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Pathogenesis of osteoarthritis

Richard F. Loeser, MD
Section Editor
David Hunter, MD, PhD
Deputy Editor
Monica Ramirez Curtis, MD, MPH


In the past, osteoarthritis (OA) was considered to be simply a degenerative “wear and tear” process and therefore often misnamed as degenerative joint disease. However, the pathogenesis of OA is much more complex than just wear and tear and the term “osteoarthritis,” where “-itis” is indicative of an inflammatory process, is indeed correct [1,2]. There are a variety of factors that play an important role in the pathogenesis of OA, including biomechanical factors, proinflammatory mediators, and proteases. By understanding the mechanisms driving joint tissue destruction in OA and identifying the key factors involved, new targets for therapy are emerging that will go beyond symptomatic relief to slowing or stopping the progression of OA [3].

This topic will review the pathogenesis of OA. The diagnosis, treatment, and other issues related to OA are discussed separately. (See "Overview of surgical therapy of knee and hip osteoarthritis" and "Investigational approaches to the management of osteoarthritis" and "Clinical manifestations and diagnosis of osteoarthritis" and "Management of knee osteoarthritis" and "Overview of the management of osteoarthritis".)


Classically, inflammatory arthritis was defined in part based on cellular inflammation represented by increased numbers of leukocytes in the affected joint tissues and synovial fluid. Classic cellular inflammation is not prominent in osteoarthritis (OA), where the number of leukocytes in the joint fluid is normally low, and rarely exceeds 1000 to 2000 cells per milliliter. This is in contrast to forms of inflammatory arthritis, such as rheumatoid arthritis (RA), where the number of synovial fluid leukocytes will commonly exceed 2000 and will be accompanied by a more extensive synovial infiltrate of leukocytes with synovial fibroblast proliferation resulting in pannus formation. Although synovial inflammation is also present in OA and in some individuals can be indistinguishable from RA, the inflammatory component of OA is best appreciated at the molecular level and is characterized by the presence of a host of proinflammatory mediators, including cytokines and chemokines, that are part of an innate immune response to joint injury [2].

As will be further discussed below, proinflammatory factors appear to be driving the production of the proteolytic enzymes responsible for the degradation of the extracellular matrix that results in joint tissue destruction. Although destruction and loss of the articular cartilage is a central component of OA, all joint tissues are affected in some way, indicating that OA is a disease of the joint as an organ [4]. Mechanical factors certainly play a key role in OA and there is some debate in the field as to the extent to which OA is mediated by abnormal joint mechanics. However, the balance of evidence suggests that rather than simply causing joint tissue damage by wear and tear, excessive or abnormal joint loading also stimulates joint tissue cells to produce proinflammatory factors and proteases that mediate joint tissue destruction. (See 'Inflammatory mediators' below and 'Proteases' below.)


Osteoarthritis (OA) is one of the most common causes of chronic disability in adults due to pain and altered joint function that result from characteristic pathologic changes in the joint tissues and their processing in a biopsychosocial context (figure 1). The pathological findings described below are present to varying degrees in all people with OA, suggesting a common response of the joint to a variety of insults.

