Skip to main content

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.

  • Review Article
  • Published:

Etiology of osteoarthritis: genetics and synovial joint development

Nature Reviews Rheumatology volume 8, pages 77–89 (2012)Cite this article

Subjects

Abstract

Osteoarthritis (OA) has a considerable hereditary component and is considered to be a polygenic disease. Data derived from genetic analyses and genome-wide screening of individuals with this disease have revealed a surprising trend: genes associated with OA tend to be related to the process of synovial joint development. Mutations in these genes might directly cause OA. In addition, they could also determine the age at which OA becomes apparent, the joint sites involved, the severity of the disease and how rapidly it progresses. In this Review, I propose that genetic mutations associated with OA can be placed on a continuum. Early-onset OA is caused by mutations in matrix molecules often associated with chondrodysplasias, whereas less destructive structural abnormalities or mutations confer increased susceptibility to injury or malalignment that can result in middle-age onset. Finally, mutations in molecules that regulate subtle aspects of joint development and structure lead to late-onset OA. In this Review, I discuss the genetics of OA in general, but focus on the potential effect of genetic mutations associated with OA on joint structure, the role of joint structure in the development of OA—using hip abnormalities as a model—and how understanding the etiology of the disease could influence treatment.

Key Points

  • Genetic factors play a key part in the etiology of all subtypes of osteoarthritis (OA), including primary OA, early-onset OA with chondrodysplasia and post-traumatic OA

  • A major risk factor for OA is an imperfect joint structure—ranging from the obvious defects of hip dysplasia to subtle alterations resulting from mutation of a developmental gene

  • Participation of a gene associated with OA in the formation of an imperfect joint could occur during development and might affect the ability of mature cartilage to be repaired

  • Mutations in genes encoding different components of the same pathway could have the same influence on susceptibility to OA as each other

  • Genes associated with OA do not have to be expressed exclusively in cartilage but could also be important for the development, function or repair of bone, tendon, ligament or menisci

  • Whether genetic risk factors for OA eventually manifest as clinical disease can depend on other physical, environmental and biochemical stresses that are placed on the joint

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: OA can be viewed as a continuum.
Figure 2: Schematic diagram of the hip joint architecture.
Figure 3: Risk factors for OA vary in their contribution to susceptibility over time.

Similar content being viewed by others

References

  1. Lawrence, R. C. et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 58, 26–35 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Guccione, A. A. et al. The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. Am. J. Public Health 84, 351–358 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Spector, T. D., Cicuttini, F., Baker, J., Loughlin, J. & Hart, D. Genetic influences on osteoarthritis in women: a twin study. BMJ 312, 940–943 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bijkerk, C. et al. Heritabilities of radiologic osteoarthritis in peripheral joints and of disc degeneration of the spine. Arthritis Rheum. 42, 1729–1735 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Jordan, J. M., Kraus, V. B. & Hochberg, M. C. Genetics of osteoarthritis. Curr. Rheumatol. Rep. 6, 7–13 (2004).

    Article  PubMed  Google Scholar 

  6. Cicuttini, F. M. & Spector, T. D. Genetics of osteoarthritis. Ann. Rheum. Dis. 55, 665–667 (2006).

    Article  Google Scholar 

  7. Kerkhof, H. J. et al. Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium. Osteoarthritis Cartilage 19, 254–264 (2011).

    Article  CAS  PubMed  Google Scholar 

  8. Panoutsopoulou, K. et al. Concise report: insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study. Ann. Rheum. Dis. 70, 864–867 (2011).

    Article  CAS  Google Scholar 

  9. Valdes, A. M. et al. Involvement of different risk factors in clinically severe large joint osteoarthritis according to the presence of hand interphalangeal nodes. Arthritis Rheum. 62, 2688–2695 (2010).

    Article  PubMed  Google Scholar 

  10. Bos, S. D., Slagboom, P. E. & Meulenbelt, I. New insights into osteoarthritis: early developmental features of an ageing-related disease. Curr. Opin. Rheumatol. 20, 553–559 (2008).

