its response to tribenoside. Pharmacology 1976; 14 : 289–296.

Walton M . Studies of degenerative joint disease in the mouse knee joint; scanning electron microscopy. J Pathol 1977; 123 : 211–217.

Poulet B, Westerhof TA, Hamilton RW et al. Spontaneous osteoarthritis in Str/ort mice is unlikely due to greater vulnerability to mechanical trauma. Osteoarthritis Cartilage 2013; 21 : 756–763.

Poulet B, Ulici V, Stone TC et al. Time-series transcriptional profiling yields new perspectives on susceptibility to murine osteoarthritis. Arthritis Rheum 2012; 64 : 3256–3266.

Sokoloff L, Crittenden LB, Yamamoto RS et al. The genetics of degenerative joint disease in mice. Arthritis Rheum 1962; 5 : 531–546.

Kamekura S, Hoshi K, Shimoaka T et al. Osteoarthritis development in novel experimental mouse models induced by knee joint instability. Osteoarthritis Cartilage 2005; 13 : 632–641.

Jimenez PA, Glasson SS, Trubetskoy OV et al. Spontaneous osteoarthritis in Dunkin Hartley guinea pigs: histologic, radiologic, and biochemical changes. Lab Anim Sci 1997; 47 : 598–601.

Thijssen E, van Caam A, van der Kraan PM . Obesity and osteoarthritis, more than just wear and tear: pivotal roles for inflamed adipose tissue and dyslipidaemia in obesity-induced osteoarthritis. Rheumatology 2015; 54 : 588–600.

Griffin TM, Huebner JL, Kraus VB et al. Induction of osteoarthritis and metabolic inflammation by a very high-fat diet in mice: effects of short-term exercise. Arthritis Rheum 2012; 64 : 443–453.

Säämänen AM, Hyttinen M, Vuorio E . Analysis of arthritic lesions in the Del1 mouse: a model for osteoarthritis. Methods Mol Med 2007; 136 : 283–302.

Chen M, Lichtler AC, Sheu T et al. Generation of a transgenic mouse model with chondrocyte-specific and tamoxifen-inducible expression of Cre recombinase. Genesis 2007; 45 : 44–50.

Henry SP, Jang CW, Deng JM et al. Generation of aggrecan-CreERT2 knockin mice for inducible Cre activity in adult cartilage. Genesis 2009; 47 : 805–814.

Kozhemyakina E, Zhang M, Ionescu A et al. Identification of a Prg4-expressing articular cartilage progenitor cell population in mice. Arthritis Rheumatol 2015; 67 : 1261–1273.

Saamanen AK, Salminen HJ, Dean PB et al. Osteoarthritis-like lesions in transgenic mice harboring a small deletion mutation in type II collagen gene. Osteoarthritis Cartilage 2000; 8 : 248–257.

Hu K, Xu L, Cao L et al. Pathogenesis of osteoarthritis-like changes in the joints of mice deficient in type IX collagen. Arthritis Rheum 2006; 54 : 2891–2900.

Wu Q, Kim KO, Sampson ER et al. Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum 2008; 58 : 3132–3144.

Lories RJ, Peeters J, Bakker A et al. Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum 2007; 56 : 4095–4103.

Weng T, Yi L, Huang J et al. Genetic inhibition of fibroblast growth factor receptor 1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice. Arthritis Rheum 2012; 64 : 3982–3992.

Wang M, Sampson ER, Jin H et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther 2013; 15 : R5.

Valdes AM, Spector TD, Tamm A et al. Genetic variation in the Smad3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum 2010; 62 : 2347–2352.

van de Laar IM, Oldenburg RA, Pals G et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet 2011; 43 : 121–126.

van de Laar IM, van der Linde D, Oei EH et al. Phenotypic spectrum of the Smad3-related aneurysms-osteoarthritis syndrome. J Med Genet 2012; 49 : 47–57.

Zhen G, Wen C, Jia X et al. Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat Med 2013; 19 : 704–712.

Wang TY, Chen D . Differential roles of TGF-β signaling in joint tissues during osteoarthritis development. Ann Rheum Dis 2016; 75 : e72.

Manning WK, Bonner WM Jr . Isolation and culture of chondrocytes from human adult articular cartilage. Arthritis Rheum 1967; 10 : 235–239.

Oseni AO, Butler PE, Seifalian AM . Optimization of chondrocyte isolation and characterization for large-scale cartilage tissue engineering. J Surg Res 2013; 181 : 41–48.

Guo JF, Jourdian GW, MacCallum DK . Culture and growth characteristics of chondrocytes encapsulated in alginate beads. Connect Tissue Res 1989; 19 : 277–297.

Bonaventure J, Kadhom N, Cohen-Solal L et al. Reexpression of cartilage-specific genes by dedifferentiated human articular chondrocytes cultured in alginate beads. Exp Cell Res 1994; 212 : 97–104.

Lafeber FP, Vander Kraan PM, Van Roy JL et al. Articular cartilage explant culture; an appropriate in vitro system to compare osteoarthritic and normal human cartilage. Connect Tissue Res 1993; 29 : 287–299.

Dhillon RS, Zhang L, Schwarz EM et al. The murine femoral bone graft model and a semiautomated histomorphometric analysis tool. Methods Mol Biol 2014; 1130 : 45–59.

Glasson SS, Chambers MG, Van Den Berg WB et al. The OARSI histopathology initiative - recommendations for histological assessments of osteoarthritis in the mouse. Osteoarthritis Cartilage 2010; 18 : S17–S23.

Waldstein W, Perino G, Gilbert SL et al. OARSI osteoarthritis cartilage histopathology assessment system: A biomechanical evaluation in the human knee. J Orthop Res 2016; 34 : 135–140.

Han L, Grodzinsky AJ, Ortiz C . Nanomechanics of the cartilage extracellular matrix. Annu Rev Mater Res 2011; 41 : 133–168.

Lin DC, Horkay F . Nanomechanics of polymer gels and biological tissues: a critical review of analytical approaches in the Hertzian regime and beyond. Soft Matter 2008; 4 : 669–682.

McLeod MA, Wilusz RE, Guilak F . Depth-dependent anisotropy of the micromechanical properties of the extracellular and pericellular matrices of articular cartilage evaluated via atomic force microscopy. J Biomech 2013; 46 : 586–592.

Kwok J, Grogan S, Meckes B et al. Atomic force microscopy reveals age-dependent changes in nanomechanical properties of the extracellular matrix of native human menisci: implications for joint degeneration and osteoarthritis. Nanomedicine 2014; 10 : 1777–1785.

Stolz M, Gottardi R, Raiteri R et al. Early detection of aging cartilage and osteoarthritis in mice and patient samples using atomic force microscopy. Nat Nanotechnol 2009; 4 : 186–192.

Wilusz RE, Zauscher S, Guilak F . Micromechanical mapping of early osteoarthritic changes in the pericellular matrix of human articular cartilage. Osteoarthritis Cartilage 2013; 21 : 1895–1903.

Desrochers J, Amrein MA, Matyas JR . Structural and functional changes of the articular surface in a post-traumatic model of early osteoarthritis measured by atomic force microscopy. J Biomech 2010; 43 : 3091–3098.

Desrochers J, Amrein MW, Matyas JR . Viscoelasticity of the articular cartilage surface in early osteoarthritis. Osteoarthritis Cartilage 2012; 20 : 413–421.

Darling EM, Topel M, Zauscher S et al. Viscoelastic properties of human mesenchymally-derived stem cells and primary osteoblasts, chondrocytes, and adipocytes. J Biomech 2008; 41 : 454–464.

Lee B, Han L, Frank EH et al. Dynamic nanomechanics of individual bone marrow stromal cells and cell-matrix composites during chondrogenic differentiation. J Biomech 2015; 48 : 171–175.

Diekman BO, Christoforou N, Willard VP et al. Cartilage tissue engineering using differentiated and purified induced pluripotent stem cells. Proc Natl Acad Sci U S A 2012; 109 : 19172–19177.

Ng L, Hung H-H, Sprunt A et al. Nanomechanical properties of individual chondrocytes and their developing growth factor-stimulated pericellular matrix. J Biomech 2007; 40 : 1011–1023.

Peñuela L, Wolf F, Raiteri R et al. Atomic force microscopy to investigate spatial patterns of response to interleukin-1beta in engineered cartilage tissue elasticity. J Biomech 2014; 47 : 2157–2164.

Ameye LG, Young MF . Animal models of osteoarthritis: lessons learned while seeking the ‘Holy Grail’. Curr Opin Rheumatol 2006; 18 : 537–547.

Coles JM, Zhang L, Blum JJ et al. Loss of cartilage structure, stiffness, and frictional properties in mice lacking PRG4. Arthritis Rheum 2010; 62 : 1666–1674.

Batista MA, Nia HT, Önnerfjord P et al. Nanomechanical phenotype of chondroadherin-null murine articular cartilage. Matrix Biol 2014; 38 : 84–90.

Li Q, Doyran B, Gamer LW et al. Biomechanical properties of murine meniscus surface via AFM-based nanoindentation. J Biomech 2015; 48 : 1364–1370.

Wilusz RE, DeFrate LE, Guilak F . Immunofluorescence-guided atomic force microscopy to measure the micromechanical properties of the pericellular matrix of porcine articular cartilage. J R Soc Interface 2012; 9 : 2997–3007.

Wilusz RE, Defrate LE, Guilak F . A biomechanical role for perlecan in the pericellular matrix of articular cartilage. Matrix Biol 2012; 31 : 320–327.

Wilusz RE, Guilak F . High resistance of the mechanical properties of the chondrocyte pericellular matrix to proteoglycan digestion by chondroitinase, aggrecanase, or hyaluronidase. J Mech Behav Biomed Mater 2014; 38 : 183–197.

Zelenski NA, Leddy HA, Sanchez-Adams J et al. Type VI collagen regulates pericellular matrix properties, chondrocyte swelling, and mechanotransduction in mouse articular cartilage. Arthritis Rheumatol 2015; 67 : 1286–1294.

Sanchez-Adams J, Wilusz RE, Guilak F . Atomic force microscopy reveals regional variations in the micromechanical properties of the pericellular and extracellular matrices of the meniscus. J Orthop Res 2013; 31 : 1218–1225.

Nia HT, Bozchalooi IS, Li Y et al. High-bandwidth AFM-based rheology reveals that cartilage is most sensitive to high loading rates at early stages of impairment. Biophys J 2013; 104 : 1529–1537.

Han L, Frank EH, Greene JJ et al. Time-dependent nanomechanics of cartilage. Biophys J 2011; 100 : 1846–1854.

Nia HT, Han L, Li Y et al. Poroelasticity of cartilage at the nanoscale. Biophys J 2011; 101 : 2304–2313.

Nia HT, Han L, Bozchalooi IS et al. Aggrecan nanoscale solid-fluid interactions are a primary determinant of cartilage dynamic mechanical properties. ACS Nano 2015; 9 : 2614–2625.

Article   PubMed   CAS   PubMed Central   Google Scholar  

Nia HT, Gauci SJ, Azadi M et al. High-bandwidth AFM-based rheology is a sensitive indicator of early cartilage aggrecan degradation relevant to mouse models of osteoarthritis. J Biomech 2015; 48 : 162–165.

Im HJ, Kim JS, Li X et al. Alteration of sensory neurons and spinal response to an experimental osteoarthritis pain model. Arthritis Rheum 2010; 62 : 2995–3005.

Lee AS, Ellman MB, Yan D et al. A current review of molecular mechanisms regarding osteoarthritis and pain. Gene 2013; 527 : 440–447.

Deshmane SL, Kremlev S, Amini S et al. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 2009; 29 : 313–326.

Harigai M, Hara M, Yoshimura T et al. Monocyte chemoattractant protein-1 (MCP-1) in inflammatory joint diseases and its involvement in the cytokine network of rheumatoid synovium. Clin Immunol Immunopathol 1993; 69 : 83–91.

Thompson WL, Karpus WJ, Van Eldik LJ . MCP-1-deficient mice show reduced neuroinflammatory responses and increased peripheral inflammatory responses to peripheral endotoxin insult. J Neuroinflammation 2008; 5 : 35–47.

Conductier G, Blondeau N, Guyon A et al. The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. J Neuroimmunol 2010; 224 : 93–100.

Thacker MA, Clark AK, Bishop T et al. CCL2 is a key mediator of microglia activation in neuropathic pain states. Eur J Pain 2009; 13 : 263–272.

Van Steenwinckel J, Reaus-Le Goazigo A, Pommier B et al. CCL2 released from neuronal synaptic vesicles in the spinal cord is a major mediator of local inflammation and pain after peripheral nerve injury. J Neurosci 2011; 31 : 5865–5875.

Miller RE, Tran PB, Das R et al. CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis. Proc Natl Acad Sci U S A 2012; 109 : 20602–20607.

Horuk R . Chemokine receptor antagonists: overcoming developmental hurdles. Nat Rev Drug Discov 2009; 8 : 23–33.

Lane NE, Schnitzer TJ, Birbara CA et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med 2010; 363 : 1521–1531.

Schnitzer TJ, Lane NE, Birbara C et al. Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain. Osteoarthritis Cartilage 2011; 19 : 639–646.

Brown MT, Murphy FT, Radin DM et al. Tanezumab reduces osteoarthritic knee pain: results of a randomized, double-blind, placebo-controlled phase III trial. J Pain 2012; 13 : 790–798.

Nagashima H, Suzuki M, Araki S et al. Preliminary assessment of the safety and efficacy of tanezumab in Japanese patients with moderate to severe osteoarthritis of the knee: a randomized, double-blind, dose-escalation, placebo-controlled study. Osteoarthritis Cartilage 2011; 19 : 1405–1412.

Obata K, Noguchi K . MAPK activation in nociceptive neurons and pain hypersensitivity. Life Sci 2004; 74 : 2643–2653.

McKelvey L, Shorten GD, O'Keeffe GW . Nerve growth factor-mediated regulation of pain signalling and proposed new intervention strategies in clinical pain management. J Neurochem 2013; 124 : 276–289.

Hefti FF, Rosenthal A, Walicke PA et al. Novel class of pain drugs based on antagonism of NGF. Trends Pharmacol Sci 2006; 27 : 85–91.

Mantyh PW, Koltzenburg M, Mendell LM et al. Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology 2011; 115 : 189–204.

Kawamoto K, Aoki J, Tanaka A et al. Nerve growth factor activates mast cells through the collaborative interaction with lysophosphatidylserine expressed on the membrane surface of activated platelets. J Immunol 2002; 168 : 6412–6419.

Seidel MF, Wise BL, Lane NE . Nerve growth factor: an update on the science and therapy. Osteoarthritis Cartilage 2013; 21 : 1223–1228.

Gee AP, Boyle MD, Munger KL et al. Nerve growth factor: stimulation of polymorphonuclear leukocyte chemotaxis in vitro . Proc Natl Acad Sci U S A 1983; 80 : 7215–7218.

Otten U, Baumann JB, Girard J . Nerve growth factor induces plasma extravasation in rat skin. Eur J Pharmacol 1984; 106 : 199–201.

Walsh DA, McWilliams DF, Turley MJ et al. Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis. Rheumatology 2010; 49 : 1852–1861.

Kc R, Li X, Kroin JS et al. PKCδ null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth. Ann Rheum Dis 2016; 75 : 2133–2141.

Hochberg MC . Serious joint-related adverse events in randomized controlled trials of anti-nerve growth factor monoclonal antibodies. Osteoarthritis Cartilage 2015; 23 : S18–S21.

Malfait AM, Ritchie J, Gil AS et al. ADAMTS-5 deficient mice do not develop mechanical allodynia associated with osteoarthritis following medial meniscal destabilization. Osteoarthritis Cartilage 2010; 18 : 572–580.

Miller RE, Tran PB, Ishihara S et al. Therapeutic effects of an anti-ADAMTS-5 antibody on joint damage and mechanical allodynia in a murine model of osteoarthritis. Osteoarthritis Cartilage 2016; 24 : 299–306.

Verma P, Dalal K . ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis. J Cell Biochem 2011; 112 : 3507–3514.

Chan CC, Roberts CR, Steeves JD et al. Aggrecan components differentially modulate nerve growth factor-responsive and neurotrophin-3-responsive dorsal root ganglion neurite growth. J Neurosci Res 2008; 86 : 581–592.

Mancuso CA, Ranawat CS, Esdaile JM et al. Indications for total hip and total knee arthroplasties. Results of orthopaedic surveys. J Arthroplasty 1996; 11 : 34–46.

Hunter DJ, McDougall JJ, Keefe FJ . The symptoms of osteoarthritis and the genesis of pain. Med Clin North Am 2009; 93 : 83–100.

Piel MJ, Kroin JS, van Wijnen AJ et al. Pain assessment in animal models of osteoarthritis. Gene 2014; 537 : 184–188.

Neugebauer V, Han JS, Adwanikar H et al. Techniques for assessing knee joint pain in arthritis. Mol Pain 2007; 3 : 8.

Malfait AM, Little CB, McDougall JJ . A commentary on modelling osteoarthritis pain in small animals. Osteoarthritis Cartilage 2013; 21 : 1316–1326.

Henze DA, Urban MO . Large animal models for pain therapeutic development. In: Kruger L, Light AR (ed.). Translational Pain Research: From Mouse to Man . London: CRC Press, 2010: 371–390.

Google Scholar  

Download references

Acknowledgements

This project has been supported by NIH grants AR055915 and AR054465 to DC.

Author information

Authors and affiliations.

Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA

Di Chen, Weiwei Zhao, John L Hamilton & Hee-Jeong Im

Department of Orthopaedic Surgery, Washington University, St Louis, MO, USA

Department of Orthopaedics & Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

Weiwei Zhao

Department of Pharmacy, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

Tingyu Wang

School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA, USA

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Di Chen .

Ethics declarations

Competing interests.

The authors declare no conflict of interest.

Rights and permissions

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Reprints and permissions

About this article

Cite this article.

Chen, D., Shen, J., Zhao, W. et al. Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res 5 , 16044 (2017). https://doi.org/10.1038/boneres.2016.44

Download citation

Received : 04 August 2016

Revised : 02 September 2016

Accepted : 08 September 2016

Published : 17 January 2017

DOI : https://doi.org/10.1038/boneres.2016.44

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

The application of extracorporeal shock wave therapy on stem cells therapy to treat various diseases.

• Dongyan Kou
• Qingyu Chen

Stem Cell Research & Therapy (2024)

Noncoding RNAs in skeletal development and disorders

• Guozhi Xiao

Biological Research (2024)

Emerging technology has a brilliant future: the CRISPR-Cas system for senescence, inflammation, and cartilage repair in osteoarthritis

• Shicheng Jia
• Rongji Liang

Cellular & Molecular Biology Letters (2024)

Dietary and serum antioxidant capacity is inversely associated with patients in osteoarthritis: a case-control study

• Beda Büşra Özalp Çolak
• Nilgün Seremet Kürklü
• Emre Adıgüzel

Journal of Health, Population and Nutrition (2024)

Targeting an inflammation-amplifying cell population can attenuate osteoarthritis-associated pain

• Akshay Pandey
• Mamta Singla
• Nidhi Bhutani

Arthritis Research & Therapy (2024)

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

• Open access
• Published: 18 February 2023

Osteoarthritis: a narrative review of molecular approaches to disease management

• Loay A. Salman 1 , 2 ,
• Ghalib Ahmed 2 ,
• Stephanie G. Dakin 1 ,
• Benjamin Kendrick 1 &
• Andrew Price 1  

Arthritis Research & Therapy volume  25 , Article number:  27 ( 2023 ) Cite this article

10k Accesses

18 Citations

3 Altmetric

Metrics details

Osteoarthritis (OA) is a chronic, progressive degenerative whole joint disease that affects the articular cartilage, subchondral bone, ligaments, capsule, and synovium. While it is still believed to be a mechanically driven disease, the role of underlying co-existing inflammatory processes and mediators in the onset of OA and its progression is now more appreciated. Post-traumatic osteoarthritis (PTOA) is a subtype of OA that occurs secondary to traumatic joint insults and is widely used in pre-clinical models to help understand OA in general. There is an urgent need to develop new treatments as the global burden is considerable and expanding. In this review, we focus on the recent pharmacological advances in the treatment of OA and summarize the most significant promising agents based on their molecular effects. Those are classified here into broad categories: anti-inflammatory, modulation of the activity of matrix metalloproteases, anabolic, and unconventional pleiotropic agents. We provide a comprehensive analysis of the pharmacological advances in each of these areas and highlight future insights and directions in the OA field.