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Literature review current through: Oct 2017. | This topic last updated: Jun 21, 2016.
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  1. Lane NE, Brandt K, Hawker G, et al. OARSI-FDA initiative: defining the disease state of osteoarthritis. Osteoarthritis Cartilage 2011; 19:478.
  2. Liu-Bryan R, Terkeltaub R. Emerging regulators of the inflammatory process in osteoarthritis. Nat Rev Rheumatol 2015; 11:35.
  3. Yu SP, Hunter DJ. Emerging drugs for the treatment of knee osteoarthritis. Expert Opin Emerg Drugs 2015; 20:361.
  4. Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum 2012; 64:1697.
  5. Sharma L, Chmiel JS, Almagor O, et al. Significance of preradiographic magnetic resonance imaging lesions in persons at increased risk of knee osteoarthritis. Arthritis Rheumatol 2014; 66:1811.
  6. Waller KA, Zhang LX, Elsaid KA, et al. Role of lubricin and boundary lubrication in the prevention of chondrocyte apoptosis. Proc Natl Acad Sci U S A 2013; 110:5852.
  7. Taljanovic MS, Graham AR, Benjamin JB, et al. Bone marrow edema pattern in advanced hip osteoarthritis: quantitative assessment with magnetic resonance imaging and correlation with clinical examination, radiographic findings, and histopathology. Skeletal Radiol 2008; 37:423.
  8. Loeuille D, Chary-Valckenaere I, Champigneulle J, et al. Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: correlating magnetic resonance imaging findings with disease severity. Arthritis Rheum 2005; 52:3492.
  9. Baker K, Grainger A, Niu J, et al. Relation of synovitis to knee pain using contrast-enhanced MRIs. Ann Rheum Dis 2010; 69:1779.
  10. Loeser RF. Aging processes and the development of osteoarthritis. Curr Opin Rheumatol 2013; 25:108.
  11. Brophy RH, Rai MF, Zhang Z, et al. Molecular analysis of age and sex-related gene expression in meniscal tears with and without a concomitant anterior cruciate ligament tear. J Bone Joint Surg Am 2012; 94:385.
  12. Roos EM, Herzog W, Block JA, Bennell KL. Muscle weakness, afferent sensory dysfunction and exercise in knee osteoarthritis. Nat Rev Rheumatol 2011; 7:57.
  13. Blagojevic M, Jinks C, Jeffery A, Jordan KP. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage 2010; 18:24.
  14. Roos H, Adalberth T, Dahlberg L, Lohmander LS. Osteoarthritis of the knee after injury to the anterior cruciate ligament or meniscus: the influence of time and age. Osteoarthritis Cartilage 1995; 3:261.
  15. Struglics A, Larsson S, Kumahashi N, et al. Changes in Cytokines and Aggrecan ARGS Neoepitope in Synovial Fluid and Serum and in C-Terminal Crosslinking Telopeptide of Type II Collagen and N-Terminal Crosslinking Telopeptide of Type I Collagen in Urine Over Five Years After Anterior Cruciate Ligament Rupture: An Exploratory Analysis in the Knee Anterior Cruciate Ligament, Nonsurgical Versus Surgical Treatment Trial. Arthritis Rheumatol 2015; 67:1816.
  16. Riordan EA, Frobell RB, Roemer FW, Hunter DJ. The health and structural consequences of acute knee injuries involving rupture of the anterior cruciate ligament. Rheum Dis Clin North Am 2013; 39:107.
  17. Kumahashi N, Swärd P, Larsson S, et al. Type II collagen C2C epitope in human synovial fluid and serum after knee injury--associations with molecular and structural markers of injury. Osteoarthritis Cartilage 2015; 23:1506.
  18. Oliveria SA, Felson DT, Cirillo PA, et al. Body weight, body mass index, and incident symptomatic osteoarthritis of the hand, hip, and knee. Epidemiology 1999; 10:161.
  19. Johnson VL, Hunter DJ. The epidemiology of osteoarthritis. Best Pract Res Clin Rheumatol 2014; 28:5.
  20. Sellam J, Berenbaum F. Is osteoarthritis a metabolic disease? Joint Bone Spine 2013; 80:568.
  21. Ratneswaran A, LeBlanc EA, Walser E, et al. Peroxisome proliferator-activated receptor δ promotes the progression of posttraumatic osteoarthritis in a mouse model. Arthritis Rheumatol 2015; 67:454.
  22. Snead MP, Yates JR. Clinical and Molecular genetics of Stickler syndrome. J Med Genet 1999; 36:353.
  23. Kannu P, Bateman JF, Randle S, et al. Premature arthritis is a distinct type II collagen phenotype. Arthritis Rheum 2010; 62:1421.
  24. Valdes AM, Spector TD. Genetic epidemiology of hip and knee osteoarthritis. Nat Rev Rheumatol 2011; 7:23.
  25. Moisio K, Chang A, Eckstein F, et al. Varus-valgus alignment: reduced risk of subsequent cartilage loss in the less loaded compartment. Arthritis Rheum 2011; 63:1002.