    Article  PubMed  Google Scholar 

  11. Valdes, A. M. & Spector, T. D. The genetic predisposition to osteoarthritis. IBMS BoneKEy 6, 181–189 (2009).

    Article  Google Scholar 

  12. Evangelou, E. et al. Large-scale analysis of association between GDF5 and FRZB variants and osteoarthritis of the hip, knee, and hand. Arthritis Rheum. 60, 1710–1721 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Loughlin, J. Knee osteoarthritis, lumbar-disc degeneration and developmental dysplasia of the hip—an emerging genetic overlap. Arthritis Res. Ther. 13, 108 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Aigner, T., Haag, J., Martin, J. & Buckwalter, J. Osteoarthritis: aging of matrix and cells—going for a remedy. Curr. Drug Targets 8, 325–331 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Goldring, M. B. & Goldring, S. R. Osteoarthritis. J. Cell Physiol. 213, 626–634 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Hashimoto, S., Ochs, R. L., Komiya, S. & Lotz, M. Linkage of chondrocyte apoptosis and cartilage degradation in human osteoarthritis. Arthritis Rheum. 41, 1632–1638 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Sandell, L. J., Hering, T. & Heinegard, D. Cell Biology, Biochemistry and Molecular and Cell Biology of Articular Cartilage in Osteoarthritis 4th edn (eds Moskowitz, R. et al.) 73–106 (Lippincott, Williams & Wilkins, USA, 2007).

    Google Scholar 

  18. Sandell, L. J. Anabolic factors in degenerative joint disease. Curr. Drug Targets 8, 359–365 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Kamekura, S. et al. Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheum. 54, 2462–2470 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Smith, M. & Little, C. B. Experimental models of osteoarthritis in Osteoarthritis 4th edn (eds Moskowitz, R. et al.) 107–125 (Lippincott, Williams & Wilkins, USA, 2007).

    Google Scholar 

  21. Gregory, J. S. et al. Early identification of radiographic osteoarthritis of the hip using an active shape model to quantify changes in bone morphometric features: can hip shape tell us anything about the progression of osteoarthritis? Arthritis Rheum. 56, 3634–3643 (2007).

    Article  PubMed  Google Scholar 

  22. Reichenbach, S. et al. Prevalence of bone attrition on knee radiographs and MRI in a community-based cohort. Osteoarthritis Cartilage 16, 1005–1010 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. van Spil, W. E., DeGroot, J., Lems, W. F., Oostveen, J. C. & Lafeber, F. P. Serum and urinary biochemical markers for knee and hip-osteoarthritis: a systematic review applying the consensus BIPED criteria. Osteoarthritis Cartilage 18, 605–612 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Kellgren, J. H., Lawrence, J. S. & Bier, F. Genetic factors in generalized osteo-arthrosis. Ann. Rheum. Dis. 22, 237–255 (1963).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lindberg, H. Prevalence of primary coxarthrosis in siblings of patients with primary coxarthrosis. Clin. Orthop. Relat. Res. 203, 273–275 (1986).

    Google Scholar 

  26. Chitnavis, J. et al. Genetic influences in end-stage osteoarthritis. Sibling risks of hip and knee replacement for idiopathic osteoarthritis. J. Bone Joint Surg. Br. 79-B, 660–664 (1997).

    Article  Google Scholar 

  27. Ala-Kokko, L., Baldwin, C. T., Moskowitz, R. W. & Prockop, D. J. Single base mutation in the type II procollagen gene (COL2A1) as a cause of primary osteoarthritis associated with a mild chondrodysplasia. Proc. Natl Acad. Sci. USA 87, 6565–6568 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Knowlton, R. G. et al. Genetic linkage and polymorphism in the type II procollagen gene (COL2A1) to primary osteoarthritis associated with mild chondrodysplasia. N. Eng. J. Med. 322, 526–530 (1990).

    Article  CAS  Google Scholar 

  29. Prockop, D. J., Ala-Kokko, L., McLain, D. A. & Williams, C. Can mutated genes cause common osteoarthritis? Br. J. Rheumatol. 36, 827–829 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Eyre, D. R., Weis, M. A. & Moskowitz, R. W. Cartilage expression of a type II collagen mutation in an inherited form of osteoarthritis associated with a mild chondrodysplasia. J. Clin. Invest. 87, 357–361 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jakkula, E. et al. The role of sequence variations within the genes encoding collagen II, IX and XI in non-syndromic, early-onset osteoarthritis. Osteoarthritis Cartilage 13, 497–507 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. McIntosh, I., Abbott, M. H. & Francomano, C. A. Concentration of mutations causing Schmid metaphyseal chondrodysplasia in the C-terminal noncollagenous domain of type X collagen. Hum. Mutat. 5, 121–125 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Harris, W. H. Etiology of osteoarthritis of the hip. Clin. Orthop. Relat. Res. 213, 20–33 (1986).