Introduction

Osteoarthritis (OA) is a chronic, progressive degenerative whole joint disease that affects the articular cartilage, subchondral bone, ligaments, capsule, and the synovium [ 1 ]. OA was earlier considered as a wear and tear mechanical disease that causes cartilage degeneration; however, it is now understood that the cross-talk between various joint structures and local inflammation is a central aspect of the underlying pathophysiology [ 2 ].

The stratification of OA into various phenotypes is becoming widely accepted. Post-traumatic OA (PTOA) is a subtype of OA that occurs secondary to traumatic joint insults such as fractures or injury to the soft tissues, such as chondral surfaces, ligaments, tendons, and menisci or even surgical intervention to the joint [ 3 , 4 , 5 , 6 ]. PTOA accounts for approximately 12% of all cases of symptomatic OA [ 7 ]. While it can potentially affect any injured joint, it is most prevalent in the ankle and knee [ 3 , 7 ], PTOA accounts for up to 78%, 10%, 8%, and 2% of all ankle, knee, shoulder, and hip OA cases, respectively [ 3 , 7 , 8 , 9 ].

PTOA shares many clinical, radiological, and genetic similarities with non-traumatic OA [ 10 ]. What differentiates PTOA is that it has a clear starting point, providing an excellent opportunity for intervention and treatment as early as the time of injury [ 10 , 11 , 12 , 13 ]. Therefore, post-injury laboratory and animal models have been widely adopted to investigate the association between injury and OA and help exploit the intracellular processes seen in these same injured tissues to advance our understanding of OA pathways as a whole. Several injury induced-models have been utilized to study OA including surgical transection models of the meniscus or anterior cruciate ligament (ACL), controlled external loading such as ACL rupture (ACLr), or destabilization of the medial meniscus (DMM) models [ 10 , 14 , 15 ].

Over the past 20 years, remarkable progress has been made in osteoarthritis research; however, many questions remain unanswered due to the complexity of OA pathophysiology. It is still believed to be a mechanically driven disease; however, the role of the underlying co-existing inflammatory processes and mediators in the onset of OA and its progression is now more appreciated [ 10 ]. A complete understanding of the pathophysiology of OA would enable identification of potential therapeutic targets.

Numerous therapeutic agents have been suggested for OA [ 16 , 17 , 18 ]; however, there is still no definitive treatment. This review will focus on the recent pharmacological advances in the treatment of OA and summarize the most promising therapeutic agents (Table 1 ), based on their molecular effects, which are broadly classified into anti-inflammatory, modulators of the matrix metalloproteases activity, anabolic, and unconventional pleiotropic agents. We will highlight the complex pathophysiology of OA with an overview of the biomechanics, inflammation, and other OA associated factors. Finally, we will discuss the evolving concepts and future directions in this field.

A thorough literature review was performed using PubMed/MIDLINE, Web of Science, and Google Scholars databases and searched from inception till June 2022 with the following search terms: “Pathophysiology,” “Epidemiology,” “Inflammation”, “Biomechanics,” “Treatment,” “Therapy,” “Pharmacological,” “Intervention,” and “Osteoarthritis.” This yielded a total of 560 articles which were screened based on title/abstract to identify original research work and review articles written in English within the past 10 years. No restrictions were placed on the types of study design. Inclusion was limited to relevant references, mainly related to the pharmacological treatment of OA. Articles focusing on other perspectives of OA and inaccessible full texts were excluded. We also included several references not identified by the search criteria which were known to the author or were manually selected from the reference lists contained within the screened articles. Selected references were then reviewed and finalized by two authors independently. As a result, 66 articles met the eligibility criteria and were included in this review. Additionally, this narrative review was conducted in line with the Scale for the Assessment of Narrative Review Articles (SANRA) quality assessment tool [ 19 ].

Pathophysiology: biomechanics and inflammation

PTOA pathogenesis occurs from the point of injury to the time of presentation of OA symptoms (Fig. 1 ). Following a traumatic injury, a state of mechanical imbalance and overload occurs, which triggers several inflammatory signaling pathways, such as the nuclear factor kappa B (NF-kB), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and poly adenosine diphosphate (ADP)-ribose pathways in the synoviocytes [ 13 , 20 ]. The activation of these inflammatory cascades along with the continuous mechanical disturbance increases the levels of inflammatory mediators and other matrix destructive enzymes, resulting in chondrocyte apoptosis, matrix degradation, leukocyte recruitment, and other structural and molecular changes associated with OA [ 10 , 11 ]. The acute inflammatory phase either progresses to OA or resolves spontaneously, depending on the presence of aggravating factors. The risk factors that stimulate the disease’s progression are similar to that described for OA [ 10 ] (Fig. 1 ).

PTOA pathogenesis. Risk factors aggravating the process. Potential therapeutic targeting points are pointed out with red X

A complete understanding of the fundamental biological pathways and mediators involved in OA (Table 2 ) would enable creating target-based, effective therapies. Pharmacological interventions have been vigorously investigated [ 17 ]; however, they are yet to be applied clinically. The current strategies in OA management is mainly conservative, with analgesics and physiotherapy in the early stages and reconstructive or replacement surgeries at advanced stages [ 13 ]. Anatomical reconstructive procedures have advanced in terms of techniques and improved outcomes; however, evidence supporting their role in preventing OA is still insufficient [ 13 ]. Anterior cruciate ligament (ACL) injury renders the knee joint mechanically unstable and expedites osteoarthritic changes [ 18 ]. It was believed that ACL reconstruction restored the joint’s stability and prevented the development of OA; however, a large meta-analysis of 38 studies demonstrated that OA occurs even after ACL reconstruction and restoration of joint stability [ 21 ]. Therefore, apart from mechanical factors, it is critical to address the molecular pathways involved in the development of OA. This necessitates an early and robust intervention, through two possible strategies: Early, preventive interventions that target the disease process at the onset, or approaches that modify the disease prognosis (Fig. 1 ).

Anti-inflammatory agents for the treatment of OA

The pathogenic role of proinflammatory mediators, such as cytokines and chemokines, is well understood [ 11 , 12 ]. Various cytokines, such as IL-1, IL-6, IL-17, and TNF-α, are involved in the acute inflammatory phase post-joint injury, with prominent crosstalk occurring between the articular cartilage and the synovium. Therefore, inhibition of these cytokines is a promising therapeutic strategy. An imbalance between the levels of pro-inflammatory (high levels of IL-1, IL6, and IL8) and anti-inflammatory (low levels of IL-1Ra, IL-4, and IL-10) cytokines is characteristic of the acute inflammatory phase [ 11 , 12 ]. The most promising cytokine targeting therapy is the inhibition of IL-1 using IL-1Ra, currently in clinical trials [ 17 , 22 ]. Inhibition of IL-1 was therapeutically effective in alleviating the progression of OA in animal models [ 23 ]. Early intervention with a single, small intraarticular dose of the human recombinant IL-1Ra, Anakinra, significantly alleviated the arthritic changes, reducing articular degeneration and synovitis in C57BL/6 mice with tibial plateau articular fracture [ 24 ]. The continuous systemic administration of IL-1Ra, however, yielded no therapeutic effect and, interestingly, led to a greater joint deterioration. IL-1Ra was proved safe in a multicenter randomized clinical trial (RCT) in patients with knee osteoarthritis [ 25 ]. IL-Ra (a single 150 mg dose) substantially improved the functional knee outcome measures, with reduced knee pain at 2 weeks, in a pilot trial for the treatment of acute (less than a month since injury) ACL injuries [ 22 ].

The inhibition of other proinflammatory cytokines, such as IL-6, IL-17, and TNF-α, is expected to reduce degenerative cartilage changes, synovial inflammation, and lubrication problems [ 13 ]; however, inhibiting TNF-α is not therapeutically effective in PTOA [ 23 , 24 ].

In a rabbit PTOA model, intraarticular administration of dexamethasone immediately after surgical drill injury attenuated proinflammatory (IL-1β, IL-6, and IL-8) cytokines and OA-like histological changes [ 26 ]. Glucocorticoids exhibit anti-inflammatory effects in different tissues through the suppression of prostaglandins [ 27 ], inflammatory cytokines [ 28 ], nitric oxide [ 29 ], and other oxygen-derived radicals [ 30 ], making them an attractive therapeutic choice [ 31 ]. Low dose of dexamethasone offers significant chondroprotection, by reducing the loss of extracellular matrix (ECM) proteoglycans and collagen in an IL-1 rich environment and by reducing the loss of glycosaminoglycans (GAGs) even in the presence of inflammatory mediators, such as TNF-α, in an in vitro study in human chondrocytes [ 31 ].

Sivelestat sodium hydrate ameliorated knee PTOA in a rat model, acting via NF-kB and HMGB1; therefore, it could be potential treatment option for OA [ 32 ]. The expression of both of these factors is suppressed, indicating a potential anti-inflammatory response. The production of the pro-inflammatory cytokines, TNF-α and IL-6, is also significantly reduced. Moreover, after receiving a once-weekly dose of 10 mg/kg for four consecutive weeks, there is a dramatic reduction in cartilage degeneration.

JQ1 and flavopiridol suppressed the development of OA in vitro and in an in vivo mouse model of ACL rupture (ACLr) [ 33 ]. This was achieved via inhibiting the rate limiting enzymes of the primary response genes (PRGs), namely, bromodomain-containing-protein-4 (Brd4) and cyclin-dependent-kinase-9 (CDK9). In cartilage explants, they work synergistically in preventing the activation and release of IL-1β-induced inflammatory factors and glycosaminoglycan. In vivo treatment with JQ1 and flavopiridol causes a significant suppression of IL-1 and IL-6 expression, MMPs, synovial inflammation, and other joint-associated inflammatory pathways, such as iNOS and COX2.

Mitochondria-associated pathways

Disruption of mitochondrial structure and/or function is one of the earliest pathogenic mechanisms that trigger the onset of OA and its progression [ 34 ]. In the sub-acute phase following injury, chondrocyte apoptosis and articular degeneration are facilitated by mitochondrial damage, resulting in decreased respiratory function and proteoglycan content and an imbalance between the anabolic and catabolic pathways in the ECM, particularly the expression of MMP-13, as observed in a mouse DMM model [ 35 , 36 ]. The pathways downstream of the mitochondrial pathways (Fig. 2 ), such as the electron transport chain and Bax/Bak pathways, are activated, resulting in the release of oxygen radicals and caspases, respectively. Antioxidants and caspase inhibitors are used to counteract these effects [ 17 , 36 ]. The antioxidants, such as N-acetyl cysteine, Mn 3 porphyrin (a superoxide dismutase mimetic), and vitamins E and C, exhibit promising chondroprotective effects in animals and in ex vivo human studies. They attenuate both mechanically induced apoptosis and the expression of ECM degrading enzymes [ 16 , 37 ]. Caspase inhibitors prevented chondrocyte apoptosis in preclinical studies [ 17 ]; however, their clinical efficacy in humans is not proven. The mitoprotective peptide, SS-31, protects an important phospholipid constituent of the mitochondrial inner cell membrane, cardiolipin [ 36 ], thereby maintaining the integrity of the electron transport chain and ensuring proper ATP production, reduced ROS production, and reduced mitochondrial-induced cell death. The therapeutic efficacy of SS-31 was established in an ex vivo model of PTOA [ 36 ]. SS-31 prevents trauma-induced chondrocyte apoptosis, cell membrane damage, cartilage GAG loss, and matrix degeneration. Although inherent challenges with targeting mitochondrial-associated pathways exist as effects are not tissue-specific, the safety of SS-31 in humans has been reported [ 38 ], enhancing its potential as a candidate for OA therapy.

Effect of mechanical injury on mitochondria-associated pathways. Effects on MT dysfunction, oxidative response, and caspase activation leading to cell death, ECM degradation, and apoptosis and subsequently PTOA. Potential inhibitory roles of certain pharmacological interventions are depicted. Adapted from Delco et al. [ 15 ]. MT, mitochondria; ROS, reactive oxygen species; ECM, extracellular matrix

Inhibitors of the action of matrix degrading enzymes

Doxycycline.

Doxycycline is a broad-spectrum tetracycline antibiotic and inhibited the progression of joint OA in a murine ACLr model [ 38 ]. There is a positive correlation between doxycycline concentrations and the degree of MMP-13 inhibition, as observed by immunohistochemistry. There is a marked reduction in MMP-13 levels and significantly less cartilage damage and synovial inflammation. A systematic review of seven animal studies indicated mixed results, with some positive effects of doxycycline in PTOA treatment [ 39 ], making it a promising therapeutic candidate for OA.

Injection of ECM blood composites

Collagen type I is one of the main components of extracellular matrix-blood composite (EMBC). It is a competitive inhibitor of MMPs, preserving the cartilage matrix. Intra-articular injection of EMBC yielded chondroprotective effects in PTOA rat models, resulting in reduced cartilage degeneration and osteophyte formation [ 40 ].

Ipriflavone

Ipriflavone is a dietary supplement with anabolic effects on the bone and an inhibitor of the Indian hedgehog (IHH) pathway. Stimulation of the IHH pathway is crucial in the progression of OA, resulting in degenerative changes through the upregulation of MMP-13 [ 41 , 42 ]. Ipriflavone mitigates cartilage degeneration in vivo (rats) and in vitro (human cartilage explants), by reducing the levels of MMP-13 and collagen type X.

Sclerostin (SOST) is a Wnt antagonist that inhibits bone osteoblastic activity. The protective role of sclerostin was studied in a tibial compression overload model in SOST transgenic and knockout mice [ 43 ]. Prolonged sclerostin exposure resulted in the activation of the NF-kB pathway and downregulation of cartilage matrix degradation enzymes (MMP-2 and MMP-3). Sclerostin-treated mice exhibited milder OA articular changes and reduced development of osteophytes. Similar effects were observed with the intraarticular administration of recombinant sclerostin protein.

Anabolic mediators

Bisphosphonates.

The use of bisphosphonates is promising for OA, because of their significant bone remodeling potential and anti-osteoclastic activity. The chondroprotective effects of alendronate and its ability to preserve subchondral bone in PTOA models have been established in preclinical studies [ 44 , 45 , 46 , 47 ]. In a rat model of PTOA, alendronate significantly inhibited osteophyte formation by up to 51% at 8 weeks post-surgery [ 46 ] and reduced cartilage degeneration. The effects of alendronate were dose-dependent but not long-lasting in a mouse ACLr model [ 47 ]. One RCT showed that bisphosphonate zoledronic acid [ 48 ] provided better symptomatic pain relief and reduced primary knee OA structural changes when compared to placebo. A statistically and clinically significant reduction (39% vs 18%, p  = 0.044) in knee bone marrow lesion size and numbers at 6 and 12 months was seen. Further clinical studies, on the dose, time of administration, and safety in patients with OA, are required.

Growth factors

Bone morphogenetic protein 7 (bmp-7).

BMP-7, also known as osteogenic protein-1 (OP-1), is a potent member of the TGF-b family and promoter of osteoblast differentiation. It modulates chondrocyte metabolism and protein synthesis [ 16 ]. The cartilage regenerative capacity of BMP-7 has been demonstrated in preclinical studies, making it a robust anabolic candidate for treating both OA and PTOA [ 16 , 49 , 50 ]. Several clinical trials of BMP-7 have been conducted in patients with knee OA [ 51 ]. Intraarticular knee administration of BMP-7 results in a toxicology profile comparable to that of the placebo group, establishing its safety; however, it could not significantly alleviate the pain [ 52 ].

Sprifermin (FGF18)

Sprifermin is a synthetic recombinant human FGF18 with promising anabolic implications in OA. A 5-year, multicenter RCT studied the effect of sprifermin on femorotibial joint cartilage thickness in 549 patients with symptomatic knee OA [ 53 ]. Intraarticular injections of 100 μg of sprifermin every 6 or 12 months resulted in a statistically significant improvement in total femorotibial joint cartilage thickness after 2 years. The functional outcome scores, however, were not different between the treatment and placebo groups, suggesting clinical irrelevance. Evaluation of its application in OA and further investigations on the clinical outcomes and their duration is therefore necessary.

Mesenchymal stromal cells (MSCs)

MSCs are multipotent heterogenous cells that differentiate into chondrocytes and, therefore, play a critical role in cartilage repair [ 54 ]. They also exhibit anti-inflammatory and immunomodulatory effects [ 55 ]. They regulate the levels of IL-1β, TNF-α, and IFN-γ, and their immunosuppressive and anti-inflammatory effects are promising for clinical applications. The exact relationship is not fully understood; however, the stimulation of anti-inflammatory cytokines, phagocytic cells, and regulatory M2 macrophages have been proposed. Intraarticular administration of MSCs effectively prevents the development of OA and preserves bone thickness, in various strains of mice [ 24 ]. Intraarticular administration of MSCs exhibits positive clinical and radiological outcomes in cartilage quality, when compared to the hyaluronan control group, in an RCT [ 56 ]. Further understanding of the specific mechanisms, tissue source, immunogenicity (allogeneic vs autogenic), storage techniques, and the doses and safety of MSC treatments in OA is required.

Unconventional targets

Glutamate and GluR are upregulated following joint injury, facilitating the onset of OA. Intraarticular administration of NBQX, a glutamate receptor inhibitor, in an ACLr mouse model at the time of injury, suppressed inflammation, pain, and joint degeneration [ 57 ]. NBQX functions through the AMPA/kainate glutamate receptor and is more efficient than the conventional treatment using hyaluronic acid and steroids. GluR antagonists are used for treating numerous CNS conditions, establishing their safety profile in humans [ 57 ]. This makes it feasible to advance them into human trials for treating OA.

Intraarticular adenosine

Intraarticular adenosine is another unconventional agent for treating OA. It is an agonist of the A2A receptor and exhibits apparent chondroprotective effects. Extracellular adenosine is critical for articular cartilage homeostasis [ 58 , 59 ]. Stimulation of the A2A receptor has protective effects on cartilage, and it downregulates the catabolic matrix-degrading enzymes. In addition, it increases the nuclear P-SMAD2/3/P-SMAD1/5/8 ratio, thereby shifting the chondrocyte balance to a healthier quiescent state [ 60 ].

Bortezomib is a proteasome inhibitor that suppresses TGF-induced collagen II degradation and MMP-13 expression, in human chondrocytes [ 61 ]. The relationship between the synovial lymphatic system and the development of OA remains unclear [ 62 ]; however, it is believed that the obstruction of the joint lymphatic system exacerbates the inflammatory phase and the progression of OA. Intraarticular administration of bortezomib ameliorates synovial lymphatic drainage, cartilage loss, reduces the number of M1-macrophages, and inhibits the expression of proinflammatory genes [ 63 ].

Erlotinib, an inhibitor of epidermal growth factor receptor (EGFR), which reduces OA-induced cartilage loss, improved subchondral bone thickness and volume owing to the protective role of integrin α1β1 and the reduction in EGFR signaling in various strains of model mice [ 64 ]. Interestingly, these effects were gender specific and observed only in female mice.

KUS121, a valosin-containing protein (VCP) modulator, was effective in vitro and in a rat model of PTOA [ 65 ]. KUS121 significantly reduced the levels of the pro-inflammatory cytokines, TNF-α and IL-6, as well as the ECM catabolic enzymes, MMP-1, MMP-13, and ADAMTS5, in human articular chondrocytes. In addition, it alleviated cartilage damage and chondrocyte apoptosis in a rat model of PTOA induced by cyclic compressive load and, therefore, is a promising therapeutic option for OA.