  26. Andriacchi TP, Favre J. The nature of in vivo mechanical signals that influence cartilage health and progression to knee osteoarthritis. Curr Rheumatol Rep 2014; 16:463.
  27. Cirillo DJ, Wallace RB, Wu L, Yood RA. Effect of hormone therapy on risk of hip and knee joint replacement in the Women's Health Initiative. Arthritis Rheum 2006; 54:3194.
  28. Hussain SM, Cicuttini FM, Bell RJ, et al. Incidence of total knee and hip replacement for osteoarthritis in relation to circulating sex steroid hormone concentrations in women. Arthritis Rheumatol 2014; 66:2144.
  29. Shane Anderson A, Loeser RF. Why is osteoarthritis an age-related disease? Best Pract Res Clin Rheumatol 2010; 24:15.
  30. Lotz M, Loeser RF. Effects of aging on articular cartilage homeostasis. Bone 2012; 51:241.
  31. Verzijl N, Bank RA, TeKoppele JM, DeGroot J. AGEing and osteoarthritis: a different perspective. Curr Opin Rheumatol 2003; 15:616.
  32. Verzijl N, DeGroot J, Thorpe SR, et al. Effect of collagen turnover on the accumulation of advanced glycation end products. J Biol Chem 2000; 275:39027.
  33. Lioté F, Ea HK. Clinical implications of pathogenic calcium crystals. Curr Opin Rheumatol 2014; 26:192.
  34. Abhishek A, Doherty M. Epidemiology of calcium pyrophosphate crystal arthritis and basic calcium phosphate crystal arthropathy. Rheum Dis Clin North Am 2014; 40:177.
  35. Sohn DH, Sokolove J, Sharpe O, et al. Plasma proteins present in osteoarthritic synovial fluid can stimulate cytokine production via Toll-like receptor 4. Arthritis Res Ther 2012; 14:R7.
  36. Little CB, Fosang AJ. Is cartilage matrix breakdown an appropriate therapeutic target in osteoarthritis--insights from studies of aggrecan and collagen proteolysis? Curr Drug Targets 2010; 11:561.
  37. Wang Q, Rozelle AL, Lepus CM, et al. Identification of a central role for complement in osteoarthritis. Nat Med 2011; 17:1674.
  38. Liu-Bryan R, Terkeltaub R. The growing array of innate inflammatory ignition switches in osteoarthritis. Arthritis Rheum 2012; 64:2055.
  39. Sofat N. Analysing the role of endogenous matrix molecules in the development of osteoarthritis. Int J Exp Pathol 2009; 90:463.
  40. Olivotto E, Otero M, Marcu KB, Goldring MB. Pathophysiology of osteoarthritis: canonical NF-κB/IKKβ-dependent and kinase-independent effects of IKKα in cartilage degradation and chondrocyte differentiation. RMD Open 2015; 1:e000061.
  41. Troeberg L, Nagase H. Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim Biophys Acta 2012; 1824:133.
  42. Tonge DP, Pearson MJ, Jones SW. The hallmarks of osteoarthritis and the potential to develop personalised disease-modifying pharmacological therapeutics. Osteoarthritis Cartilage 2014; 22:609.
  43. Loeser RF. Osteoarthritis year in review 2013: biology. Osteoarthritis Cartilage 2013; 21:1436.
  44. Luyten FP, Tylzanowski P, Lories RJ. Wnt signaling and osteoarthritis. Bone 2009; 44:522.
  45. van der Kraan PM, van den Berg WB. Osteophytes: relevance and biology. Osteoarthritis Cartilage 2007; 15:237.
  46. Blaney Davidson EN, Vitters EL, Bennink MB, et al. Inducible chondrocyte-specific overexpression of BMP2 in young mice results in severe aggravation of osteophyte formation in experimental OA without altering cartilage damage. Ann Rheum Dis 2015; 74:1257.
  47. Blom AB, Brockbank SM, van Lent PL, et al. Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1. Arthritis Rheum 2009; 60:501.
  48. 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.
  49. Gabay O, Sanchez C. Epigenetics, sirtuins and osteoarthritis. Joint Bone Spine 2012; 79:570.
  50. Tsezou A. Osteoarthritis year in review 2014: genetics and genomics. Osteoarthritis Cartilage 2014; 22:2017.
  51. Liu Q, Zhang X, Dai L, et al. Long noncoding RNA related to cartilage injury promotes chondrocyte extracellular matrix degradation in osteoarthritis. Arthritis Rheumatol 2014; 66:969.
  52. Leibiger IB, Berggren PO. Sirt1: a metabolic master switch that modulates lifespan. Nat Med 2006; 12:34.
  53. Nagai K, Matsushita T, Matsuzaki T, et al. Depletion of SIRT6 causes cellular senescence, DNA damage, and telomere dysfunction in human chondrocytes. Osteoarthritis Cartilage 2015; 23:1412.
  54. Hunter DJ, Nevitt M, Losina E, Kraus V. Biomarkers for osteoarthritis: current position and steps towards further validation. Best Pract Res Clin Rheumatol 2014; 28:61.