    Google Scholar 

  34. MacGregor, A. J., Antoniades, L., Matson, M., Andrew, T. & Spector, T. D. The genetic contribution to radiographic hip osteoarthritis in women: results of a classic twin study. Arthritis Rheum. 43, 2410–2416 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Mabuchi, A., Nakamura, S., Takatori, Y. & Ikegawa, S. Familial osteoarthritis of the hip joint associated with acetabular dysplasia maps to chromosome 13q. Am. J. Hum. Genet. 79, 163–168 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ganz, R. et al. Femoroacetabular impingement: a cause for osteoarthritis of the hip. Clin. Orthop. Relat. Res. 417, 112–120 (2003).

    Google Scholar 

  37. Lynch, J. A., Parimi, N., Chaganti, R. K., Nevitt, M. C. & Lane, N. E. The association of proximal femoral shape and incident radiographic hip OA in elderly women. Osteoarthritis Cartilage 17, 1313–1318 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lane, N. E. et al. Association of mild acetabular dysplasia with an increased risk of incident hip osteoarthritis in elderly white women: the study of osteoporotic fractures. Arthritis Rheum. 43, 400–404 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Doherty, M. et al. Nonspherical femoral head shape (pistol grip deformity), neck shaft angle, and risk of hip osteoarthritis: a case–control study. Arthritis Rheum. 58, 3172–3182 (2008).

    Article  PubMed  Google Scholar 

  40. Waarsing, J. H. et al. Osteoarthritis susceptibility genes influence the association between hip morphology and osteoarthritis. Arthritis Rheum. 63, 1349–1354 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Clohisy, J. C., Beaule, P. E., O'Malley, A., Safran, M. R. & Schoenecker, P. AOA symposium. Hip disease in the young adult: current concepts of etiology and surgical treatment. J. Bone Joint Surg. Am. 90, 2267–2281 (2008).

    Article  PubMed  Google Scholar 

  42. Salter, R. B. Etiology, pathogenesis and possible prevention of congenital dislocation of the hip. Can. Med. Assoc. J. 98, 933–945 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Weinstein, S. L. Natural history of congenital hip dislocation (CDH) and hip dysplasia. Clin. Orthop. Relat. Res. 225, 62–76 (1987).

    Google Scholar 

  44. Cardinal, E. & White, S. J. Imaging pediatric hip disorders and residual dysplasia of adult hips. Curr. Opin. Radiol. 4, 83–89 (1992).

    CAS  PubMed  Google Scholar 

  45. Pazzaglia, U. E., Ceciliani, L., Wilkinson, M. J. & Dell'Orbo, C. Involvement of metal particles in loosening of metal-plastic total hip prostheses. Arch. Orthop. Trauma Surg. 104, 164–174 (1985).

    Article  CAS  PubMed  Google Scholar 

  46. Demirjian, Z., Sara, M., Stulberg, D. & Harris, W. H. Disseminated intravascular coagulation in patients undergoing orthopedic surgery. Clin. Orthop. Relat. Res. 102, 174–180 (1974).

    Article  Google Scholar 

  47. Murphy, G., Hembry, R., Hughes, C. E., Fosang, A. J. & Hardingham, T. E. Role and regulation of metalloproteinases in connective tissue turnover. Biochem. Soc. Trans. 18, 812–815 (1990).

    Article  CAS  PubMed  Google Scholar 

  48. Murray, R. O. The aetiology of primary osteoarthritis of the hip. Br. J. Radiol. 38, 810–824 (1965).

    Article  CAS  PubMed  Google Scholar 

  49. Weinstein, S. L. Congenital hip dislocation. Long-range problems, residual signs, and symptoms after successful treatment. Clin. Orthop. Relat. Res. 281, 69–74 (1992).

    Google Scholar 

  50. Dai, J. et al. Association of a single nucleotide polymorphism in growth differentiate factor 5 with congenital dysplasia of the hip: a case–control study. Arthritis Res. Ther. 10, R126 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Rouault, K. et al. Evidence of association between GDF5 polymorphisms and congenital dislocation of the hip in a Caucasian population. Osteoarthritis Cartilage 18, 1144–1149 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Williams, F. et al. GDF5 single-nucleotide polymorphism rs143383 is associated with lumbar disc disease in Northern European women. Arthritis Rheum. 63, 708–712 (2010).