Rebamipide has protective effects on articular cartilage degeneration, both in vivo and in vitro [ 66 ]. A once-weekly injection of rebamipide into the knee joints of mice and the treatment of human chondrocyte explants with rebamipide increased the expression of cellular protective factors, such as COL2A, TIMP3, TGFβ, and FGF2, in chondrocytes and suppressed the expression of pro-inflammatory and catabolic factors, such as IL-1β, TNF-α, NF-κB, MMP-3, MMP-13, and ADAMTS5.

Future directions

PTOA is one of the most debilitating subtypes of OA, because it affects the younger active population, resulting in a considerable impact on the healthcare system. However, it offers a massive opportunity for advancing our knowledge on osteoarthritis, understanding the underlying pathogenic mechanisms, and exploring therapeutic options. This opportunity arises from the fact that PTOA, unlike other OA phenotypes, is associated clearly with an onset event, the joint injury. Most of the studies described in this review are preclinical, conducted on animal and in vitro human chondrocytes models; however, therapeutic agents, such as IL-1Ra, dexamethasone, bisphosphonates, and MSCs are under clinical trials, with promising findings. The translation of these findings to clinical practice is challenging, because of the vast differences between lab models and humans, with respect to biomechanics, genetics, and systemic body response. Identification and validation of more sensitive biomarkers and radiographic signs with high OA predictive value will improve the practical application of the results from future clinical trials and circumvent the long-term follow-up periods. Finally, with osteoarthritis stratification gaining much recognition, precision-medicine can play key diagnostic and therapeutic roles in the field of OA, with opportunities for further exploration.

The burden of OA and the lack of consensus in early treatment options was the motivation for this review. A successful pharmacological treatment, along with conservative measures, could alleviate the need for surgical interventions in managing OA. Therapeutic agents, such as IL-1Ra, dexamethasone, bisphosphonates, and MSCs are in clinical trials, with promising findings. The future direction of OA treatment includes translating experimental findings to clinical practice by designing feasible clinical trials with short-term, objective outcomes, in addition to exploring other therapeutic options, such as genetics and nanotherapy-based interventions.

Abbreviations

• Osteoarthritis

Post-traumatic osteoarthritis

Anterior cruciate ligament

Anterior cruciate ligament rupture

Destabilization of the medial meniscus

Scale for the Assessment of Narrative Review Articles quality assessment tool

Extracellular matrix

Glycosaminoglycans

Interleukin

Matrix metalloproteinase

Tumor necrosis factor

Transforming growth factor

Nuclear factor kappa B

Cyclooxygenase-2

Inducible nitric oxide synthase

Indian hedgehog

Bone morphogenetic protein 7

Mesenchymal stem cells

Primary response genes

Bromodomain-containing-protein-4

Cyclin-dependent-kinase-9

Loeser RF, et al. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64(6):1697–707.

Article   PubMed   PubMed Central   Google Scholar  

Mazur CM, Bailey KN, Alliston T. Joint cross-talk among bone, synovium, and articular cartilage. In: Aaron R, editor. Orthopaedic basic science: foundations of clincal practice: Wolters Kluwer, American Academy of Orthopaedic Surgeons (AAOS). 2021.

Thomas AC, et al. Epidemiology of posttraumatic osteoarthritis. J Athl Train. 2017;52(6):491–6.

Little CB, Hunter DJ. Post-traumatic osteoarthritis: from mouse models to clinical trials. Nat Rev Rheumatol. 2013;9(8):485–97.

Article   CAS   PubMed   Google Scholar  

Muthuri SG, et al. History of knee injuries and knee osteoarthritis: a meta-analysis of observational studies. Osteoarthritis Cartilage. 2011;19(11):1286–93.

Lohmander LS, et al. The long-term consequence of anterior cruciate ligament and meniscus injuries: osteoarthritis. Am J Sports Med. 2007;35(10):1756–69.

Article   PubMed   Google Scholar  

Brown TD, et al. Posttraumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of disease. J Orthop Trauma. 2006;20(10):739–44.

Saltzman CL, et al. Epidemiology of ankle arthritis: report of a consecutive series of 639 patients from a tertiary orthopaedic center. Iowa Orthop J. 2005;25:44–6.

PubMed   PubMed Central   Google Scholar  

Valderrabano V, et al. Etiology of ankle osteoarthritis. Clin Orthop Relat Res. 2009;467(7):1800–6.

Watt FE. Posttraumatic osteoarthritis: what have we learned to advance osteoarthritis? Curr Opin Rheumatol. 2021;33(1):74–83.

Punzi L, et al. Post-traumatic arthritis: overview on pathogenic mechanisms and role of inflammation. RMD Open. 2016;2(2):e000279.

Lieberthal J, Sambamurthy N, Scanzello CR. Inflammation in joint injury and post-traumatic osteoarthritis. Osteoarthritis Cartilage. 2015;23(11):1825–34.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Riordan EA, Little C, Hunter D. Pathogenesis of post-traumatic OA with a view to intervention. Best Pract Res Clin Rheumatol. 2014;28(1):17–30.

Christiansen BA, et al. Non-invasive mouse models of post-traumatic osteoarthritis. Osteoarthritis Cartilage. 2015;23(10):1627–38.

Gilbert SJ, et al. Inflammatory and degenerative phases resulting from anterior cruciate rupture in a non-invasive murine model of post-traumatic osteoarthritis. J Orthop Res. 2018;36(8):2118–27.

Lotz MK, Kraus VB. New developments in osteoarthritis. Posttraumatic osteoarthritis: pathogenesis and pharmacological treatment options. Arthritis Res Ther. 2010;12(3):211.

Chubinskaya S, Wimmer MA. Key pathways to prevent posttraumatic arthritis for future molecule-based therapy. Cartilage. 2013;4(3_suppl):13S–21S.

Wang LJ, et al. Post-traumatic osteoarthritis following ACL injury. Arthritis Res Ther. 2020;22(1):57.

Baethge C, Goldbeck-Wood S, Mertens S. SANRA—a scale for the quality assessment of narrative review articles. Res Integr Peer Rev. 2019;4(1):5.

Morisugi T, et al. Mechanical stretch enhances NF-kappaB-dependent gene expression and poly (ADP-ribose) synthesis in synovial cells. J Biochem. 2010;147(5):633–44.

Cinque ME, et al. High rates of osteoarthritis develop after anterior cruciate ligament surgery: an analysis of 4108 patients. Am J Sports Med. 2018;46(8):2011–9.

Kraus VB, et al. Effects of intraarticular IL1-Ra for acute anterior cruciate ligament knee injury: a randomized controlled pilot trial (NCT00332254). Osteoarthritis Cartilage. 2012;20(4):271–8.

Furman BD, et al. Targeting pro-inflammatory cytokines following joint injury: acute intra-articular inhibition of interleukin-1 following knee injury prevents post-traumatic arthritis. Arthritis Res Ther. 2014;16(3):R134.

Olson SA, et al. Therapeutic opportunities to prevent post-traumatic arthritis: Lessons from the natural history of arthritis after articular fracture. J Orthop Res. 2015;33(9):1266–77.

Chevalier X, et al. Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2009;61(3):344–52.

Heard BJ, et al. Single intra-articular dexamethasone injection immediately post-surgery in a rabbit model mitigates early inflammatory responses and post-traumatic osteoarthritis-like alterations. J Orthop Res. 2015;33(12):1826–34.

Shimpo H, et al. Regulation of prostaglandin E(2) synthesis in cells derived from chondrocytes of patients with osteoarthritis. J Orthop Sci. 2009;14(5):611–7.

Uddin MN, et al. Potentiation of pro-inflammatory cytokine suppression and survival by microencapsulated dexamethasone in the treatment of experimental sepsis. J Drug Target. 2011;19(9):752–60.

Pudrith C, et al. Glucocorticoids reduce nitric oxide concentration in middle ear effusion from lipopolysaccharide induced otitis media. Int J Pediatr Otorhinolaryngol. 2010;74(4):384–6.

Huo Y, et al. Dexamethasone inhibits the Nox-dependent ROS production via suppression of MKP-1-dependent MAPK pathways in activated microglia. BMC Neurosci. 2011;12:49.

Grodzinsky AJ, et al. Intra-articular dexamethasone to inhibit the development of post-traumatic osteoarthritis. J Orthop Res. 2017;35(3):406–11.

Yu X, et al. Sivelestat sodium hydrate improves post-traumatic knee osteoarthritis through nuclear factor-κB in a rat model. Exp Ther Med. 2017;14(2):1531–7.

Fukui T, et al. Bromodomain-containing-protein-4 and cyclin-dependent-kinase-9 inhibitors interact synergistically in vitro and combined treatment reduces post-traumatic osteoarthritis severity in mice. Osteoarthritis Cartilage. 2021;29(1):68–77.

Blanco FJ, Rego I, Ruiz-Romero C. The role of mitochondria in osteoarthritis. Nat Rev Rheumatol. 2011;7(3):161–9.

Koike M, et al. Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration. Sci Rep. 2015;5:11722.

Delco ML, et al. Mitoprotective therapy preserves chondrocyte viability and prevents cartilage degeneration in an ex vivo model of posttraumatic osteoarthritis. J Orthop Res. 2018. https://doi.org/10.1002/jor.23882 .

Riegger J, et al. Antioxidative therapy in an ex vivo human cartilage trauma-model: attenuation of trauma-induced cell loss and ECM-destructive enzymes by N-acetyl cysteine. Osteoarthritis Cartilage. 2016;24(12):2171–80.

Zhang X, et al. Matrix metalloproteinase inhibition with doxycycline affects the progression of posttraumatic osteoarthritis after anterior cruciate ligament rupture: evaluation in a new nonsurgical murine ACL rupture model. Am J Sports Med. 2020;48(1):143–52.

Kraeutler MJ, et al. A systematic review of basic science and animal studies on the use of doxycycline to reduce the risk of posttraumatic osteoarthritis after anterior cruciate ligament rupture/transection. Am J Sports Med. 2020:363546520965971.

Proffen BL, et al. Extracellular matrix-blood composite injection reduces post-traumatic osteoarthritis after anterior cruciate ligament injury in the rat. J Orthop Res. 2016;34(6):995–1003.

Guo L, et al. Ipriflavone attenuates the degeneration of cartilage by blocking the Indian hedgehog pathway. Arthritis Res Ther. 2019;21(1):109.

Wei F, et al. Activation of Indian hedgehog promotes chondrocyte hypertrophy and upregulation of MMP-13 in human osteoarthritic cartilage. Osteoarthritis Cartilage. 2012;20(7):755–63.

Chang JC, et al. SOST/sclerostin improves posttraumatic osteoarthritis and inhibits MMP2/3 expression after injury. J Bone Miner Res. 2018;33(6):1105–13.

Hayami T, et al. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum. 2004;50(4):1193–206.

Shirai T, et al. Chondroprotective effect of alendronate in a rabbit model of osteoarthritis. J Orthop Res. 2011;29(10):1572–7.

Panahifar A, Maksymowych WP, Doschak MR. Potential mechanism of alendronate inhibition of osteophyte formation in the rat model of post-traumatic osteoarthritis: evaluation of elemental strontium as a molecular tracer of bone formation. Osteoarthritis Cartilage. 2012;20(7):694–702.

Khorasani MS, et al. Effect of alendronate on post-traumatic osteoarthritis induced by anterior cruciate ligament rupture in mice. Arthritis Res Ther. 2015;17(1):30.

Laslett LL, et al. Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a randomised controlled trial. Ann Rheum Dis. 2012;71(8):1322–8.

Cook SD, et al. Repair of articular cartilage defects with osteogenic protein-1 (BMP-7) in dogs. J Bone Joint Surg Am. 2003;85-A(Suppl 3):116–23.

Article   Google Scholar  

Louwerse RT, et al. Use of recombinant human osteogenic protein-1 for the repair of subchondral defects in articular cartilage in goats. J Biomed Mater Res. 2000;49(4):506–16.

Grässel S, Muschter D. Recent advances in the treatment of osteoarthritis. F1000Res. 2020;9:F1000 Faculty Rev-325.

Evans CH, Kraus VB, Setton LA. Progress in intra-articular therapy. Nat Rev Rheumatol. 2014;10(1):11–22.

Hochberg MC, et al. Effect of intra-articular sprifermin vs placebo on femorotibial joint cartilage thickness in patients with osteoarthritis: the FORWARD randomized clinical trial. JAMA. 2019;322(14):1360–70.

Murphy JM, et al. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum. 2003;48(12):3464–74.

Theeuwes WF, et al. The role of inflammation in mesenchymal stromal cell therapy in osteoarthritis, perspectives for post-traumatic osteoarthritis: a review. Rheumatology (Oxford). 2021;60(3):1042–53.

Vega A, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015;99(8):1681–90.

Bonnet CS, et al. AMPA/kainate glutamate receptor antagonists prevent posttraumatic osteoarthritis. JCI Insight. 2020;5(13):e134055.

Corciulo C, et al. Endogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression. Nat Commun. 2017;8:15019.

Tesch AM, et al. Endogenously produced adenosine regulates articular cartilage matrix homeostasis: enzymatic depletion of adenosine stimulates matrix degradation. Osteoarthritis Cartilage. 2004;12(5):349–59.

Corciulo C, et al. Intraarticular injection of liposomal adenosine reduces cartilage damage in established murine and rat models of osteoarthritis. Sci Rep. 2020;10(1):13477.

Hu W, et al. Bortezomib prevents the expression of MMP-13 and the degradation of collagen type 2 in human chondrocytes. Biochem Biophys Res Commun. 2014;452(3):526–30.

Shi J, et al. Distribution and alteration of lymphatic vessels in knee joints of normal and osteoarthritic mice. Arthritis Rheumatol. 2014;66(3):657–66.

Wang W, et al. Attenuated joint tissue damage associated with improved synovial lymphatic function following treatment with bortezomib in a mouse model of experimental posttraumatic osteoarthritis. Arthritis Rheumatol. 2019;71(2):244–57.

Shin SY, et al. Integrin α1β1 protects against signs of post-traumatic osteoarthritis in the female murine knee partially via regulation of epidermal growth factor receptor signalling. Osteoarthritis Cartilage. 2016;24(10):1795–806.

Saito M, et al. A VCP modulator, KUS121, as a promising therapeutic agent for post-traumatic osteoarthritis. Sci Rep. 2020;10(1):20787.

Suzuki Y, et al. Intra-articular injection of rebamipide prevents articular cartilage degeneration in murine post-traumatic osteoarthritis models. Mod Rheumatol. 2020;30(4):765–72.

Download references

Open Access funding provided by the Qatar National Library.

Author information

Authors and affiliations.

Present Address: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK

Loay A. Salman, Stephanie G. Dakin, Benjamin Kendrick & Andrew Price

Orthopedics Department, Hamad General Hospital, Hamad Medical Corporation, PO Box 3050, Doha, Qatar

Loay A. Salman & Ghalib Ahmed

You can also search for this author in PubMed   Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, literature review, and data collection were performed by LAS, and GA. The first draft of the manuscript was written by LAS and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Loay A. Salman .

Ethics declarations

Competing interests.

The authors declare no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Salman, L.A., Ahmed, G., Dakin, S.G. et al. Osteoarthritis: a narrative review of molecular approaches to disease management. Arthritis Res Ther 25 , 27 (2023). https://doi.org/10.1186/s13075-023-03006-w

Download citation

Received : 02 September 2022

Accepted : 04 February 2023

Published : 18 February 2023

DOI : https://doi.org/10.1186/s13075-023-03006-w

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Posttraumatic
• Animal models
• Pharmacological
• Biomechanics

Arthritis Research & Therapy

ISSN: 1478-6362

• General enquiries: [email protected]

• - Google Chrome

Intended for healthcare professionals

• My email alerts
• BMA member login
• Username * Password * Forgot your log in details? Need to activate BMA Member Log In Log in via OpenAthens Log in via your institution

Search form

• Advanced search
• Search responses
• Search blogs
• Arthroscopic surgery...

Arthroscopic surgery for degenerative knee arthritis and meniscal tears: a clinical practice guideline

Choice of intervention, recommendations, strong weak we recommend against arthroscopic knee surgery in patients with degenerative knee disease all applies to click for details  weak benefits outweigh harms for the majority, but not for everyone. the majority of patients would likely want this option. strong benefits outweigh harms for almost everyone. all or nearly all informed patients would likely want this option., comparison of benefits and harms, pain high 18.8 21.9 no important difference more, function moderate 13.3 10.1 no important difference more, pain high 15.0 5.38 higher 20.4 more, function moderate 9.3 4.94 higher 14.2 more, venous thromboembolism low 5 5 fewer 0 more, infection low 2 2 fewer 0 more.

©BMJ Publishing Group Limited.

Disclaimer: This infographic is not a validated clinical decision aid. This information is provided without any representations, conditions or warranties that it is accurate or up to date. BMJ and its licensors assume no responsibility for any aspect of treatment administered with the aid of this information. Any reliance placed on this information is strictly at the user's own risk. For the full disclaimer wording see BMJ's terms and conditions: https://www.bmj.com/company/legal-information/

• Related content
• Peer review
• Reed A C Siemieniuk , methodologist, panel chair 1 2 ,
• Ian A Harris , professor of orthopaedic surgery 3 4 ,
• Thomas Agoritsas , assistant professor 1 5 ,
• Rudolf W Poolman , orthopaedic surgeon 6 ,
• Romina Brignardello-Petersen , methodologist 1 7 ,
• Stijn Van de Velde , methodologist and physiotherapist 8 ,
• Rachelle Buchbinder , professor and rheumatologist 9 10 ,
• Martin Englund , associate professor and epidemiologist 11 ,
• Lyubov Lytvyn , patient liaison expert 12 ,
• Casey Quinlan , patient representative 13 ,
• Lise Helsingen , PhD student 14 ,
• Gunnar Knutsen , orthopaedic surgeon 15 ,
• Nina Rydland Olsen , associate professor and physiotherapist 16 ,
• Helen Macdonald , general practitioner and clinical editor 17 ,
• Louise Hailey , physiotherapist 18 ,
• Hazel M Wilson , patient representative 19 ,
• Anne Lydiatt , patient representative 20 ,
• Annette Kristiansen , general internist, methods editor 21 22
• 1 Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada L8S 4L8
• 2 Department of Medicine, University of Toronto, Toronto, Ontario, Canada
• 3 South Western Sydney Clinical School, UNSW, Australia
• 4 Whitlam Orthopaedic Research Centre, Ingham Institute for Applied Medical Research, Liverpool, NSW 2170, Australia
• 5 Division General Internal Medicine & Division of Clinical Epidemiology, University Hospitals of Geneva, CH-1211, Geneva, Switzerland
• 6 Department of Orthopaedic Surgery, Joint Research, OLVG, 1090 HM Amsterdam, The Netherlands
• 7 Faculty of Dentistry, Universidad de Chile, Independencia, Santiago, Chile
• 8 Norwegian Institute of Public Health, Nydalen, N-0403 Oslo, Norway
• 9 Department of Epidemiology and Preventive Medicine, School of Public Health & Preventive Medicine, Monash University, Melbourne, Vic 3004, Australia
• 10 Monash Department of Clinical Epidemiology, Cabrini Institute; Suite 41 Cabrini Medical Centre, Malvern Vic, 3144, Australia
• 11 Clinical Epidemiology Unit, Orthopaedics, Department of Clinical Sciences Lund Faculty of Medicine, Lund University, SE-221 85 Lund, Sweden
• 12 Oslo University Hospital, Blindern 0317 Oslo, Norway
• 13 Richmond, Virginia, USA
• 14 Clinical Effectiveness Research Group, Institute of Health and Society, University of Oslo, Blindern 0317 Oslo, Norway
• 15 University Hospital North Norway, 9038 Tromso, Norway
• 16 Department of Occupational Therapy, Physiotherapy and Radiography, Faculty of Health and Social sciences, Bergen University College, 5020 Bergen, Norway
• 17 BMJ Editorial, BMA House, London WC1H 9JR, UK
• 18 Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7HE, UK
• 19 London, Ontario, Canada
• 20 Ingersoll, Ontario, Canada N5C 3N1
• 21 Department of Health and Science, University of Oslo, Oslo, Norway
• 22 Department of Medicine, Hospital Innlandet Trust, Gjøvik, Norway
• Correspondence to: R Siemieniuk, Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada reed.siemieniuk{at}medportal.ca

What you need to know

We make a strong recommendation against the use of arthroscopy in nearly all patients with degenerative knee disease, based on linked systematic reviews; further research is unlikely to alter this recommendation

This recommendation applies to patients with or without imaging evidence of osteoarthritis, mechanical symptoms, or sudden symptom onset

Healthcare administrators and funders may use the number of arthroscopies performed in patients with degenerative knee disease as an indicator of quality care.

Knee arthroscopy is the most common orthopaedic procedure in countries with available data

This Rapid Recommendation package was triggered by a randomised controlled trial published in The BMJ in June 2016 which found that, among patients with a degenerative medial meniscus tear, knee arthroscopy was no better than exercise therapy

What is the role of arthroscopic surgery in degenerative knee disease? An expert panel produced these recommendations based on a linked systematic review triggered by a randomised trial published in The BMJ in June 2016, which found that, among patients with a degenerative medial meniscus tear, knee arthroscopy was no better than exercise therapy. The panel make a strong recommendation against arthroscopy for degenerative knee disease. Box 1 shows all of the articles and evidence linked in this Rapid Recommendation package. The infographic provides an overview of the absolute benefits and harms of arthroscopy in standard GRADE format. Table 2 below shows any evidence that has emerged since the publication of this article.

Box 1: Linked articles in this BMJ Rapid Recommendations cluster

Siemieniuk RAC, Harris IA, Agoritsas T, et al. Arthroscopic surgery for degenerative knee arthritis and meniscal tears: a clinical practice guideline. BMJ 2017;257:j1982. doi: 10.1136/bmj.j1982

Summary of the results from the Rapid Recommendation process

Brignardello-Peterson R, Guyatt GH, Schandelmaier S, et al. Knee arthroscopy versus conservative management in patients with degenerative knee disease: a systematic review. BMJ Open 2017;7:e016114. doi: doi:10.1136/bmjopen-2017-161114

Review of all available randomised trials that assessed the benefits of knee arthroscopy compared with non-operative care and observational studies that assessed risks

Devji T, Guyatt GH, Lytvyn L, et al. Application of minimal important differences in degenerative knee disease outcomes: a systematic review and case study to inform BMJ Rapid Recommendations. BMJ Open 2017;7:e015587. doi: doi:10.1136/bmjopen-2016-015587

Review addressing what level of individual change on a given scale is important to patients (minimally important difference). The study informed sensitivity analyses for the review on net benefit, informed discussions on patient values and preferences, and was key to interpreting the magnitude of effect sizes and the strength of the recommendation

MAGICapp ( www.magicapp.org )

Expanded version of the results with multilayered recommendations, evidence summaries, and decision aids for use on all devices

Current practice

Approximately 25% of people older than 50 years experience knee pain from degenerative knee disease (box 2). 2 3 Management options include watchful waiting, weight loss if overweight, a variety of interventions led by physical therapists, exercise, oral or topical pain medications such as non-steroidal anti-inflammatory drugs, intra-articular corticosteroid and other injections, arthroscopic knee surgery, and knee replacement or osteotomy. The preferred combination or sequence of these options is not clear and probably varies between patients.

Box 2: What is degenerative knee disease?

Degenerative knee disease is an inclusive term, which many consider synonymous with osteoarthritis. We use the term degenerative knee disease to explicitly include patients with knee pain, particularly if they are >35 years old, with or without:

Imaging evidence of osteoarthritis

Meniscus tears

Locking, clicking, or other mechanical symptoms except persistent objective locked knee

Acute or subacute onset of symptoms

Most people with degenerative arthritis have at least one of these characteristics. 1 The term degenerative knee disease does not include patients having recent debut of their symptoms after a major knee trauma with acute onset of joint swelling (such as haemarthrosis)

Knee replacement is the only definitive therapy, but it is reserved for patients with severe disease after non-operative management has been unsuccessful. 4 5 Some believe that arthroscopic debridement, including washout of intra-articular debris, with or without arthroscopic partial meniscectomy to remove damaged meniscus, may improve pain and function.

Current guidelines generally discourage arthroscopy for patients with clear radiographic evidence of osteoarthritis alone, but several support or do not make clear statements regarding arthroscopic surgery in other common groups of patients (table 1 ⇓ ).

Support from current guidance for arthroscopic surgery in patients with subgroups of degenerative knee disease

• View inline

Arthroscopic knee surgery for degenerative knee disease is the most common orthopaedic procedure in countries with available data 14 and on a global scale is performed more than two million times each year (fig 1 ⇓ ). 15 16 17 18 Arthroscopic procedures for degenerative knee disease cost more than $3bn per year in the US alone. 19 A high prevalence of features advocated to respond positively to arthroscopic surgery (such as meniscal tears, mechanical symptoms, and sudden symptom onset) as well as financial incentives may explain why arthroscopic knee surgery continues to be so common despite recommendations against its use for osteoarthritis. Further, patients may be frustrated with their symptoms, having tried several less invasive management strategies by the time that they see the surgeon, and in many cases this may come with an expectation for surgical management. Moreover, many patients experience important and marked improvements after arthroscopy, which may be erroneously attributed to the effects of the procedure itself instead of the natural course of the disease, co-interventions, or placebo effects.

Fig 1 Population adjusted trends in frequency of knee arthroscopy; percent. Arthroscopic knee surgery remains common despite accumulating evidence suggesting little benefit

• Download figure
• Open in new tab
• Download powerpoint

How the recommendation was created

A randomised controlled trial published in The BMJ in June 2016 found that, among patients with a degenerative medial meniscus tear, knee arthroscopy was no better than exercise therapy. 32 This study adds to the body of evidence suggesting that the benefits of arthroscopy may not outweigh the burden and risks. 33 34 The RapidRecs executive felt that the study, when considered in context of the full body of evidence, might change practice. 35

Our international panel including orthopaedic surgeons, a rheumatologist, physiotherapists, a general practitioner, general internists, epidemiologists, methodologists, and people with lived experience of degenerative knee disease (including those who had undergone and those who had not undergone arthroscopy) met to discuss the evidence. No person had financial conflicts of interest; intellectual and professional conflicts were minimised and managed (see appendix 1 on bmj.com).

The panel followed the BMJ Rapid Recommendations procedures for creating a trustworthy recommendation 35 36 and used the GRADE approach to critically appraise the evidence and create recommendations (appendix 2). 37 The panel considered the balance of benefits, harms, and burdens of the procedure, the quality of evidence for each outcome, typical and expected variations in patient values and preferences, and acceptability. Recommendations can be strong or weak, for or against a course of action.

The evidence

The panel requested two systematic reviews to inform the recommendation. 20 21

The systematic review on the net benefit of knee arthroscopy compared with non-operative care pools data from 13 randomised trials for benefit outcomes (1668 patients) and an additional 12 observational studies for complications (>1.8 million patients). 21 Figure 2 ⇓ gives an overview of the patients included, the study funding, and patient involvement in the design of the studies.

Fig 2 Characteristics of patients and trials included in systematic review of arthroscopic knee surgery

Panel members identified three outcomes—pain, function, and quality of life—as the most important for patients with degenerative knee disease who are considering surgery. Although the included studies reported these patient-important outcomes, it is difficult to know whether changes recorded on an instrument measuring subjective symptoms are important to those with symptoms—for example, a change of three points might have completely different meanings in two different pain scales.

Therefore, a second team performed a linked systematic review addressing what level of individual change on a given scale is important to patients, 20 a characteristic called the minimally important difference (MID). 22 The study identified a range of credible MIDs for each key outcome; this range of MID estimates informed sensitivity analyses for the review on net benefit, informed discussions on the patient values and preferences, and was key to interpreting the magnitude of effect sizes as well as the strength of the recommendation. 20

Understanding the recommendations

The infographic provides an overview of the benefits and harms of arthroscopy in standard GRADE format. Estimates of baseline risk for effects comes from the control arms of the trials; for complications, comparator risk was assumed to be nil.

The panel is confident that arthroscopic knee surgery does not, on average, result in an improvement in long term pain or function. Most patients will experience an important improvement in pain and function without arthroscopy. However, in <15% of participants, arthroscopic surgery resulted in a small or very small improvement in pain or function at three months after surgery—this benefit was not sustained at one year. In addition to the burden of undergoing knee arthroscopy (see practical issues below), there are rare but important harms, although the precision in these estimates is uncertain (low quality of evidence).

It is unlikely that new information will change interpretation of the key outcomes of pain, knee function, and quality of life (as implied by high to moderate quality of evidence).

The panel is confident that the randomised controlled trials included adequate representation from groups commonly cited to derive benefit from arthroscopic knee surgery for degenerative knee disease—notably those with meniscal tears, no or minimal radiographic evidence of osteoarthritis, and those with sudden but non-traumatic symptom onset. Thus the recommendation applies to all or almost all patients with degenerative knee disease. Further, the evidence applies to patients with any severity of mechanical symptoms, with the only possible exception being those who are objectively unable to fully extend their knee (that is, a true locked knee). We did not consider young patients with sports related injuries or patients with major trauma in any age.

Trials that enrolled a majority of patients without radiographic osteoarthritis showed similar effect sizes to trials enrolling patients with radiographic evidence of osteoarthritis. Most of these trials exclusively included patients with meniscus tears. Meniscus tears are common, usually incidental findings, and unlikely to be the cause of knee pain, aching, or stiffness. 1 Mechanical symptoms were also a prominent feature for most trial participants, and many had sudden or subacute onset of symptoms. 23 24 25 26 Given that there is evidence of harm and no evidence of important lasting benefit in any subgroup, the panel believes that the burden of proof rests with those who suggest benefit for any other particular subgroup before arthroscopic surgery is routinely performed in any subgroup of patients.

Practical issues

It takes between two and six weeks to recover from arthroscopy, during which time patients may experience pain, swelling, and limited function. 27 28 Most patients cannot bear full weight on the leg (that is, they may need crutches) in the first week after surgery, and driving or physical activity is limited during the recovery period. 27 Figure 3 ⇓ outlines the key practical issues for those considering arthroscopic knee surgery versus non-surgical management for degenerative knee disease.

Fig 3 Practical issues about use of arthroscopic knee surgery versus non-surgical management for degenerative knee disease

Degenerative knee disease is a chronic condition in which symptoms fluctuate. On average, pain tends to improve over time after seeing a physician for pain, 21 29 and delaying knee replacement is encouraged when possible. 4

Values and preferences

Our strong recommendation against arthroscopy reflects a low value on a modest probability (<15%) of small or very small improvement in short term pain and function that does not persist to one year, and a higher value on avoiding the burden, postoperative limitations, and rare serious adverse effects associated with knee arthroscopy. The panel, including the patient participants, felt that almost all patients would share these values. The recommendation is not applicable to patients who do not share these values (that is, those who place a high value on a small, uncertain, and transient reduction in pain and function, and a low value on avoiding the burden and postoperative limitation associated with arthroscopy).

Costs and resources

The panel focused on the patient perspective rather than that of society when formulating the recommendation. However, implementation of this recommendation will almost certainly result in considerable cost savings for health funders. A rigorous economic analysis found that knee arthroscopy for degenerative knee disease is not close to cost effective by traditional standards, even in extreme scenarios that assume a benefit with arthroscopy. 30 The panel made a strong recommendation against arthroscopy, which applies to almost all patients with degenerative knee disease, implying that non-use of knee arthroscopy can be used as a performance measure or tied to health funding. 31

Future research

Key research questions to inform decision makers and future guidelines are:

Randomised trials—Does arthroscopic knee surgery benefit patients who are objectively unable to fully extend their knee or who have persistent, severe, and frequent mechanical symptoms?

Implementation studies—What are the most effective ways to reduce the overuse of arthroscopic surgery for degenerative knee disease?

Updates to this article

Table 2 ⇓ shows evidence which has emerged since the publication of this article. As new evidence is published, a group will assess the new evidence and make a judgment on to what extent it is expected to alter the recommendation.

New evidence which has emerged after initial publication

How patients were involved in the creation of this article:

Three people with lived experience of osteoarthritis, one of whom had arthroscopic knee surgery, were full panel members. These panel members identified important outcomes and led the discussion on values and preferences. Pain was weighed as higher importance for most patients: for example, the patient panel members felt that a possible small benefit to function without a reduction in pain would be unimportant to almost all patients. Those with lived experience identified key practical issues including concerns with cost and accessibility for both arthroscopy and interventions provided by physiotherapists. The members participated in the teleconferences and email discussions and met all authorship criteria.

Education into practice

•Project: how many arthroscopic procedures are scheduled in your organisation for degenerative knee disease?

•Based on the information you have read in this article or in this package of Rapid Recommendation articles, is there anything which you might alter your practice?

•To what extent might you use information in this article to alter the conversations you have with patients with degenerative knee disease, or those considering arthroscopic surgery?

This BMJ Rapid Recommendation article is one of a series that provides clinicians with trustworthy recommendations for potentially practice changing evidence. BMJ Rapid Recommendations represent a collaborative effort between the MAGIC group ( www.magicproject.org ) and The BMJ . A summary is offered here and the full version including decision aids is on the MAGICapp ( www.magicapp.org ), for all devices in multilayered formats. Those reading and using these recommendations should consider individual patient circumstances, and their values and preferences and may want to use consultation decision aids in MAGICapp to facilitate shared decision making with patients. We encourage adaptation and contextualisation of our recommendations to local contexts. Those considering use or adaptation of content may go to MAGICapp to link or extract its content or contact The BMJ for permission to reuse content in this article.

We thank Alison Hoens for critical review of the recommendation and manuscript. We also thank Tahira Devji for expertly leading the systematic review of minimally important differences.

Funding: This guideline was not funded.

Competing interests: All authors have completed the BMJ Rapid Recommendations interests disclosure form, and a detailed, contextualised description of all disclosures is reported in appendix 1. As with all BMJ Rapid Recommendations, the executive team and The BMJ judged that no panel member had any financial conflict of interest. Professional and academic interests are minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions.

Transparency: R Siemieniuk affirms that the manuscript is an honest, accurate, and transparent account of the recommendation being reported; that no important aspects of the recommendation have been omitted; and that any discrepancies from the recommendation as planned (and, if relevant, registered) have been explained.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

• ↵ Englund M, Guermazi A, Gale D, et al. Incidental meniscal findings on knee MRI in middle-aged and elderly persons. N Engl J Med 2008 ; 359 : 1108 - 15 . doi:10.1056/NEJMoa0800777 pmid:18784100 . OpenUrl
• ↵ Nguyen US, Zhang Y, Zhu Y, Niu J, Zhang B, Felson DT. Increasing prevalence of knee pain and symptomatic knee osteoarthritis: survey and cohort data. Ann Intern Med 2011 ; 155 : 725 - 32 . doi:10.7326/0003-4819-155-11-201112060-00004 pmid:22147711 . OpenUrl
• ↵ Turkiewicz A, Gerhardsson de Verdier M, Engström G, et al. Prevalence of knee pain and knee OA in southern Sweden and the proportion that seeks medical care. Rheumatology (Oxford) 2015 ; 54 : 827 - 35 . doi:10.1093/rheumatology/keu409 pmid:25313145 . OpenUrl
• ↵ McGrory B, Weber K, Lynott JA, et al. American Academy of Orthopaedic Surgeons. The American Academy of Orthopaedic Surgeons evidence-based clinical practice guideline on surgical management of osteoarthritis of the knee. J Bone Joint Surg Am 2016 ; 98 : 688 - 92 . doi:10.2106/JBJS.15.01311 pmid:27098328 . OpenUrl
• ↵ Skou ST, Roos EM, Laursen MB, et al. A randomized, controlled trial of total knee replacement. N Engl J Med 2015 ; 373 : 1597 - 606 . doi:10.1056/NEJMoa1505467 pmid:26488691 . OpenUrl
• Jevsevar DS. Treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg 2013 ; 21 : 571 - 6 . pmid:23996988 . OpenUrl
• National Institute for Health and Clinical Excellence. Arthroscopic knee washout, with or without debridement, for the treatment of osteoarthritis (Interventional procedures guidance IPG230). 2007. www.nice.org.uk/guidance/ipg230 .
• National Institute for Health and Clinical Excellence. Osteoarthritis: care and management (clinical guideline CG177). 2014. www.nice.org.uk/guidance/cg177 .
• Beaufils P, Roland B. ESSKA Meniscus Consensus Project. Degenerative meniscus lesions. European Society for Sports Traumatology, Knee Surgery and Arthroscopy, 2016. http://c.ymcdn.com/sites/www.esska.org/resource/resmgr/Docs/2016-meniscus-consensus-proj.pdf .
• British Orthopaedic Association, British Association for Surgery of the Knee. BOA/BASK response to media reports regarding knee arthroscopy. 2015. www.boa.ac.uk/latest-news/boabask-response-to-media-reports-regarding-knee-arthroscopy/ .
• Australian Knee Society on Arthroscopic Surgery of the Knee. Position statement from the Australian Knee Society on Arthroscopic Surgery of the Knee, including reference to the presence of osteoarthritis or degenerative joint disease. 2016. www.kneesociety.org.au/resources/aks-arthroscopy-position-statement.pdf .
• Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008 ; 16 : 137 - 62 . doi:10.1016/j.joca.2007.12.013 pmid:18279766 . OpenUrl
• Zhang W, Nuki G, Moskowitz RW, et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage 2010 ; 18 : 476 - 99 . doi:10.1016/j.joca.2010.01.013 pmid:20170770 . OpenUrl
• ↵ Cullen KA, Hall MJ, Golosinskiy A. Ambulatory surgery in the United States, 2006. Natl Health Stat Report 2009 ;( 11 ): 1 - 25 . pmid:19294964 .
• ↵ Adelani MA, Harris AH, Bowe TR, Giori NJ. Arthroscopy for knee osteoarthritis has not decreased after a clinical trial. Clin Orthop Relat Res 2016 ; 474 : 489 - 94 . doi:10.1007/s11999-015-4514-4 pmid:26290345 . OpenUrl
• ↵ Bohensky MA, Sundararajan V, Andrianopoulos N, et al. Trends in elective knee arthroscopies in a population-based cohort, 2000-2009. Med J Aust 2012 ; 197 : 399 - 403 . doi:10.5694/mja11.11645 pmid:23025737 . OpenUrl
• ↵ Hamilton DF, Howie CR. Knee arthroscopy: influence of systems for delivering healthcare on procedure rates. BMJ 2015 ; 351 : h4720 . doi:10.1136/bmj.h4720 pmid:26405226 . OpenUrl
• ↵ Thorlund JB, Hare KB, Lohmander LS. Large increase in arthroscopic meniscus surgery in the middle-aged and older population in Denmark from 2000 to 2011. Acta Orthop 2014 ; 85 : 287 - 92 . doi:10.3109/17453674.2014.919558 pmid:24800623 . OpenUrl
• ↵ Järvinen TL, Guyatt GH. Arthroscopic surgery for knee pain. BMJ 2016 ; 354 : i3934 . doi:10.1136/bmj.i3934 pmid:27439983 . OpenUrl
• ↵ Devji T, Guyatt GH, Lytvyn L, et al. Application of minimal important differences in degenerative knee disease outcomes: a systematic review and case study to inform BMJ Rapid Recommendations. BMJ Open 2017 ; 7 : e015587 . doi:10.1136/bmjopen-2016-015587 . OpenUrl
• ↵ Brignardello-Peterson R, Guyatt GH, Schandelmaier S, et al. Knee arthroscopy versus conservative management in patients with degenerative knee disease: a systematic review. BMJ Open 2017 ; 7 : e016114 . doi:10.1136/bmjopen-2017-016114 . OpenUrl
• ↵ Guyatt GH, Juniper EF, Walter SD, Griffith LE, Goldstein RS. Interpreting treatment effects in randomised trials. BMJ 1998 ; 316 : 690 - 3 . doi:10.1136/bmj.316.7132.690 pmid:9522799 . OpenUrl
• ↵ Gauffin H, Tagesson S, Meunier A, Magnusson H, Kvist J. Knee arthroscopic surgery is beneficial to middle-aged patients with meniscal symptoms: a prospective, randomised, single-blinded study. Osteoarthritis Cartilage 2014 ; 22 : 1808 - 16 . doi:10.1016/j.joca.2014.07.017 pmid:25086401 . OpenUrl
• ↵ Kirkley A, Birmingham TB, Litchfield RB, et al. A randomized trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med 2008 ; 359 : 1097 - 107 . doi:10.1056/NEJMoa0708333 pmid:18784099 . OpenUrl
• ↵ Sihvonen R, Englund M, Turkiewicz A, Järvinen TL. Finnish Degenerative Meniscal Lesion Study Group. Mechanical symptoms and arthroscopic partial meniscectomy in patients with degenerative meniscus tear: a secondary analysis of a randomized trial. Ann Intern Med 2016 ; 164 : 449 - 55 . doi:10.7326/M15-0899 pmid:26856620 . OpenUrl
• ↵ Sihvonen R, Paavola M, Malmivaara A, et al. Finnish Degenerative Meniscal Lesion Study (FIDELITY) Group. Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. N Engl J Med 2013 ; 369 : 2515 - 24 . doi:10.1056/NEJMoa1305189 pmid:24369076 . OpenUrl
• ↵ Lubowitz JH, Ayala M, Appleby D. Return to activity after knee arthroscopy. Arthroscopy 2008 ; 24 : 58 - 61.e4 . doi:10.1016/j.arthro.2007.07.026 pmid:18182203 . OpenUrl
• ↵ Pihl K, Roos EM, Nissen N, JøRgensen U, Schjerning J, Thorlund JB. Over-optimistic patient expectations of recovery and leisure activities after arthroscopic meniscus surgery. Acta Orthop 2016 ; 87 : 615 - 21 . doi:10.1080/17453674.2016.1228411 pmid:27622598 . OpenUrl
• ↵ de Rooij M, van der Leeden M, Heymans MW, et al. Prognosis of pain and physical functioning in patients with knee osteoarthritis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2016 ; 68 : 481 - 92 . doi:10.1002/acr.22693 pmid:26316234 . OpenUrl
• ↵ Marsh JD, Birmingham TB, Giffin JR, et al. Cost-effectiveness analysis of arthroscopic surgery compared with non-operative management for osteoarthritis of the knee. BMJ Open 2016 ; 6 : e009949 . doi:10.1136/bmjopen-2015-009949 pmid:26758265 . OpenUrl
• ↵ Andrews JC, Schünemann HJ, Oxman AD, et al. GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation’s direction and strength. J Clin Epidemiol 2013 ; 66 : 726 - 35 . doi:10.1016/j.jclinepi.2013.02.003 pmid:23570745 . OpenUrl
• ↵ Kise NJ, Risberg MA, Stensrud S, Ranstam J, Engebretsen L, Roos EM. Exercise therapy versus arthroscopic partial meniscectomy for degenerative meniscal tear in middle aged patients: randomised controlled trial with two year follow-up. BMJ 2016 ; 354 : i3740 . doi:10.1136/bmj.i3740 pmid:27440192 . OpenUrl
• ↵ Khan M, Evaniew N, Bedi A, Ayeni OR, Bhandari M. Arthroscopic surgery for degenerative tears of the meniscus: a systematic review and meta-analysis. CMAJ 2014 ; 186 : 1057 - 64 . doi:10.1503/cmaj.140433 pmid:25157057 . OpenUrl
• ↵ Thorlund JB, Juhl CB, Roos EM, Lohmander LS. Arthroscopic surgery for degenerative knee: systematic review and meta-analysis of benefits and harms. BMJ 2015 ; 350 : h2747 . doi:10.1136/bmj.h2747 pmid:26080045 . OpenUrl
• ↵ Siemieniuk RA, Agoritsas T, Macdonald H, Guyatt GH, Brandt L, Vandvik PO. Introduction to BMJ Rapid Recommendations. BMJ 2016 ; 354 : i5191 . doi:10.1136/bmj.i5191 pmid:27680768 . OpenUrl
• ↵ Vandvik PO, Otto CM, Siemieniuk RA, et al. Transcatheter or surgical aortic valve replacement for patients with severe, symptomatic, aortic stenosis at low to intermediate surgical risk: a clinical practice guideline. BMJ 2016 ; 354 : i5085 . doi:10.1136/bmj.i5085 pmid:27680583 . OpenUrl
• ↵ Guyatt GH, Oxman AD, Vist GE, et al. GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008 ; 336 : 924 - 6 . doi:10.1136/bmj.39489.470347.AD pmid:18436948 . OpenUrl