    Article  CAS  Google Scholar 

  53. Lane, N. E. et al. Frizzled-related protein variants are risk factors for hip osteoarthritis. Arthritis Rheum. 54, 1246–1254 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Shi, D. et al. Association of the D repeat polymorphism in the ASPN gene with developmental dysplasia of the hip: a case-control study in Han Chinese. Arthritis Res. Ther. 13, R27 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Jiang, Q. et al. Replication of the association of the aspartic acid repeat polymorphism in the asporin gene with knee-osteoarthritis susceptibility in Han Chinese. J. Hum. Genet. 51, 1068–1072 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Song, Y. Q. et al. Association of the asporin D14 allele with lumbar-disc degeneration in Asians. Am. J. Hum. Genet. 82, 744–747 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Feldman, G. et al. The Otto Aufranc Award: Identification of a 4 Mb region on chromosome 17q21 linked to developmental dysplasia of the hip in one 18-member, multigeneration family. Clin. Orthop. Relat. Res. 468, 337–344 (2010).

    Article  PubMed  Google Scholar 

  58. Rouault, K. et al. Do HOXB9 and COL1A1 genes play a role in congenital dislocation of the hip? Study in a Caucasian population. Osteoarthritis Cartilage 17, 1099–1105 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Kapoor, B. et al. Vitamin D and oestrogen receptor polymorphisms in developmental dysplasia of the hip and primary protrusio acetabuli—a preliminary study. J. Negat. Results Biomed. 6, 7 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Rubini, M., Cavallaro, A., Calzolari, E., Bighetti, G. & Sollazzo, V. Exclusion of COL2A1 and VDR as developmental dysplasia of the hip genes. Clin. Orthop. Relat. Res. 466, 878–883 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Farquhar, T., Bertram, J., Todhunter, R. J., Burton-Wurster, N. & Lust, G. Variations in composition of cartilage from the shoulder joints of young adult dogs at risk for developing canine hip dysplasia. J. Am. Vet. Med. Assoc. 210, 1483–1485 (1997).

    CAS  PubMed  Google Scholar 

  62. Lust, G. et al. Joint laxity and its association with hip dysplasia in Labrador retrievers. Am. J. Vet. Res. 54, 1990–1999 (1993).

    CAS  PubMed  Google Scholar 

  63. Cardinet, G. H. 3rd & Lust, G. The international symposium on hip dysplasia and osteoarthritis in dogs. J. Am. Vet. Med. Assoc. 210, 1417–1418 (1997).

    PubMed  Google Scholar 

  64. Todhunter, R. J. et al. An outcrossed canine pedigree for linkage analysis of hip dysplasia. J. Hered. 90, 83–92 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Nakamura, S., Ninomiya, S. & Nakamura, T. Primary osteoarthritis of the hip joint in Japan. Clin. Orthop. Relat. Res. 241, 190–196 (1989).

    Google Scholar 

  66. Yoshimura, N. et al. Acetabular dysplasia and hip osteoarthritis in Britain and Japan. Br. J. Rheumatol. 37, 1193–1197 (1998).

    Article  CAS  PubMed  Google Scholar 

  67. Clements, D. N., Carter, S. D., Innes, J. F. & Ollier, W. E. Genetic basis of secondary osteoarthritis in dogs with joint dysplasia. Am. J. Vet. Res. 67, 909–918 (2006).

    Article  CAS  PubMed  Google Scholar 

  68. Zhou, Z. et al. Differential genetic regulation of canine hip dysplasia and osteoarthritis. PLoS One 5, e13219 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Jacobsen, S. Adult hip dysplasia and osteoarthritis. Studies in radiology and clinical epidemiology. Acta Orthop. Suppl. 77, 1–37 (2006).

    Article  PubMed  Google Scholar 

  70. Friedenberg, S. G. et al. Evaluation of a fibrillin 2 gene haplotype associated with hip dysplasia and incipient osteoarthritis in dogs. Am. J. Vet. Res. 72, 530–540 (2011).

    Article  PubMed  Google Scholar 

  71. Zhang, H., Hu, W. & Ramirez, F. Developmental expression of fibrillin genes suggests heterogeneity of extracellular microfibrils. J. Cell Biol. 129, 1165–1176 (1995).

    Article  CAS  PubMed  Google Scholar 

  72. Parker, H. G. et al. An expressed FGF4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs. Science 325, 995–998 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Horton, W. E. et al. An association between an aggrecan polymorphic allele and bilateral hand osteoarthritis in elderly white men: data from the Baltimore Longitudinal Study of Aging (BLSA). Osteoarthritis Cartilage 6, 245–251 (1998).

    Article  PubMed  Google Scholar 

  74. Klaue, K., Durnin, C. W. & Ganz, R. The acetabular rim syndrome. A clinical presentation of dysplasia of the hip. J. Bone Joint Surg. Br. 73-B, 423–429 (1991).

    Article  Google Scholar 

  75. Leunig, M. et al. Fibrocystic changes at anterosuperior femoral neck: prevalence in hips with femoroacetabular impingement. Radiology 236, 237–246 (2005).

    Article  PubMed  Google Scholar 

  76. Loughlin, J. et al. Functional variants within the secreted frizzled-related protein 3 gene are associated with hip osteoarthritis in females. Proc. Natl Acad. Sci. USA 101, 9757–9762 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Lories, R. J. et al. Articular cartilage and biomechanical properties of the long bones in Frzb-knockout mice. Arthritis Rheum. 56, 4095–4103 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Kerkhof, H. J. et al. A genome-wide association study identifies an osteoarthritis susceptibility locus on chromosome 7q22. Arthritis Rheum. 62, 499–510 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Evangelou, E. et al. Meta-analysis of genome-wide association studies confirms a susceptibility locus for knee osteoarthritis on chromosome 7q22. Ann. Rheum. Dis. 70, 349–355 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Zhai, G. et al. A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: the Treat-OA consortium. J. Med. Genet. 46, 614–616 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Valdes, A. M. et al. Genome-wide association scan identifies a prostaglandin-endoperoxide synthase 2 variant involved in risk of knee osteoarthritis. Am. J. Hum. Genet. 82, 1231–1240 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Miyamoto, Y. et al. Common variants in DVWA on chromosome 3p24.3 are associated with susceptibility to knee osteoarthritis. Nat. Genet. 40, 994–998 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Wagener, R., Gara, S. K., Kobbe, B., Paulsson, M. & Zaucke, F. The knee osteoarthritis susceptibility locus DVWA on chromosome 3p24.3 is the 5' part of the split COL6A4 gene. Matrix Biol. 28, 307–310 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Valdes, A. M. et al. Association of the DVWA and GDF5 polymorphisms with osteoarthritis in UK populations. Ann. Rheum. Dis. 68, 1916–1920 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Meulenbelt, I. et al. Large replication study and meta-analyses of DVWA as an osteoarthritis susceptibility locus in European and Asian populations. Hum. Mol. Genet. 18, 1518–1523 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Heap, G. A. & van Heel, D. A. The genetics of chronic inflammatory diseases. Hum. Mol. Genet. 18, R101–R106 (2009).

    Article  CAS  PubMed  Google Scholar 

  87. Spagnoli, A. et al. TGF-β signaling is essential for joint morphogenesis. J. Cell Biol. 177, 1105–1117 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. van de Laar, I. M. et al. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat. Genet. 43, 121–126 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Kizawa, H. et al. An aspartic acid repeat polymorphism in asporin inhibits chondrogenesis and increases susceptibility to osteoarthritis. Nat. Genet. 37, 138–144 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Nakajima, M. et al. Mechanisms for asporin function and regulation in articular cartilage. J. Biol. Chem. 282, 32185–32192 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Rodriguez-Lopez, J., Pombo-Suarez, M., Liz, M., Gomez-Reino, J. J. & Gonzalez, A. Lack of association of a variable number of aspartic acid residues in the asporin gene with osteoarthritis susceptibility: case–control studies in Spanish Caucasians. Arthritis Res. Ther. 8, R55 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Atif, U. et al. Absence of association of asporin polymorphisms and osteoarthritis susceptibility in US Caucasians. Osteoarthritis Cartilage 16, 1174–1177 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Valdes, A. M. et al. Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee. Arthritis Rheum. 56, 137–146 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Nakamura, T. et al. Meta-analysis of association between the ASPN D-repeat and osteoarthritis. Hum. Mol. Genet. 16, 1676–1681 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Storm, E. E. et al. Limb alterations in brachypodism mice due to mutations in a new member of the TGFβ-superfamily. Nature 368, 639–643 (1994).