Information

• Author Services

Initiatives

You are accessing a machine-readable page. In order to be human-readable, please install an RSS reader.

All articles published by MDPI are made immediately available worldwide under an open access license. No special permission is required to reuse all or part of the article published by MDPI, including figures and tables. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited. For more information, please refer to https://www.mdpi.com/openaccess .

Feature papers represent the most advanced research with significant potential for high impact in the field. A Feature Paper should be a substantial original Article that involves several techniques or approaches, provides an outlook for future research directions and describes possible research applications.

Feature papers are submitted upon individual invitation or recommendation by the scientific editors and must receive positive feedback from the reviewers.

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

Original Submission Date Received: .

• Active Journals
• Find a Journal
• Proceedings Series
• For Authors
• For Reviewers
• For Editors
• For Librarians
• For Publishers
• For Societies
• For Conference Organizers
• Open Access Policy
• Institutional Open Access Program
• Special Issues Guidelines
• Editorial Process
• Research and Publication Ethics
• Article Processing Charges
• Testimonials
• Preprints.org
• SciProfiles
• Encyclopedia

Article Menu

• Subscribe SciFeed
• Recommended Articles
• PubMed/Medline
• Google Scholar
• on Google Scholar
• Table of Contents

Find support for a specific problem in the support section of our website.

Please let us know what you think of our products and services.

Visit our dedicated information section to learn more about MDPI.

JSmol Viewer

Degenerative meniscus in knee osteoarthritis: from pathology to treatment.

1. Introduction

2. meniscus structures and functions, 3. meniscus pathology and knee oa, 3.1. traumatic meniscal tears, 3.2. degenerative meniscus lesions, 3.3. meniscal extrusion, 4. treatment for degenerative meniscal lesions, 4.1. meniscectomy versus conservative treatment, 4.2. meniscus preservation surgery, 4.3. knee osteotomy, 4.4. meniscus replacement, 4.5. orthobiologics, 5. conclusions, author contributions, institutional review board statement, informed consent statement, acknowledgments, conflicts of interest, abbreviations.

• Jang, S.; Lee, K.; Ju, J.H. Recent Updates of Diagnosis, Pathophysiology, and Treatment on Osteoarthritis of the Knee. Int. J. Mol. Sci. 2021 , 22 , 2619. [ Google Scholar ] [ CrossRef ]
• Magnusson, K.; Turkiewicz, A.; Snoeker, B.; Hughes, V.; Englund, M. The heritability of doctor-diagnosed traumatic and degenerative meniscus tears. Osteoarthr. Cartil. 2021 , 29 , 979–985. [ Google Scholar ] [ CrossRef ]
• Zhang, Y.; Jordan, J.M. Epidemiology of osteoarthritis. Clin. Geriatr. Med. 2010 , 26 , 355–369. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Katano, H.; Ozeki, N.; Kohno, Y.; Nakagawa, Y.; Koga, H.; Watanabe, T.; Jinno, T.; Sekiya, I. Trends in arthroplasty in Japan by a complete survey, 2014–2017. J. Orthop. Sci. 2021 , 26 , 812–822. [ Google Scholar ] [ CrossRef ]
• Latourte, A.; Kloppenburg, M.; Richette, P. Emerging pharmaceutical therapies for osteoarthritis. Nat. Rev. Rheumatol. 2020 , 16 , 673–688. [ Google Scholar ] [ CrossRef ]
• Kraus, V.B.; Blanco, F.J.; Englund, M.; Karsdal, M.A.; Lohmander, L.S. Call for standardized definitions of osteoarthritis and risk stratification for clinical trials and clinical use. Osteoarthr. Cartil. 2015 , 23 , 1233–1241. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Driban, J.B.; Davis, J.E.; Lu, B.; Price, L.L.; Ward, R.J.; MacKay, J.W.; Eaton, C.B.; Lo, G.H.; Barbe, M.F.; Zhang, M.; et al. Accelerated Knee Osteoarthritis Is Characterized by Destabilizing Meniscal Tears and Preradiographic Structural Disease Burden. Arthritis Rheumatol. 2019 , 71 , 1089–1100. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Englund, M.; Paradowski, P.T.; Lohmander, L.S. Association of radiographic hand osteoarthritis with radiographic knee osteoarthritis after meniscectomy. Arthritis Rheumatol. 2004 , 50 , 469–475. [ Google Scholar ] [ CrossRef ]
• Englund, M.; Lohmander, L.S. Risk factors for symptomatic knee osteoarthritis fifteen to twenty-two years after meniscectomy. Arthritis Rheumatol. 2004 , 50 , 2811–2819. [ Google Scholar ] [ CrossRef ]
• Englund, M.; Guermazi, A.; Gale, D.; Hunter, D.J.; Aliabadi, P.; Clancy, M.; Felson, D.T. Incidental meniscal findings on knee MRI in middle-aged and elderly persons. N. Engl. J. Med. 2008 , 359 , 1108–1115. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Sihvonen, R.; Paavola, M.; Malmivaara, A.; Itala, A.; Joukainen, A.; Nurmi, H.; Kalske, J.; Jarvinen, T.L.; Finnish Degenerative Meniscal Lesion Study Group. Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. N. Engl. J. Med. 2013 , 369 , 2515–2524. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Katz, J.N.; Brophy, R.H.; Chaisson, C.E.; de Chaves, L.; Cole, B.J.; Dahm, D.L.; Donnell-Fink, L.A.; Guermazi, A.; Haas, A.K.; Jones, M.H.; et al. Arthroscopic Partial Meniscectomy Was Not More Effective Than Physical Therapy for Meniscal Tear and Knee Osteoarthritis. J. Bone Jt. Surg. Ser. A 2013 , 95 , 2058. [ Google Scholar ] [ CrossRef ]
• Beaufils, P.; Becker, R.; Kopf, S.; Englund, M.; Verdonk, R.; Ollivier, M.; Seil, R. Surgical management of degenerative meniscus lesions: The 2016 ESSKA meniscus consensus. Joints 2017 , 5 , 59–69. [ Google Scholar ] [ CrossRef ]
• Wadhwa, V.; Omar, H.; Coyner, K.; Khazzam, M.; Robertson, W.; Chhabra, A. ISAKOS classification of meniscal tears-illustration on 2D and 3D isotropic spin echo MR imaging. Eur. J. Radiol. 2016 , 85 , 15–24. [ Google Scholar ] [ CrossRef ]
• Ozeki, N.; Seil, R.; Krych, A.J.; Koga, H. Surgical treatment of complex meniscus tear and disease: State of the Art. J. ISAKOS 2020 , 6 , 35–45. [ Google Scholar ] [ CrossRef ]
• Krych, A.J.; Reardon, P.J.; Johnson, N.R.; Mohan, R.; Peter, L.; Levy, B.A.; Stuart, M.J. Non-operative management of medial meniscus posterior horn root tears is associated with worsening arthritis and poor clinical outcome at 5-year follow-up. Knee Surg. Sports Traumatol. Arthrosc. 2017 , 25 , 383–389. [ Google Scholar ] [ CrossRef ]
• Takahashi, A.; Umehara, J.; Kamimura, M.; Aizawa, T.; Itoi, E. Obesity is a risk factor for osteoarthritis progression and spontaneous osteoporosis is a risk for the development of spontaneous osteonecrosis in patients with medial meniscus posterior root tear. J. Orthop. Sci. 2021 , 26 , 844–849. [ Google Scholar ] [ CrossRef ]
• Fox, A.J.; Wanivenhaus, F.; Burge, A.J.; Warren, R.F.; Rodeo, S.A. The human meniscus: A review of anatomy, function, injury, and advances in treatment. Clin. Anat. 2015 , 28 , 269–287. [ Google Scholar ] [ CrossRef ]
• Fairbank, T.J. Knee joint changes after meniscectomy. J. Bone Jt. Surg. Br. 1948 , 30B , 664–670. [ Google Scholar ] [ CrossRef ]
• Fukubayashi, T.; Kurosawa, H. The contact area and pressure distribution pattern of the knee: A study of normal and osteoarthrotic knee joints. Acta Orthop. Scand. 1980 , 51 , 871–879. [ Google Scholar ] [ CrossRef ]
• Arnoczky, S.P.; Warren, R.F. Microvasculature of the human meniscus. Am. J. Sports Med. 1982 , 10 , 90–95. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Hagmeijer, M.H.; Hevesi, M.; Desai, V.S.; Sanders, T.L.; Camp, C.L.; Hewett, T.E.; Stuart, M.J.; Saris, D.B.F.; Krych, A.J. Secondary Meniscal Tears in Patients with Anterior Cruciate Ligament Injury: Relationship Among Operative Management, Osteoarthritis, and Arthroplasty at 18-Year Mean Follow-up. Am. J. Sports Med. 2019 , 47 , 1583–1590. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Behairy, N.H.; Dorgham, M.A.; Khaled, S.A. Accuracy of routine magnetic resonance imaging in meniscal and ligamentous injuries of the knee: Comparison with arthroscopy. Int. Orthop. 2009 , 33 , 961–967. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Shiozaki, Y.; Horibe, S.; Mitsuoka, T.; Nakamura, N.; Toritsuka, Y.; Shino, K. Prediction of reparability of isolated semilunar lateral meniscus tears by magnetic resonance imaging. Knee Surg. Sports Traumatol. Arthrosc. 2002 , 10 , 213–217. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Nourissat, G.; Beaufils, P.; Charrois, O.; Selmi, T.A.; Thoreux, P.; Moyen, B.; Cassard, X.; French Society of Arthroscopy. Magnetic resonance imaging as a tool to predict reparability of longitudinal full-thickness meniscus lesions. Knee Surg. Sports Traumatol. Arthrosc. 2008 , 16 , 482–486. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Bedi, A.; Kelly, N.; Baad, M.; Fox, A.J.S.; Ma, Y.; Warren, R.F.; Maher, S.A. Dynamic Contact Mechanics of Radial Tears of the Lateral Meniscus: Implications for Treatment. Arthrosc. J. Arthrosc. Relat. Surg. 2012 , 28 , 372–381. [ Google Scholar ] [ CrossRef ]
• Forkel, P.; Reuter, S.; Sprenker, F.; Achtnich, A.; Herbst, E.; Imhoff, A.; Petersen, W. Different patterns of lateral meniscus root tears in ACL injuries: Application of a differentiated classification system. Knee Surg. Sports Traumatol. Arthrosc. 2015 , 23 , 112–118. [ Google Scholar ] [ CrossRef ]
• Minami, T.; Muneta, T.; Sekiya, I.; Watanabe, T.; Mochizuki, T.; Horie, M.; Katagiri, H.; Otabe, K.; Ohara, T.; Katakura, M.; et al. Lateral meniscus posterior root tear contributes to anterolateral rotational instability and meniscus extrusion in anterior cruciate ligament-injured patients. Knee Surg. Sports Traumatol. Arthrosc. 2018 , 26 , 1174–1181. [ Google Scholar ] [ CrossRef ]
• Allaire, R.; Muriuki, M.; Gilbertson, L.; Harner, C.D. Biomechanical consequences of a tear of the posterior root of the medial meniscus. Similar to total meniscectomy. J. Bone Jt. Surg. Am. 2008 , 90 , 1922–1931. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Hussain, Z.B.; Chahla, J.; Mandelbaum, B.R.; Gomoll, A.H.; LaPrade, R.F. The Role of Meniscal Tears in Spontaneous Osteonecrosis of the Knee: A Systematic Review of Suspected Etiology and a Call to Revisit Nomenclature. Am. J. Sports Med. 2019 , 47 , 501–507. [ Google Scholar ] [ CrossRef ]
• Bhatia, S.; LaPrade, C.M.; Ellman, M.B.; LaPrade, R.F. Meniscal root tears: Significance, diagnosis, and treatment. Am. J. Sports Med. 2014 , 42 , 3016–3030. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Kumm, J.; Roemer, F.W.; Guermazi, A.; Turkiewicz, A.; Englund, M. Natural History of Intrameniscal Signal Intensity on Knee MR Images: Six Years of Data from the Osteoarthritis Initiative. Radiology 2016 , 278 , 164–171. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Mesiha, M.; Zurakowski, D.; Soriano, J.; Nielson, J.H.; Zarins, B.; Murray, M.M. Pathologic characteristics of the torn human meniscus. Am. J. Sports Med. 2007 , 35 , 103–112. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Pauli, C.; Grogan, S.P.; Patil, S.; Otsuki, S.; Hasegawa, A.; Koziol, J.; Lotz, M.K.; D’Lima, D.D. Macroscopic and histopathologic analysis of human knee menisci in aging and osteoarthritis. Osteoarthr. Cartil. 2011 , 19 , 1132–1141. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Englund, M.; Guermazi, A.; Roemer, F.W.; Aliabadi, P.; Yang, M.; Lewis, C.E.; Torner, J.; Nevitt, M.C.; Sack, B.; Felson, D.T. Meniscal tear in knees without surgery and the development of radiographic osteoarthritis among middle-aged and elderly persons: The Multicenter Osteoarthritis Study. Arthritis Rheumatol. 2009 , 60 , 831–839. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Khan, H.; Chou, L.; Aitken, T.; McBride, A.; Ding, C.; Blizzard, L. Correlation between changes in global knee structures assessed by magnetic resonance imaging and radiographic osteoarthritis changes over ten years in a midlife cohort. Arthritis Care Res. 2016 , 68 , 958–964. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Badlani, J.T.; Borrero, C.; Golla, S.; Harner, C.D.; Irrgang, J.J. The effects of meniscus injury on the development of knee osteoarthritis: Data from the osteoarthritis initiative. Am. J. Sports Med. 2013 , 41 , 1238–1244. [ Google Scholar ] [ CrossRef ]
• Katz, J.N.; Losina, E. Surgery versus physical therapy for meniscal tear and osteoarthritis. N. Engl. J. Med. 2013 , 369 , 677–678. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Katz, J.N.; Shrestha, S.; Losina, E.; Jones, M.H.; Marx, R.G.; Mandl, L.A.; Levy, B.A.; MacFarlane, L.A.; Spindler, K.P.; Silva, G.S.; et al. Five-Year Outcome of Operative and Nonoperative Management of Meniscal Tear in Persons Older Than Forty-Five Years. Arthritis Rheumatol. 2020 , 72 , 273–281. [ Google Scholar ] [ CrossRef ]
• Swamy, N.; Wadhwa, V.; Bajaj, G.; Chhabra, A.; Pandey, T. Medial meniscal extrusion: Detection, evaluation and clinical implications. Eur. J. Radiol. 2018 , 102 , 115–124. [ Google Scholar ] [ CrossRef ]
• Hada, S.; Ishijima, M.; Kaneko, H.; Kinoshita, M.; Liu, L.; Sadatsuki, R.; Futami, I.; Yusup, A.; Takamura, T.; Arita, H.; et al. Association of medial meniscal extrusion with medial tibial osteophyte distance detected by T2 mapping MRI in patients with early-stage knee osteoarthritis. Arthritis Res. Ther. 2017 , 19 , 201. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Krych, A.J.; Bernard, C.D.; Leland, D.P.; Camp, C.L.; Johnson, A.C.; Finnoff, J.T.; Stuart, M.J. Isolated meniscus extrusion associated with meniscotibial ligament abnormality. Knee Surg. Sports Traumatol. Arthrosc. 2020 , 28 , 3599–3605. [ Google Scholar ] [ CrossRef ]
• Adams, J.G.; McAlindon, T.; Dimasi, M.; Carey, J.; Eustace, S. Contribution of meniscal extrusion and cartilage loss to joint space narrowing in osteoarthritis. Clin. Radiol. 1999 , 54 , 502–506. [ Google Scholar ] [ CrossRef ]
• Hunter, D.J.; Zhang, Y.Q.; Tu, X.; Lavalley, M.; Niu, J.B.; Amin, S.; Guermazi, A.; Genant, H.; Gale, D.; Felson, D.T. Change in joint space width: Hyaline articular cartilage loss or alteration in meniscus? Arthritis Rheumatol. 2006 , 54 , 2488–2495. [ Google Scholar ] [ CrossRef ]
• Roemer, F.W.; Zhang, Y.; Niu, J.; Lynch, J.A.; Crema, M.D.; Marra, M.D.; Nevitt, M.C.; Felson, D.T.; Hughes, L.B.; El-Khoury, G.Y.; et al. Tibiofemoral joint osteoarthritis: Risk factors for MR-depicted fast cartilage loss over a 30-month period in the multicenter osteoarthritis study. Radiology 2009 , 252 , 772–780. [ Google Scholar ] [ CrossRef ]
• Roemer, F.W.; Kwoh, C.K.; Hannon, M.J.; Green, S.M.; Jakicic, J.M.; Boudreau, R.; Crema, M.D.; Moore, C.E.; Guermazi, A. Risk factors for magnetic resonance imaging-detected patellofemoral and tibiofemoral cartilage loss during a six-month period: The joints on glucosamine study. Arthritis Rheumatol. 2012 , 64 , 1888–1898. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Wenger, A.; Englund, M.; Wirth, W.; Hudelmaier, M.; Kwoh, K.; Eckstein, F.; OAI Investigators. Relationship of 3D meniscal morphology and position with knee pain in subjects with knee osteoarthritis: A pilot study. Eur. Radiol. 2012 , 22 , 211–220. [ Google Scholar ] [ CrossRef ]
• Roubille, C.; Raynauld, J.P.; Abram, F.; Paiement, P.; Dorais, M.; Delorme, P.; Bessette, L.; Beaulieu, A.D.; Martel-Pelletier, J.; Pelletier, J.P. The presence of meniscal lesions is a strong predictor of neuropathic pain in symptomatic knee osteoarthritis: A cross-sectional pilot study. Arthritis Res. Ther. 2014 , 16 , 507. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Costa, C.R.; Morrison, W.B.; Carrino, J.A. Medial meniscus extrusion on knee MRI: Is extent associated with severity of degeneration or type of tear? AJR Am. J. Roentgenol. 2004 , 183 , 17–23. [ Google Scholar ] [ CrossRef ]
• Ding, C.; Martel-Pelletier, J.; Pelletier, J.P.; Abram, F.; Raynauld, J.P.; Cicuttini, F.; Jones, G. Knee meniscal extrusion in a largely non-osteoarthritic cohort: Association with greater loss of cartilage volume. Arthritis Res. Ther. 2007 , 9 , R21. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Crema, M.D.; Roemer, F.W.; Felson, D.T.; Englund, M.; Wang, K.; Jarraya, M.; Nevitt, M.C.; Marra, M.D.; Torner, J.C.; Lewis, C.E.; et al. Factors associated with meniscal extrusion in knees with or at risk for osteoarthritis: The Multicenter Osteoarthritis study. Radiology 2012 , 264 , 494–503. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Sharma, L.; Nevitt, M.; Hochberg, M.; Guermazi, A.; Roemer, F.W.; Crema, M.; Eaton, C.; Jackson, R.; Kwoh, K.; Cauley, J.; et al. Clinical significance of worsening versus stable preradiographic MRI lesions in a cohort study of persons at higher risk for knee osteoarthritis. Ann. Rheum. Dis. 2016 , 75 , 1630–1636. [ Google Scholar ] [ CrossRef ]
• Hunter, D.J.; Guermazi, A.; Lo, G.H.; Grainger, A.J.; Conaghan, P.G.; Boudreau, R.M.; Roemer, F.W. Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI Osteoarthritis Knee Score). Osteoarthr. Cartil. 2011 , 19 , 990–1002. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Wenger, A.; Wirth, W.; Hudelmaier, M.; Noebauer-Huhmann, I.; Trattnig, S.; Bloecker, K.; Frobell, R.B.; Kwoh, C.K.; Eckstein, F.; Englund, M. Meniscus body position, size, and shape in persons with and persons without radiographic knee osteoarthritis: Quantitative analyses of knee magnetic resonance images from the osteoarthritis initiative. Arthritis Rheumatol. 2013 , 65 , 1804–1811. [ Google Scholar ] [ CrossRef ]
• Sharma, K.; Eckstein, F.; Wirth, W.; Emmanuel, K. Meniscus position and size in knees with versus without structural knee osteoarthritis progression: Data from the osteoarthritis initiative. Skelet. Radiol. 2021 , 51 , 997–1006. [ Google Scholar ] [ CrossRef ]
• Kawaguchi, K.; Enokida, M.; Otsuki, R.; Teshima, R. Ultrasonographic evaluation of medial radial displacement of the medial meniscus in knee osteoarthritis. Arthritis Rheumatol. 2012 , 64 , 173–180. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Shimozaki, K.; Nakase, J.; Oshima, T.; Asai, K.; Toyooka, K.; Ohno, N.; Miyati, T.; Tsuchiya, H. Investigation of extrusion of the medial meniscus under full weight-loading conditions using upright weight-loading magnetic resonance imaging and ultrasonography. J. Orthop. Sci. 2020 , 25 , 652–657. [ Google Scholar ] [ CrossRef ]
• Englund, M.; Roemer, F.W.; Hayashi, D.; Crema, M.D.; Guermazi, A. Meniscus pathology, osteoarthritis and the treatment controversy. Nat. Rev. Rheumatol. 2012 , 8 , 412–419. [ Google Scholar ] [ CrossRef ]
• Pengas, I.P.; Assiotis, A.; Nash, W.; Hatcher, J.; Banks, J.; McNicholas, M.J. Total meniscectomy in adolescents: A 40-year follow-up. J. Bone Jt. Surg. Br. 2012 , 94 , 1649–1654. [ Google Scholar ] [ CrossRef ]
• Englund, M.; Roos, E.M.; Lohmander, L.S. Impact of type of meniscal tear on radiographic and symptomatic knee osteoarthritis: A sixteen-year followup of meniscectomy with matched controls. Arthritis Rheumatol. 2003 , 48 , 2178–2187. [ Google Scholar ] [ CrossRef ]
• Katano, H.; Koga, H.; Ozeki, N.; Otabe, K.; Mizuno, M.; Tomita, M.; Muneta, T.; Sekiya, I. Trends in isolated meniscus repair and meniscectomy in Japan, 2011–2016. J. Orthop. Sci. 2018 , 23 , 676–681. [ Google Scholar ] [ CrossRef ]
• Herrlin, S.V.; Wange, P.O.; Lapidus, G.; Hallander, M.; Werner, S.; Weidenhielm, L. Is arthroscopic surgery beneficial in treating non-traumatic, degenerative medial meniscal tears? A five year follow-up. Knee Surg. Sports Traumatol. Arthrosc. 2013 , 21 , 358–364. [ Google Scholar ] [ CrossRef ]
• Shelbourne, K.D.; Benner, R.W.; Gray, T. Results of Anterior Cruciate Ligament Reconstruction with Patellar Tendon Autografts: Objective Factors Associated with the Development of Osteoarthritis at 20 to 33 Years After Surgery. Am. J. Sports Med. 2017 , 45 , 2730–2738. [ Google Scholar ] [ CrossRef ]
• Paxton, E.S.; Stock, M.V.; Brophy, R.H. Meniscal repair versus partial meniscectomy: A systematic review comparing reoperation rates and clinical outcomes. Arthroscopy 2011 , 27 , 1275–1288. [ Google Scholar ] [ CrossRef ]
• Lutz, C.; Dalmay, F.; Ehkirch, F.P.; Cucurulo, T.; Laporte, C.; Le Henaff, G.; Potel, J.F.; Pujol, N.; Rochcongar, G.; Salledechou, E.; et al. Meniscectomy versus meniscal repair: 10 years radiological and clinical results in vertical lesions in stable knee. Orthop. Traumatol. Surg. Res. 2015 , 101 , S327–S331. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Okazaki, Y.; Furumatsu, T.; Yamaguchi, T.; Kodama, Y.; Kamatsuki, Y.; Masuda, S.; Okazaki, Y.; Hiranaka, T.; Zhang, X.; Ozaki, T. Medial meniscus posterior root tear causes swelling of the medial meniscus and expansion of the extruded meniscus: A comparative analysis between 2D and 3D MRI. Knee Surg. Sports Traumatol. Arthrosc. 2020 , 28 , 3405–3415. [ Google Scholar ] [ CrossRef ]
• Chung, K.S.; Noh, J.M.; Ha, J.K.; Ra, H.J.; Park, S.B.; Kim, H.K.; Kim, J.G. Survivorship Analysis and Clinical Outcomes of Transtibial Pullout Repair for Medial Meniscus Posterior Root Tears: A 5- to 10-Year Follow-up Study. Arthroscopy 2018 , 34 , 530–535. [ Google Scholar ] [ CrossRef ]
• Feucht, M.J.; Kuhle, J.; Bode, G.; Mehl, J.; Schmal, H.; Sudkamp, N.P.; Niemeyer, P. Arthroscopic Transtibial Pullout Repair for Posterior Medial Meniscus Root Tears: A Systematic Review of Clinical, Radiographic, and Second-Look Arthroscopic Results. Arthroscopy 2015 , 31 , 1808–1816. [ Google Scholar ] [ CrossRef ]
• Koga, H.; Watanabe, T.; Horie, M.; Katagiri, H.; Otabe, K.; Ohara, T.; Katakura, M.; Sekiya, I.; Muneta, T. Augmentation of the pullout repair of a medial meniscus posterior root tear by arthroscopic centralization. Arthrosc. Tech. 2017 , 6 , e1335–e1339. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Faucett, S.C.; Geisler, B.P.; Chahla, J.; Krych, A.J.; Kurzweil, P.R.; Garner, A.M.; Liu, S.; LaPrade, R.F.; Pietzsch, J.B. Meniscus Root Repair vs. Meniscectomy or Nonoperative Management to Prevent Knee Osteoarthritis After Medial Meniscus Root Tears: Clinical and Economic Effectiveness. Am. J. Sports Med. 2019 , 47 , 762–769. [ Google Scholar ] [ CrossRef ]
• Koga, H.; Muneta, T.; Yagishita, K.; Watanabe, T.; Mochizuki, T.; Horie, M.; Nakamura, T.; Okawa, A.; Sekiya, I. Arthroscopic centralization of an extruded lateral meniscus. Arthrosc. Tech. 2012 , 1 , e209–e212. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Koga, H.; Muneta, T.; Watanabe, T.; Mochizuki, T.; Horie, M.; Nakamura, T.; Otabe, K.; Nakagawa, Y.; Sekiya, I. Two-Year Outcomes After Arthroscopic Lateral Meniscus Centralization. Arthrosc. J. Arthrosc. Relat. Surg. 2016 , 32 , 2000–2008. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Daney, B.T.; Aman, Z.S.; Krob, J.J.; Storaci, H.W.; Brady, A.W.; Nakama, G.; Dornan, G.J.; Provencher, M.T.; LaPrade, R.F. Utilization of Transtibial Centralization Suture Best Minimizes Extrusion and Restores Tibiofemoral Contact Mechanics for Anatomic Medial Meniscal Root Repairs in a Cadaveric Model. Am. J. Sports Med. 2019 , 47 , 1591–1600. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Masferrer-Pino, A.; Monllau, J.C.; Abat, F.; Gelber, P.E. Capsular fixation limits graft extrusion in lateral meniscal allograft transplantation. Int. Orthop. 2019 , 43 , 2549–2556. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Ozeki, N.; Koga, H.; Matsuda, J.; Kohno, Y.; Mizuno, M.; Katano, H.; Tsuji, K.; Saito, T.; Muneta, T.; Sekiya, I. Biomechanical analysis of the centralization procedure for extruded lateral menisci with posterior root deficiency in a porcine model. J. Orthop. Sci. 2020 , 25 , 161–166. [ Google Scholar ] [ CrossRef ]
• Kubota, R.; Koga, H.; Ozeki, N.; Matsuda, J.; Kohno, Y.; Mizuno, M.; Katano, H.; Sekiya, I. The effect of a centralization procedure for extruded lateral meniscus on load distribution in porcine knee joints at different flexion angles. BMC Musculoskelet. Disord. 2020 , 21 , 205. [ Google Scholar ] [ CrossRef ]
• Kohno, Y.; Koga, H.; Ozeki, N.; Matsuda, J.; Mizuno, M.; Katano, H.; Sekiya, I. Biomechanical analysis of a centralization procedure for extruded lateral meniscus after meniscectomy in porcine knee joints. J. Orthop. Res. 2021 , 40 , 1097–1103. [ Google Scholar ] [ CrossRef ]
• Nakayama, H.; Kanto, R.; Kambara, S.; Iseki, T.; Onishi, S.; Yoshiya, S. Successful treatment of degenerative medial meniscal tears in well-alignedss knees with fibrin clot implantation. Knee Surg. Sports Traumatol. Arthrosc. 2020 , 28 , 3466–3473. [ Google Scholar ] [ CrossRef ]
• Ekhtiari, S.; Haldane, C.E.; de Sa, D.; Simunovic, N.; Musahl, V.; Ayeni, O.R. Return to Work and Sport Following High Tibial Osteotomy: A Systematic Review. J. Bone Jt. Surg. Am. 2016 , 98 , 1568–1577. [ Google Scholar ] [ CrossRef ]
• Katagiri, H.; Nakagawa, Y.; Miyatake, K.; Ohara, T.; Shioda, M.; Sekiya, I.; Koga, H. Short-Term Outcomes after High Tibial Osteotomy Aimed at Neutral Alignment Combined with Arthroscopic Centralization of Medial Meniscus in Osteoarthritis Patients. J. Knee Surg. 2021 . [ Google Scholar ] [ CrossRef ]
• Choi, H.G.; Kang, Y.S.; Kim, J.S.; Lee, H.S.; Lee, Y.S. Meniscal and Cartilage Changes on Serial MRI After Medial Opening-Wedge High Tibial Osteotomy. Orthop. J. Sports Med. 2021 , 9 , 23259671211047904. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Astur, D.C.; Novaretti, J.V.; Gomes, M.L.; Rodrigues, A.G., Jr.; Kaleka, C.C.; Cavalcante, E.L.B.; Debieux, P.; Amaro, J.T.; Cohen, M. Medial Opening Wedge High Tibial Osteotomy Decreases Medial Meniscal Extrusion and Improves Clinical Outcomes and Return to Activity. Orthop. J. Sports Med. 2020 , 8 , 2325967120913531. [ Google Scholar ] [ CrossRef ]
• Hergan, D.; Thut, D.; Sherman, O.; Day, M.S. Meniscal allograft transplantation. Arthroscopy 2011 , 27 , 101–112. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Verdonk, R.; Volpi, P.; Verdonk, P.; Van der Bracht, H.; Van Laer, M.; Almqvist, K.F.; Vander Eecken, S.; Prospero, E.; Quaglia, A. Indications and limits of meniscal allografts. Injury 2013 , 44 (Suppl. S1), S21–S27. [ Google Scholar ] [ CrossRef ]
• Zaffagnini, S.; Marcheggiani Muccioli, G.M.; Lopomo, N.; Bruni, D.; Giordano, G.; Ravazzolo, G.; Molinari, M.; Marcacci, M. Prospective long-term outcomes of the medial collagen meniscus implant versus partial medial meniscectomy: A minimum 10-year follow-up study. Am. J. Sports Med. 2011 , 39 , 977–985. [ Google Scholar ] [ CrossRef ]
• Toanen, C.; Dhollander, A.; Bulgheroni, P.; Filardo, G.; Zaffagnini, S.; Spalding, T.; Monllau, J.C.; Gelber, P.; Verdonk, R.; Beaufils, P.; et al. Polyurethane Meniscal Scaffold for the Treatment of Partial Meniscal Deficiency: 5-Year Follow-up Outcomes: A European Multicentric Study. Am. J. Sports Med. 2020 , 48 , 1347–1355. [ Google Scholar ] [ CrossRef ]
• Kohn, D.; Wirth, C.J.; Reiss, G.; Plitz, W.; Maschek, H.; Erhardt, W.; Wülker, N. Medial meniscus replacement by a tendon autograft. Experiments in sheep. J. Bone Jt. Surg. Br. 1992 , 74 , 910–917. [ Google Scholar ] [ CrossRef ]
• Ozeki, N.; Muneta, T.; Koga, H.; Katagiri, H.; Otabe, K.; Okuno, M.; Tsuji, K.; Kobayashi, E.; Matsumoto, K.; Saito, H.; et al. Transplantation of Achilles tendon treated with bone morphogenetic protein 7 promotes meniscus regeneration in a rat model of massive meniscal defect. Arthritis Rheumatol. 2013 , 65 , 2876–2886. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Johnson, L.L.; Feagin, J.A. Autogenous tendon graft substitution for absent knee joint meniscus: A pilot study. Arthroscopy 2000 , 16 , 191–196. [ Google Scholar ] [ CrossRef ]
• Ronnblad, E.; Rotzius, P.; Eriksson, K. Autologous semitendinosus tendon graft could function as a meniscal transplant. Knee Surg. Sports Traumatol. Arthrosc. 2021 . [ Google Scholar ] [ CrossRef ]
• Patel, J.M.; Merriam, A.R.; Culp, B.M.; Gatt, C.J., Jr.; Dunn, M.G. One-Year Outcomes of Total Meniscus Reconstruction Using a Novel Fiber-Reinforced Scaffold in an Ovine Model. Am. J. Sports Med. 2016 , 44 , 898–907. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Watanabe, N.; Mizuno, M.; Matsuda, J.; Nakamura, N.; Otabe, K.; Katano, H.; Ozeki, N.; Kohno, Y.; Kimura, T.; Tsuji, K.; et al. Comparison of High-Hydrostatic-Pressure Decellularized Versus Freeze-Thawed Porcine Menisci. J. Orthop. Res. 2019 , 37 , 2466–2475. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Kwon, H.; Brown, W.E.; Lee, C.A.; Wang, D.; Paschos, N.; Hu, J.C.; Athanasiou, K.A. Surgical and tissue engineering strategies for articular cartilage and meniscus repair. Nat. Rev. Rheumatol. 2019 , 15 , 550–570. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Korpershoek, J.V.; de Windt, T.S.; Hagmeijer, M.H.; Vonk, L.A.; Saris, D.B. Cell-Based Meniscus Repair and Regeneration: At the Brink of Clinical Translation? A Systematic Review of Preclinical Studies. Orthop. J. Sports Med. 2017 , 5 , 2325967117690131. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Wasserstein, D.; Dwyer, T.; Gandhi, R.; Austin, P.C.; Mahomed, N.; Ogilvie-Harris, D. A matched-cohort population study of reoperation after meniscal repair with and without concomitant anterior cruciate ligament reconstruction. Am. J. Sports Med. 2013 , 41 , 349–355. [ Google Scholar ] [ CrossRef ]
• Dean, C.S.; Chahla, J.; Matheny, L.M.; Mitchell, J.J.; LaPrade, R.F. Outcomes After Biologically Augmented Isolated Meniscal Repair with Marrow Venting Are Comparable with Those After Meniscal Repair with Concomitant Anterior Cruciate Ligament Reconstruction. Am. J. Sports Med. 2017 , 45 , 1341–1348. [ Google Scholar ] [ CrossRef ]
• Van Trommel, M.F.; Simonian, P.T.; Potter, H.G.; Wickiewicz, T.L. Arthroscopic meniscal repair with fibrin clot of complete radial tears of the lateral meniscus in the avascular zone. Arthroscopy 1998 , 14 , 360–365. [ Google Scholar ] [ CrossRef ]
• Aoki, H.; Ozeki, N.; Katano, H.; Hyodo, A.; Miura, Y.; Matsuda, J.; Takanashi, K.; Suzuki, K.; Masumoto, J.; Okanouchi, N.; et al. Relationship between medial meniscus extrusion and cartilage measurements in the knee by fully automatic three-dimensional MRI analysis. BMC Musculoskelet. Disord. 2020 , 21 , 742. [ Google Scholar ] [ CrossRef ]
• Haunschild, E.D.; Huddleston, H.P.; Chahla, J.; Gilat, R.; Cole, B.J.; Yanke, A.B. Platelet-Rich Plasma Augmentation in Meniscal Repair Surgery: A Systematic Review of Comparative Studies. Arthroscopy 2020 , 36 , 1765–1774. [ Google Scholar ] [ CrossRef ]
• Everhart, J.S.; Cavendish, P.A.; Eikenberry, A.; Magnussen, R.A.; Kaeding, C.C.; Flanigan, D.C. Platelet-Rich Plasma Reduces Failure Risk for Isolated Meniscal Repairs but Provides No Benefit for Meniscal Repairs with Anterior Cruciate Ligament Reconstruction. Am. J. Sports Med. 2019 , 47 , 1789–1796. [ Google Scholar ] [ CrossRef ]
• Whitehouse, M.R.; Howells, N.R.; Parry, M.C.; Austin, E.; Kafienah, W.; Brady, K.; Goodship, A.E.; Eldridge, J.D.; Blom, A.W.; Hollander, A.P. Repair of Torn Avascular Meniscal Cartilage Using Undifferentiated Autologous Mesenchymal Stem Cells: From In Vitro Optimization to a First-in-Human Study. Stem Cells Transl. Med. 2017 , 6 , 1237–1248. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Sakaguchi, Y.; Sekiya, I.; Yagishita, K.; Muneta, T. Comparison of human stem cells derived from various mesenchymal tissues: Superiority of synovium as a cell source. Arthritis Rheumatol. 2005 , 52 , 2521–2529. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Segawa, Y.; Muneta, T.; Makino, H.; Nimura, A.; Mochizuki, T.; Ju, Y.J.; Ezura, Y.; Umezawa, A.; Sekiya, I. Mesenchymal stem cells derived from synovium, meniscus, anterior cruciate ligament, and articular chondrocytes share similar gene expression profiles. J. Orthop. Res. 2009 , 27 , 435–441. [ Google Scholar ] [ CrossRef ] [ PubMed ]
• Sekiya, I.; Koga, H.; Otabe, K.; Nakagawa, Y.; Katano, H.; Ozeki, N.; Mizuno, M.; Horie, M.; Kohno, Y.; Katagiri, K.; et al. Additional Use of Synovial Mesenchymal Stem Cell Transplantation Following Surgical Repair of a Complex Degenerative Tear of the Medial Meniscus of the Knee: A Case Report. Cell Transplant. 2019 , 28 , 1445–1454. [ Google Scholar ] [ CrossRef ] [ PubMed ] [ Green Version ]
• Vangsness, C.T., Jr.; Farr, J., II; Boyd, J.; Dellaero, D.T.; Mills, C.R.; LeRoux-Williams, M. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: A randomized, double-blind, controlled study. J. Bone Jt. Surg. Am. 2014 , 96 , 90–98. [ Google Scholar ] [ CrossRef ] [ Green Version ]
• Olivos-Meza, A.; Perez Jimenez, F.J.; Granados-Montiel, J.; Landa-Solis, C.; Cortes Gonzalez, S.; Jimenez Aroche, C.A.; Valdez Chavez, M.; Renan Leon, S.; Gomez-Garcia, R.; Martinez-Lopez, V.; et al. First Clinical Application of Polyurethane Meniscal Scaffolds with Mesenchymal Stem Cells and Assessment of Cartilage Quality with T2 Mapping at 12 Months. Cartilage 2021 , 13 , 197S–207S. [ Google Scholar ] [ CrossRef ]

Click here to enlarge figure

Share and Cite

Ozeki, N.; Koga, H.; Sekiya, I. Degenerative Meniscus in Knee Osteoarthritis: From Pathology to Treatment. Life 2022 , 12 , 603. https://doi.org/10.3390/life12040603

Ozeki N, Koga H, Sekiya I. Degenerative Meniscus in Knee Osteoarthritis: From Pathology to Treatment. Life . 2022; 12(4):603. https://doi.org/10.3390/life12040603

Ozeki, Nobutake, Hideyuki Koga, and Ichiro Sekiya. 2022. "Degenerative Meniscus in Knee Osteoarthritis: From Pathology to Treatment" Life 12, no. 4: 603. https://doi.org/10.3390/life12040603

Article Metrics

Article access statistics, further information, mdpi initiatives, follow mdpi.

Subscribe to receive issue release notifications and newsletters from MDPI journals

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings
• My Bibliography
• Collections
• Citation manager

Save citation to file

Email citation, add to collections.

• Create a new collection
• Add to an existing collection

Add to My Bibliography

Your saved search, create a file for external citation management software, your rss feed.

• Search in PubMed
• Search in NLM Catalog
• Add to Search

Flat foot and spinal degeneration: Evidence from nationwide population-based cohort study

Affiliations.

• 1 Department of Recreation and Sports Management, Tajen University, Pingtung, Taiwan; Department of Physical Medicine and Rehabilitation, Kaohsiung Veterans General Hospital, Pingtung Branch, Pingtung, Taiwan; Graduate Institute of Bioresources, National Pingtung University of Science and Technology, Pingtung, Taiwan. Electronic address: [email protected].
• 2 Center for Health Data Science, Chung Shan Medical University Hospital, Taichung, Taiwan; Institute of Medicine, College of Medicine, Chung Shan Medical University, Taichung, Taiwan. Electronic address: [email protected].
• 3 Office for Medical Education and Research, Kaohsiung Municipal United Hospital, Kaohsiung, Taiwan; School of Medicine, National Yang Ming University, Taipei, Taiwan; Department of Senior Citizen Service Management, Yuhing Junior College of Health Care and Management, Kaohsiung, Taiwan. Electronic address: [email protected].
• 4 Department of Recreational Sport & Health Promotion, National Pingtung University of Science and Technology, Pingtung, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan. Electronic address: [email protected].
• 5 Department of Emergency Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Recreation and Sports Management, Tajen University, Pingtung, Taiwan. Electronic address: [email protected].
• 6 Division of Allergy, Immunology and Rheumatology, Chung Shan Medical University Hospital Taichung, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan. Electronic address: [email protected].
• PMID: 33423898
• DOI: 10.1016/j.jfma.2020.12.019

Background/purpose: Flat foot can alter the lower limb alignment and cause knee and back pain. To explore the association between flat foot and spinal degeneration.

Methods: By using a claims dataset containing 1 million random samples, individuals with flat foot were identified between January 1, 2000, and December 31, 2013. The study assembled a flat foot group and a matched non-flat foot group. Definition of flat foot was according to International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. The diagnosis date was defined as the index date for follow-up initiation. The follow-up period was defined as the duration from the index date (or nested index date for controls) to the occurrence of spinal degenerative joint disease (DJD), or December 31, 2013. The primary outcome was record of spinal DJD retrieved from the same database. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), with the control group as a reference.

Results: We identified 13,965 patients (most aged <30 years, 88%); 2793 patients were assigned to the flat foot group and 11,172 individuals to the non-flat foot group matched by age, sex, and index year. The mean follow-up duration was approximately 74 months. In total, 329 (11.78%) patients in the study group and 931 (8.33%) patients in the comparison group developed spinal DJD. The adjusted HR (95% CI) of spinal DJD for study group was 1.423(1.250-1.619) compared with the control. Sensitivity analyses with propensity score match and different scenario about spinal DJD enrollment showed similar results. Subgroup analysis showed that in patients aged >45 years with history of flat foot, the adjusted hazard ratios were 1.434, 3.065, 3.110, and 2.061 in association with spondylosis, intervertebral disc disorder, cervical stenosis, thoracic-lumbar-sacral stenosis, respectively.

Conclusion: Flat foot was found to be an independent risk factor for subsequent spinal DJD.

Keywords: Flat foot; Intervertebral disc disorder; Pes planus; Spinal degeneration; Spondylosis.

Copyright © 2020 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest The authors have no conflicts of interest relevant to this article.

Similar articles

• Comparison of pedicle screw-based dynamic stabilization and fusion surgery in the treatment of radiographic adjacent-segment degeneration: a retrospective analysis of single L5-S1 degenerative spondylosis covering 4 years. Han Y, Sun J, Luo C, Huang S, Li L, Ji X, Duan X, Wang Z, Pi G. Han Y, et al. J Neurosurg Spine. 2016 Dec;25(6):706-712. doi: 10.3171/2016.4.SPINE1679. Epub 2016 Jun 24. J Neurosurg Spine. 2016. PMID: 27341057
• [Adjacent segment degeneration after lumbosacral fusion in spondylolisthesis: a retrospective radiological and clinical analysis]. Zencica P, Chaloupka R, Hladíková J, Krbec M. Zencica P, et al. Acta Chir Orthop Traumatol Cech. 2010 Apr;77(2):124-30. Acta Chir Orthop Traumatol Cech. 2010. PMID: 20447355 Czech.
• Demographic, Clinical, and Operative Factors Affecting Long-Term Revision Rates After Cervical Spine Arthrodesis. Derman PB, Lampe LP, Hughes AP, Pan TJ, Kueper J, Girardi FP, Albert TJ, Lyman S. Derman PB, et al. J Bone Joint Surg Am. 2016 Sep 21;98(18):1533-40. doi: 10.2106/JBJS.15.00938. J Bone Joint Surg Am. 2016. PMID: 27655980
• [Topping-off surgery versus double-segment fusion for treatment of lumbar degenerative disease with mid-long term follow-up]. Chen XL, Hai Y, Guan L, Liu YZ, Yang JC, Su QJ, Kang N, Meng XL, Yang L, Wang Y. Chen XL, et al. Zhonghua Yi Xue Za Zhi. 2017 Mar 21;97(11):857-863. doi: 10.3760/cma.j.issn.0376-2491.2017.11.013. Zhonghua Yi Xue Za Zhi. 2017. PMID: 28355743 Chinese.
• Total disc replacement for chronic back pain in the presence of disc degeneration. Jacobs W, Van der Gaag NA, Tuschel A, de Kleuver M, Peul W, Verbout AJ, Oner FC. Jacobs W, et al. Cochrane Database Syst Rev. 2012 Sep 12;(9):CD008326. doi: 10.1002/14651858.CD008326.pub2. Cochrane Database Syst Rev. 2012. PMID: 22972118 Review.
• Effect of Foot Rehabilitation Exercises for Painful Flat Foot in a 20-Year-Old Female: A Case Study Analysis. Kolhe PD, Sharath HV, Rathi SG, Patil DS. Kolhe PD, et al. Cureus. 2024 Apr 30;16(4):e59377. doi: 10.7759/cureus.59377. eCollection 2024 Apr. Cureus. 2024. PMID: 38817516 Free PMC article.
• A deep learning method for foot-type classification using plantar pressure images. Zhao Y, Zhou J, Qiu F, Liao X, Jiang J, Chen H, Lin X, Hu Y, He J, Chen J. Zhao Y, et al. Front Bioeng Biotechnol. 2023 Sep 11;11:1239246. doi: 10.3389/fbioe.2023.1239246. eCollection 2023. Front Bioeng Biotechnol. 2023. PMID: 37767108 Free PMC article.
• Association of Hallux Valgus with Degenerative Spinal Diseases: A Population-Based Cohort Study. Hsu TL, Lee YH, Wang YH, Chang R, Wei JC. Hsu TL, et al. Int J Environ Res Public Health. 2023 Jan 9;20(2):1152. doi: 10.3390/ijerph20021152. Int J Environ Res Public Health. 2023. PMID: 36673906 Free PMC article.
• Decision Tree-Based Foot Orthosis Prescription for Patients with Pes Planus. Jung JY, Yang CM, Kim JJ. Jung JY, et al. Int J Environ Res Public Health. 2022 Sep 30;19(19):12484. doi: 10.3390/ijerph191912484. Int J Environ Res Public Health. 2022. PMID: 36231782 Free PMC article.
• HyProCure for Pediatric Flexible Flatfoot: What Affects the Outcome. Chen C, Jiang J, Fu S, Wang C, Su Y, Mei G, Xue J, Zou J, Li X, Shi Z. Chen C, et al. Front Pediatr. 2022 Apr 14;10:857458. doi: 10.3389/fped.2022.857458. eCollection 2022. Front Pediatr. 2022. PMID: 35498774 Free PMC article.
• Search in MeSH

Related information

Linkout - more resources, full text sources.

• Elsevier Science

Other Literature Sources

• scite Smart Citations
• MedlinePlus Health Information

• Citation Manager

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

Academia.edu no longer supports Internet Explorer.

To browse Academia.edu and the wider internet faster and more securely, please take a few seconds to  upgrade your browser .

•  We're Hiring!
•  Help Center

Degenerative Joint Disease (DJD)

• Most Cited Papers
• Most Downloaded Papers
• Newest Papers
• Last »
• Entheseal Changes Follow Following
• Human Osteology Follow Following
• Long Bone Biomechanics Follow Following
• Forensic Anthropology Follow Following
• Bioarchaeology Follow Following
• Comtemporary European Philosophy, Cultural Studies, Political Philosophy Follow Following
• Paleonutrition Follow Following
• Panic Attacks Follow Following
• Social Status and Prestige Follow Following
• Hypothyroidism Follow Following

Enter the email address you signed up with and we'll email you a reset link.

• Academia.edu Journals
•   We're Hiring!
•   Help Center
• Find new research papers in:
• Health Sciences
• Earth Sciences
• Cognitive Science
• Mathematics
• Computer Science
• Academia ©2024

• Frontiers in Physiology
• Integrative Physiology
• Research Topics

The Role of Ageing in Degenerative Joint and Bone Diseases

Total Downloads

Total Views and Downloads

About this Research Topic

During the nineteenth and early twentieth centuries, an increase in life expectancy was driven mainly by improvements in sanitation, housing, and education, causing a steady decline in early and mid-life mortality. The rise of the elderly population presents several public health challenges, including an ...

Keywords : Ageing, Degenerative Joint, bone diseases, biomarkers, ageing pathways, autophagy, osteoarthritis, therapeutic targets

Important Note : All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

Topic Editors

Topic coordinators, recent articles, submission deadlines.

Submission closed.

Participating Journals

Total views.

• Demographics

No records found

total views article views downloads topic views

Top countries

Top referring sites, about frontiers research topics.

With their unique mixes of varied contributions from Original Research to Review Articles, Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author.

• 2024 Agenda and Event Details
• Registration
• Hotel and Travel
• Plenary Speakers
• Your In-Person Assembly Experience
• Your Virtual Assembly Experience
• In-Person Registration FAQs
• Virtual Assembly FAQs
• Registration FAQs
• Unauthorized Solicitation
• General Disclaimer and Other Policies
• Child Care Services
• Satellite Symposium
• Job and Fellowship Fair Exhibitor Information
• AAPM&R Business Meeting
• Exploring PM&R Open House 
• Pricing + Registration
• CME/MOC Credit Information
• Step One: Ultrasound Clinical Applications of the Extremities
• Next Step Interventional Ultrasound Course
• Interventional Spasticity Management Applications
• Step Two: Concussion and Mild TBI Live Course
• Online Modules
• Program Candidates
• WatchME Instructional Videos
• Claim Your CME
• CME Transcript
• Online Education Subscription
• Practice & Career Resources
• PM&R Knowledge NOW®
• Opioid Prescribing Training
• Future and Past Meetings
• National Grand Rounds Series
• Residents & New Graduates Virtual Course: Building the Career You Want
• AAPM&R Department Chairs Summit
• AAPM&R Resident Retreat
• Medical Student Program
• AAPM&R Endorsed Activities
• Patient-Reported Outcomes
• Participate
• Improvement Activities
• Promoting Interoperability
• Current Models
• AAPM&R Spine Care Toolkit
• AAPM&R Stroke Rehabilitation Toolkit
• AAPM&R Endorsed or Affirmed Guidelines
• Guideline Endorsement Policy
• AAPM&R Practice Guidance Statements
• Medicare Resources
• Expansion of Covered Services Provided Via Telehealth
• Technology-Based Services
• Significant Waivers and Rule Changes
• G2211 Education
• Patient Safety Notices & Resources
• Introduction
• Patient Eligibility
• Facility Regulations
• Payment: Facility
• Payment: Physician
• Measurement Tools
• Quality Measures
• Value-Based Purchasing, Narrow Networks, ACOs
• Telehealth Resources
• Medicare Physician Fee Schedule Rule
• RUC and CPT Activities
• Protecting Physiatry’s Leadership Within Rehabilitation Hospitals
• OIG IRF Medical Necessity Audit
• Telehealth Advocacy
• Call to Action
• PASC Guidance
• Consensus Process
• Collaborative Participants
• AAPM&R COVID-19 Webinars
• Pain Management
• MOC Advocacy
• Patient Advocacy
• Take Action Now
• Advocacy Wins
• AMA House of Delegates
• State PM&R Societies
• The Physiatrist's Advocacy Bag
• Contact Information for State Legislatures
• Organize a "Doctor for a Day" Program
• AAPM&R's Hill Day
• AAPM&R's Future Leaders Hill Day
• Testimony and Written Comments
• Position Statements
• Roadmap to Finding and Landing a Job in Physiatry
• PM&R Aspire Career Exploration Platform
• Find a Fellowship Program
• Job and Fellowship Fair
• Hire a PM&R Physician
• Physician Wellness Resources
• Practice and Marketing Tools
• PM&R Resource Links
• Virtual Mentoring
• Cancer Rehabilitation FAQ
• Stroke Patient Care
• CMSS Equity Matters Video Series
• FAQs and Tips
• Roadmap to Finding a Job
• Clinical Toolkits
• Self-Assessment Exam for Residents (SAE-R)
• Residents Research Packet
• Get Involved
• Find a Job or Fellowship
• Reviewing for the Boards
• Polishing Your CV
• PGY1 Advice from PM&R Residents
• Post-Residency Planning Advice (PGY3, PGY4)
• Resources for Foreign Medical Student Graduates Interested in PM&R
• Podcasts and Videos
• Roadmap to a Fellowship
• Medical Student Roadmap
• What is Physiatry
• What is the History of the Specialty
• What Does a Physiatrist Do
• What is the Difference Between Physical Therapy and Physiatry
• What Conditions Do Physiatrists Treat
• What Types of Treatments and Procedures Do Physiatrists Perform
• What Makes the Practice of Physiatry Multidisciplinary
• What is a Residency in PM&R Like
• How Can I Best Prepare to be a Good Residency Candidate
• How Should I Prepare for a PM&R Rotation
• What Rotations are Good for Someone Going Into PM&R
• What is a Career in Physiatry Like
• How Much Do Physiatrists Make
• What are Organizations in Which Physiatrists Can Participate
• What Reading Materials are Helpful to Learn More About PM&R
• PM&R Programs Map
• A Step by Step Guide to Applying for a PM&R Residency
• Q&A with Residents
• Podcasts from the Medical Student Program
• Learn About PM&R from Practicing Physicians
• Starting a PM&R Interest Group
• Member Applications
• All Member Benefits
• Advance Practice Providers: FAQs
• Member Deals
• Early Career and Fellowship
• Active Member Communities
• Member Community Resources
• Member Community Leaders
• Assembly of Delegates
• Member Community Meet-Ups
• Member Directory
• PHiT Board Nomination Process
• PHiT Ambassador Nomination Process
• ACGME Resident Review Committee
• PHiT Alumni
• Innovators & Influencers
• PM&R Awareness Ambassadors
• Award Descriptions
• Past Award Recipients
• Member Stories
• AAPM&R in the News
• Press Releases
• Academy Updates
• Physiatry News
• Members in the News
• PM&R Journal
• The Physiatrist Newsletter
• AAPM&R Connection E-Newsletter
• PHiT Newsletter Updates
• PM&R Residency Program E-Newsletter
• Medical Student E-Newsletter
• Career Corner
• Advancing PM&R Podcast Series
• Q&A Video Conversations
• Member Submitted Research
• What is a Physiatrist?
• Why Visit a PM&R Physician
• FAQs About Physiatry
• Directory of Organizations for Athletes with Disabilites
• Find a PM&R Physician
• Conditions and Treatments Page Volunteers
• History of the Specialty
• Foundation for PM&R
• History of AAPM&R
• Strategic Plan
• Member Insights
• Advancing the Awareness and Value of PM&R
• About PM&R BOLD
• Cancer Rehabilitation Medicine Practice Area
• Musculoskeletal Care Practice Area
• Pain Management and Spine Rehabilitation Practice Area
• Pediatric Rehabilitation Medicine Practice Area
• Rehabilitation Care Continuum Practice Area
• The Path to the Vision
• About Learning Collaboratives
• Principles of Inclusion and Engagement
• Critical Conversations on Equity, Access, and Inclusion in PM&R, Health Care, and Society
• Board of Governors
• PM&R Editorial Board
• Past Presidents
• Articles I through V
• Articles VI through VIII
• Articles IX through XI
• Articles XII through XVIII
• Anti-Harassment Policy
• Volunteer Opportunities
• Current Volunteer Resources
• Open AAPM&R Call Fors
• 2025 AAPM&R Slate
• Current Opportunities
• Industry Relations Council
• Institution Partners Council
• Disclosures and Policies
• Year-Round Sponsors
• Staff Directory
• Alphabetical Staff Listing
• Careers at AAPM&R

Degenerative Joint Disease

About Physiatry

Do you work with an institution or company looking to learn more about physiatry?