    Article  CAS  PubMed  Google Scholar 

  96. Brunet, L. J., McMahon, J. A., McMahon, A. P. & Harland, R. M. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 280, 1455–1457 (1998).

    Article  CAS  PubMed  Google Scholar 

  97. Mikic, B. Multiple effects of GDF5 deficiency on skeletal tissues: implications for therapeutic bioengineering. Ann. Biomed. Eng. 32, 466–476 (2004).

    Article  PubMed  Google Scholar 

  98. Masuya, H. et al. A novel dominant-negative mutation in Gdf5 generated by ENU mutagenesis impairs joint formation and causes osteoarthritis in mice. Hum. Mol. Genet. 16, 2366–2375 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Miyamoto, Y. et al. A functional polymorphism in the 5' UTR of GDF5 is associated with susceptibility to osteoarthritis. Nat. Genet. 39, 529–533 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Chapman, K. et al. A meta-analysis of European and Asian cohorts reveals a global role of a functional SNP in the 5' UTR of GDF5 with osteoarthritis susceptibility. Hum. Mol. Genet. 17, 1497–1504 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Valdes, A. M., Doherty, M. & Spector, T. D. The additive effect of individual genes in predicting risk of knee osteoarthritis. Ann. Rheum. Dis. 67, 124–127 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Vaes, R. B. et al. Genetic variation in the GDF5 region is associated with osteoarthritis, height, hip axis length and fracture risk: the Rotterdam study. Ann. Rheum. Dis. 68, 1754–1760 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Dodd, A. W. et al. Deep sequencing of GDF5 reveals the absence of rare variants at this important osteoarthritis susceptibility locus. Osteoarthritis Cartilage 19, 430–434 (2011).

    Article  CAS  PubMed  Google Scholar 

  104. Valdes, A. M. et al. Reproducible genetic associations between candidate genes and clinical knee osteoarthritis in men and women. Arthritis Rheum. 54, 533–539 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Borrelli, J. Jr, Silva, M. J., Zaegel, M. A., Franz, C. & Sandell, L. J. Single high-energy impact load causes posttraumatic OA in young rabbits via a decrease in cellular metabolism. J. Orthop. Res. 27, 347–352 (2009).

    Article  PubMed  Google Scholar 

  106. Tochigi, Y. et al. Distribution and progression of chondrocyte damage in a whole-organ model of human ankle intra-articular fracture. J. Bone Joint Surg. Am. 93, 533–539 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Glasson, S. S. In vivo osteoarthritis target validation utilizing genetically-modified mice. Curr. Drug Targets 8, 367–376 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Eltawil, N. M., De Bari, C., Achan, P., Pitzalis, C. & Dell'accio, F. A novel in vivo murine model of cartilage regeneration. Age and strain-dependent outcome after joint surface injury. Osteoarthritis Cartilage 17, 695–704 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ward, B. D. et al. Absence of posttraumatic arthritis following intraarticular fracture in the MRL/MpJ mouse. Arthritis Rheum. 58, 744–753 (2008).

    Article  PubMed  Google Scholar 

  110. Dell'accio, F., De Bari, C., Eltawil, N. M., Vanhummelen, P. & Pitzalis, C. Identification of the molecular response of articular cartilage to injury, by microarray screening: Wnt16 expression and signaling after injury and in osteoarthritis. Arthritis Rheum. 58, 1410–1421 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Herrero-Beaumont, G., Roman-Blas, J. A., Castaňeda, S. & Jimenez, S. A. Primary osteoarthritis no longer primary: three subsets with distinct etiological, clinical, and therapeutic characteristics. Semin. Arthritis Rheum. 39, 71–80 (2009).

    Article  PubMed  Google Scholar 

  112. McGonagle, D., Tan, A. L., Carey, J. & Benjamin, M. The anatomical basis for a novel classification of osteoarthritis and allied disorders. J. Anat. 216, 279–291 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Moskowitz, R. W. Specific gene defects leading to osteoarthritis. J. Rheumatol. Suppl. 70, 16–21 (2004).