Learn more about partnerships with AAPM&R .

PM&R Knowledge NOW® Authors Needed

Participate in the development of PM&R Knowledge NOW® by applying to be an author of a 1,700-word summary of a clinical topic. View a list of available topics and learn more about how to apply . Volunteering your time and expertise to is a great way to get published and recognized among your peers as a participant in this ground-breaking initiative!

(Advertisement)

Condition: Degenerative joint disease, also known as osteoarthritis (OA), is a common “wear and tear” disease.  The underlying cause of this condition is typically chronic repetitive motion that results in inflammation and structural joint damage.  Inflammation causes pain, redness, and swelling. The tiniest amount of trauma triggers inflammation as the body attempts to clean-up/protect damaged tissue.  This cycle of joint damage and inflammation leads to the break-down of cartilage that serves as a smooth gliding surface and cushion in the joints.  Any joint can be affected, but frequently found in the knees, hands, hips, and spine.  

Background: More than 50% of adults over the age of 65 are affected by degenerative joint disease. This condition is associated with pain, loss of function, and reduced endurance, ultimately leading to weight gain and associated complications.

Risk Factors: Predisposing factors include repetitive motion, infection, rheumatoid arthritis, post-joint trauma, muscular dystrophy, osteoporosis, hormone disorders, obesity, sickle cell disease, and bone disorders. OA equally occurrence in men and women before age 55 but increases in women after that. Knee OA is more common in African American women. Higher rates are observed in the knees of women and the hips in men.

History and Symptoms: Patients may have pain, stiffness, limited range of motion, loss of flexibility, swelling, weakness deformed joints, and damaged cartilage. As the disease progresses, joint pain and discomfort that could be relieved with rest become persistent and limit activity and reduce the quality of life. 

Physical Exam: Physical examination will focus on the joint range of motion, structure, tenderness, and strength of the associated muscles. Walking ability will be examined, as well. Evaluation of self-care and depression in the face of chronic pain are also necessary.

Diagnostic Process: OA is often diagnosed by physicians trained in muscles and bones, such as a PM&R physician, using a patient’s history, physical exam, imaging, and sometimes other techniques.  Imaging used includes X-rays, MRI, CT, or bone scans. Other techniques include fluid removal from an affected joint that is analyzed, and arthroscopy, which involves the insertion of a small scope into the joint, can be used to view the damage.

Rehab Management: Arthritis is managed best initially by a physical medicine and rehabilitation (PM&R) physician who is highly trained in the conservative treatment of joint and muscle problems. Treatment methods used include weight loss, acetaminophen, NSAIDs, corticosteroid injections, viscosupplementation and rehabilitation. Viscosupplementation has recently become more common as it helps to alleviate arthritis pain through injection of a gel-like substance that mimics the natural lubricant created in the joint to allow more “cushion” within the joint.  If pain is still persistent regardless of conservative management, a referral from a PM&R physician to an orthopedic surgeon may be necessary to consider total joint arthroplasty.

Other Resources for Patients and Families: Patient and family education about weight reduction, exercise, and use of pain medications is beneficial. Several organizations can offer information and support for patients and families.

For Patients and Families:

View all Conditions & Treatments Learn more about Physiatry

Patient and Family Handouts (printable PDF):

Degenerative Joint Disease - English

Enfermedad degenerativa de las articulaciones - Español

Physicians:

Read the full PM&R Knowledge Now ® article: 

Warning: The NCBI web site requires JavaScript to function. more...

An official website of the United States government

The .gov means it's official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings
• Browse Titles

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Osteoarthritis.

Rouhin Sen ; John A. Hurley .

Affiliations

Last Update: February 20, 2023 .

• Continuing Education Activity

Osteoarthritis (OA) is the most common form of arthritis in the world. It can be classified into two categories: primary osteoarthritis and secondary osteoarthritis. Classically, OA presents with joint pain and loss of function; however, the disease is clinically very variable and can present merely as an asymptomatic incidental finding to a devastating and permanently disabling disorder. This activity reviews the etiology, presentation, evaluation, and management of osteoarthritis and reviews the interprofessional team's role in evaluating, diagnosing, and managing the condition.

• Describe in detail the pathophysiology of primary and secondary osteoarthritis.
• Review the components of a proper evaluation of a patient presenting with osteoarthritis, including any indicated imaging studies.
• Discuss the various treatment options available for osteoarthritis.
• Evaluate possible interprofessional team strategies for improving care coordination and communication to advance the evaluation and treatment of osteoarthritis and improve outcomes.
• Introduction

Osteoarthritis (OA) is the most common form of arthritis in the world. It can be classified into 2 categories: primary osteoarthritis and secondary osteoarthritis. Classically, OA presents with joint pain and loss of function; however, the disease is clinically very variable and can present merely as an asymptomatic incidental finding to a devastating and permanently disabling disorder. [1] [2] [3]

Risk factors for developing OA include age, female gender, obesity, anatomical factors, muscle weakness, and joint injury (occupation/sports activities).

Primary OA is the most common subset of the disease and is diagnosed in the absence of a predisposing trauma or disease but is associated with the risk factors listed above.

Secondary OA occurs with a preexisting joint abnormality. Predisposing conditions include trauma or injury, congenital joint disorders, inflammatory arthritis, avascular necrosis, infectious arthritis, Paget disease, osteopetrosis, osteochondritis dissecans, metabolic disorders (hemochromatosis, Wilson’s disease), hemoglobinopathy, Ehlers-Danlos syndrome, or Marfan syndrome. [4] [5]

• Epidemiology

OA affects about 3.3 to 3.6% of the population globally. It causes moderate to severe disability in 43 million people, making it the 11th most debilitating disease worldwide. In the United States, it is estimated that 80% of the population over 65 years old has radiographic evidence of OA, although only 60% of this subset has symptoms. This is because radiographic OA is at least twice as common as symptomatic OA. Therefore, radiographic changes do not prove that OA is the cause of the patient’s joint pain. In 2011, there were almost 1 million hospitalizations for OA, with an aggregate cost of nearly $15 billion, making it the second most expensive disease seen in the United States. [1] [3]

• Pathophysiology

OA is a disease of the entire joint sparing no tissues. The cause of OA is an interplay of risk factors (mentioned above), mechanical stress, and abnormal joint mechanics. The combination leads to pro-inflammatory markers and proteases that eventually mediate joint destruction. The complete pathway that leads to the destruction of the entire joint is unknown.

Usually, the earliest changes that occur in OA are at the level of the articular cartilage that develops surface fibrillation, irregularity, and focal erosions. These erosions eventually extend down to the bone and continually expand to involve more of the joint surface. On a microscopic level, after cartilage injury, the collagen matrix is damaged, causing chondrocytes to proliferate and form clusters. A phenotypic change to hypertrophic chondrocyte occurs, causing cartilage outgrowths that ossify and form osteophytes. As more of the collagen matrix is damaged, chondrocytes undergo apoptosis. Improperly mineralized collagen causes subchondral bone thickening; in advanced disease, bone cysts infrequently occur. Even rarer, bony erosions appear in erosive OA.

There is also some degree of synovial inflammation and hypertrophy, although this is not the inciting factor as is the case with inflammatory arthritis. Soft-tissue structures (ligaments, joint capsule, menisci) are also affected. In end-stage OA, both calcium phosphate and calcium pyrophosphate dihydrate crystals are present. Their role is unclear, but they are thought to contribute to synovial inflammation. [6] [7] [8]

• History and Physical

The presentation and progression of OA vary greatly from person to person. The triad of symptoms of OA is joint pain, stiffness, and locomotor restriction. Patients can also present with muscle weakness and balance issues.

Pain is typically related to activity and resolves with rest. In those patients in whom the disease progresses, pain is more continuous and begins to affect activities of daily living, eventually causing severe limitations in function. Patients may also experience bony swelling, joint deformity, and instability (patients complain that the joint is “giving way” or “buckling,” a sign of muscle weakness).

OA typically affects proximal and distal interphalangeal joints, first carpometacarpal (CMC) joints, hips, knees, first metatarsophalangeal joints, and joints of the lower cervical and lumbar spine. OA can be monoarticular or polyarticular in the presentation. Joints can be at different stages of disease progression. Typical exam findings in OA include bony enlargement, crepitus, effusions (non-inflammatory), and a limited range of motions. Tenderness may be present at joint lines, and there may be pain upon passive motion. Classic physical exam findings in hand OA include Heberden’s nodes (posterolateral swellings of DIP joints), Bouchard’s nodes (posterolateral swellings of PIP joints), and “squaring” at the base of the thumb (first CMC joints). See Image.  Osteoarthritis, Hand.

A thorough history and physical exam (with a focused musculoskeletal exam) should be performed on all patients, with some findings summarized above. OA is a clinical diagnosis and can be diagnosed with confidence if the following are present: 1) pain worse with activity and better with rest, 2) age more than 45 years, 3) morning stiffness lasting less than 30 minutes, 4) bony joint enlargement, and 5) limitation in range of motion. A differential diagnosis should include rheumatoid arthritis, psoriatic arthritis, crystalline arthritis, hemochromatosis, bursitis, avascular necrosis, tendinitis, radiculopathy, among other soft tissue abnormalities. [9] [10]

Blood tests such as CBC, ESR, rheumatoid factor, ANA are usually normal in OA, although they may be ordered to rule out inflammatory arthritis. If the synovial fluid is obtained, the white blood cell count should be less than 2000/microL, predominantly mononuclear cells (non-inflammatory), which is consistent with a diagnosis of OA.

X-rays of the affected joint can show findings consistent with OA, such as marginal osteophytes, joint space narrowing, subchondral sclerosis, and cysts; however, radiographic findings do not correlate to the severity of disease and may not be present early in the disease. MRI is not routinely indicated for OA workup; however, it can detect OA at earlier stages than normal radiographs. Ultrasound can also identify synovial inflammation, effusion, and osteophytes which can be related to OA.

There are several classification systems for OA. In general, they include the effects on joints, the age of onset, radiographic appearance, presumed etiology (primary vs. secondary), and rate of progression. The American College of Rheumatology classification is the most widely used classification system. At this time, it is not possible to predict which patients will progress to severe OA and which patients will have their disease arrest at earlier stages.

• Treatment / Management

Treatment goals for OA are to minimize both pain and functional loss. Comprehensive management of the disease involves both non-pharmacologic and pharmacologic therapies. Typically, patients with mild symptoms can be managed by the former, while more advanced diseases need a combination of both. [11] [12] [13]

Mainstays for non-pharmacologic therapy include 1) avoidance of activities exacerbating pain or overloading the joint, 2) exercise to improve strength, 3) weight loss, and 4) occupational therapy for unloading joints via brace, splint, cane, or crutch. Weight loss is a critical intervention in those who are overweight and obese; each pound of weight loss can decrease the load across the knee 3 to 6-fold. Formal physical therapy can immensely assist patients in using equipment such as canes appropriately while also instructing them on exercises. Exercise programs that combine both aerobic and resistance training have been shown to decrease pain and improve physical function in multiple trials and should be encouraged by physicians regularly. Malalignment of joints should be corrected via mechanical means such as realignment knee brace or orthotics.

Pharmacotherapy of OA involves oral, topical, and/or intraarticular options. Acetaminophen and oral NSAIDs are the most popular and affordable options for OA and are usually the initial choice of pharmacologic treatment. NSAIDs are usually prescribed orally or topically and, initially, should be started as needed rather than scheduled. Due to gastrointestinal toxicity, and renal and cardiovascular side effects, oral NSAIDs should be used very cautiously with close monitoring long term. Topical NSAIDs are less efficacious than their oral counterparts but offer fewer gastrointestinal and other systemic side effects; however, they often cause local skin irritation.

Intraarticular joint injections can also be an effective treatment for OA, especially in a setting of acute pain. Glucocorticoid injections have a variable response, and there is ongoing controversy regarding repeated injections. Hyaluronic acid injections are another option, but their efficacy over placebo is also controversial. Notably, there is no role for oral glucocorticoids.

Duloxetine has modest efficacy in OA; opioids can be used in those patients without an adequate response to the above and who may not be candidates for surgery or refuse it altogether.

It is important to note that patients vary greatly in their response to treatment, and there is a large component of trial and error in selecting the agents that will be most effective. In those patients specifically with knee or hip OA who have failed multiple non-pharmacologic and pharmacologic treatment modalities, surgery is the next option. Failure rates for both knee and hip replacements are quite low, and they can provide pain relief and increased functionality. The timing of surgery is key to predict success. Very poor functional status and considerable muscle weakness may not lead to improved postoperative functional status versus those undergoing surgery earlier in the disease course. [14] [15]

• Differential Diagnosis

Differentials include:

• Rheumatoid arthritis
• Psoriatic arthritis
• Crystalline arthritis
• Hemochromatosis
• Avascular necrosis
• Radiculopathy
• Other soft-tissue conditions

The prognosis for osteoarthritis patients depends on which joints are affected and the level of symptomatology and functional impairment. Some patients remain relatively unaffected by osteoarthritis, while others can experience severe disability. In some cases, joint replacement surgery offers the best long-term outcome.

• Complications
• Difficulty ambulation
• Joint malalignment
• Decreased range of motion of the joint
• Radiculopathies
• Postoperative and Rehabilitation Care

Lifestyle changes - especially enrollment in exercise and weight reduction.

• Deterrence and Patient Education

The clinical team needs to explain the etiology and pathophysiology of the arthritic process and outline the plan for intervention, which will vary significantly based on the degree of pathology, joints affected, level of dysfunction, age of the patient, expectations for future activities, and what is therapeutically possibly. Compliance with medication, weight loss, and exercise/physical therapy routines must be stressed.

• Enhancing Healthcare Team Outcomes

Osteoarthritis is a chronic progressive disorder that affects millions of people with advancing age. The condition has no cure and is managed by a team of healthcare professionals that include an internist, radiologist, endocrinologist, orthopedic surgeon, and rheumatologist. The nurse, pharmacist, and physical therapist are also integral members of the interprofessional healthcare team. Only through cohesive activity and communication involving all healthcare disciplines are optimal results achievable. [Level 5]

Patients with osteoarthritis require education on the natural history of the disease and understand their treatment options. Obese patients need a dietary consult and enroll in an exercise program. Evidence shows that water-based activities can help relieve symptoms and improve joint function; hence consultation with a physical therapist is recommended. Further, many of these patients may benefit from a walking aid. Patients with pain should become familiar with the types of drugs and supplements available and their potential adverse effects. Only through the education of the patient can the morbidity of this disorder be decreased. [16] [17] [18]  [Level 5]

Evidence-Based Outcomes

The prognosis for osteoarthritis patients depends on the joint involved, how many joints are involved, and the severity. There is no cure for osteoarthritis, and all the currently available treatments are directed towards reducing symptoms. Factors associated with the rapid progression of the disease include obesity, advanced age, multiple joint involvement, and the presence of varus deformity. Patients who undergo joint replacement tend to have a good prognosis with success rates of over 80%. However, most prosthetic joints wear out in 10 to 15 years, and repeat surgery is required. Also important is that patients must undergo preoperative workup as the post-surgical complications can be serious and disabling. [19] [20] [21]  [Level 5]

• Review Questions
• Access free multiple choice questions on this topic.
• Comment on this article.

Osteoarthritis, Hand. This image shows osteoarthritis of the first metatarsal phalangeal joint. Note the dorsal-lateral erosion and exposed subchondral bone. Contributed by MA Dreyer, DPM, FACFAS

Disclosure: Rouhin Sen declares no relevant financial relationships with ineligible companies.

Disclosure: John Hurley declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Sen R, Hurley JA. Osteoarthritis. [Updated 2023 Feb 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

In this Page

Bulk download.

• Bulk download StatPearls data from FTP

Related information

• PMC PubMed Central citations
• PubMed Links to PubMed

Similar articles in PubMed

• Review Peripheral Mechanisms Contributing to Osteoarthritis Pain. [Curr Rheumatol Rep. 2018] Review Peripheral Mechanisms Contributing to Osteoarthritis Pain. Syx D, Tran PB, Miller RE, Malfait AM. Curr Rheumatol Rep. 2018 Feb 26; 20(2):9. Epub 2018 Feb 26.
• Arthroscopic lavage and debridement for osteoarthritis of the knee: an evidence-based analysis. [Ont Health Technol Assess Ser....] Arthroscopic lavage and debridement for osteoarthritis of the knee: an evidence-based analysis. Medical Advisory Secretariat. Ont Health Technol Assess Ser. 2005; 5(12):1-37. Epub 2005 Sep 1.
• Review Prevalence of acromioclavicular joint osteoarthritis in people not seeking care: A systematic review. [J Orthop. 2022] Review Prevalence of acromioclavicular joint osteoarthritis in people not seeking care: A systematic review. Rossano A, Manohar N, Veenendaal WJ, van den Bekerom MPJ, Ring D, Fatehi A. J Orthop. 2022 Jul-Aug; 32:85-91. Epub 2022 May 20.
• Review Diagnosis and Treatment of Hip and Knee Osteoarthritis: A Review. [JAMA. 2021] Review Diagnosis and Treatment of Hip and Knee Osteoarthritis: A Review. Katz JN, Arant KR, Loeser RF. JAMA. 2021 Feb 9; 325(6):568-578.
• Measurement of serum C-reactive protein concentration for discriminating between suppurative arthritis and osteoarthritis in dogs. [BMC Vet Res. 2016] Measurement of serum C-reactive protein concentration for discriminating between suppurative arthritis and osteoarthritis in dogs. Hillström A, Bylin J, Hagman R, Björhall K, Tvedten H, Königsson K, Fall T, Kjelgaard-Hansen M. BMC Vet Res. 2016 Oct 28; 12(1):240. Epub 2016 Oct 28.

Recent Activity

• Osteoarthritis - StatPearls Osteoarthritis - StatPearls

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Connect with NLM

National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894

Web Policies FOIA HHS Vulnerability Disclosure

Help Accessibility Careers