    PubMed  Google Scholar 

  114. Takahashi, H. et al. Prediction model for knee osteoarthritis based on genetic and clinical information. Arthritis Res. Ther. 12, R187 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Blom, A. B., van Lent, P. L., van der Kraan, P. M. & van den Berg, W. B. To seek shelter from the Wnt in osteoarthritis? Wnt-signaling as a target for osteoarthritis therapy. Curr. Drug Targets 11, 620–629 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Blagojevic, M., Jinks, C., Jeffery, A. & Jordan, K. P. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage 18, 24–33 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Mustafa, Z. et al. Investigating the aspartic acid (D) repeat of asporin as a risk factor for osteoarthritis in a UK Caucasian population. Arthritis Rheum. 52, 3502–3506 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Kaliakatsos, M. et al. Asporin and knee osteoarthritis in patients of Greek origin. Osteoarthritis Cartilage 14, 609–611 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Valdes, A. M. et al. Association study of candidate genes for the prevalence and progression of knee osteoarthritis. Arthritis Rheum. 50, 2497–2507 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Meulenbelt, I. et al. Identification of DIO2 as a new susceptibility locus for symptomatic osteoarthritis. Hum. Mol. Genet. 17, 1867–1875 (2008).

    Article  CAS  PubMed  Google Scholar 

  121. Meulenbelt, H. E., Geertzen, J. H., Jonkman, M. F. & Dijkstra, P. U. Skin problems of the stump in lower limb amputees: 1. A clinical study. Acta Derm. Venereol. 91, 173–177 (2011).

    Article  PubMed  Google Scholar 

  122. Nakajima, M., Miyamoto, Y. & Ikegawa, S. Cloning and characterization of the osteoarthritis-associated gene DVWA. J. Bone Miner. Metab. 29, 300–308 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Jin, S. Y. et al. Association of estrogen receptor 1 intron 1 C/T polymorphism in Korean vitiligo patients. J. Dermatol. Sci. 35, 181–186 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Fytili, P. et al. Association of repeat polymorphisms in the estrogen receptors α, β, and androgen receptor genes with knee osteoarthritis. Clin. Genet. 68, 268–277 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. Gordon, A. et al. Variation in the secreted frizzled-related protein3 gene and risk of osteolysis and heterotopic ossification after total hip arthroplasty. J. Orthop. Res. 25, 1665–1670 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Uitterlinden, A. G. et al. Adjacent genes, for COL2A1 and the vitamin D receptor, are associated with separate features of radiographic osteoarthritis of the knee. Arthritis Rheum. 43, 1456–1464 (2000).

    Article  CAS  PubMed  Google Scholar 

  127. Urano, T. et al. Association of a single nucleotide polymorphism in the WISP1 gene with spinal osteoarthritis in postmenopausal Japanese women. J. Bone Miner. Metab. 25, 253–258 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Echtermeyer, F. et al. Syndecan4 regulates ADAMTS5 activation and cartilage breakdown in osteoarthritis. Nat. Med. 15, 1072–1076 (2009).

    Article  CAS  PubMed  Google Scholar 

  129. Glasson, S. S. et al. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature 434, 644–648 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Little, C. B. et al. Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum. 60, 3723–3733 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Lin, A. C. et al. Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat. Med. 15, 1421–1425 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. Hirata, M. et al. C/EBPβ promotes transition from proliferation to hypertrophic differentiation of chondrocytes through transactivation of p57Kip2. PLoS One 4, e4543 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Little, C. B. et al. Blocking aggrecanase cleavage in the aggrecan interglobular domain abrogates cartilage erosion and promotes cartilage repair. J. Clin. Invest. 117, 1627–1636 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author thanks J. Clohisy (Washington University School of Medicine, USA) and I. Meulenbelt (Leiden University Medical Center, The Netherlands) for their comments on the manuscript before submission; R. Todhunter (Cornell School of Veterinary Medicine, USA) for providing information prior to publication; and H. Kawaguchi (University of Tokyo Graduate School of Medicine, Japan) and C. Little (University of Sidney, Australia) for their help in producing Table 2.

Author information

Authors and Affiliations

  1. Department of Orthopedic Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, 63108, MO, USA

    Linda J. Sandell

Authors
  1. Linda J. Sandell
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sandell, L. Etiology of osteoarthritis: genetics and synovial joint development. Nat Rev Rheumatol 8, 77–89 (2012). https://doi.org/10.1038/nrrheum.2011.199

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2011.199

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing