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:

Insights from human genetic studies into the pathways involved in osteoarthritis

Nature Reviews Rheumatology volume 9, pages 573–583 (2013)Cite this article

Subjects

Abstract

Genetic studies have revealed that most loci associated with osteoarthritis (OA) show ethnic stratification, with limited overlap between Asian and European populations. Consequently, such studies have often focused on particular ethnic groups, with those performed in European cohorts yielding the most replicated associations. As for other common diseases, the OA susceptibility loci mapped to date account for only a fraction of disease heritability. Nevertheless, analysis of these loci could identify biological pathways related to OA pathogenesis. Such an approach is taken in this Review and provides valuable insights into OA aetiology. For example, several of the loci associated with OA contain genes encoding key regulators of skeletogenesis and endochondral ossification. Furthermore, direct and indirect regulation of gene transcription is highlighted as an important factor in this disease. Interestingly, genes encoding structural proteins of the cartilage extracellular matrix do not seem to be a repository for OA susceptibility. Therefore, susceptibility might operate at a regulatory rather than a structural level, which is a potentially promising finding, as the activities of regulators are amenable to therapeutic modulation. Greater clarity will emerge as more association signals are identified; nonetheless, patterns of aetiology are clearly discernible, from a molecular perspective, even with the relatively small number currently available.

Key Points

  • The currently available data suggest that genetic risk of osteoarthritis (OA) manifests through multiple biological pathways

  • Several core pathways are implicated in OA pathogenesis, in particular those mediating skeletogenesis, encompassing development and differentiation of osteoblasts and chondrocytes

  • Genes encoding structural proteins do not seem to be major contributors to OA susceptibility

  • Transcriptional regulation is a key process associated with OA risk; several susceptibility genes encode either direct transcriptional regulators or indirect regulators that operate via cellular signalling pathways

  • Such regulators are potentially amenable to modulation, more so than structural proteins, offering the possibility of exploiting genetic advances for the development of novel therapeutics

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: Biological processes enriched for OA-associated genes and thus implicated in OA pathogenesis.
Figure 2: Interactions between OA susceptibility genes during endochondral ossification.

Similar content being viewed by others

References

  1. Reynard, L. N. & Loughlin, J. The genetics and functional analysis of primary osteoarthritis susceptibility. Expert Rev. Mol. Med. 15, e2 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jackson, G. C. et al. Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution. Hum. Mutat. 33, 144–157 (2012).

    Article  CAS  PubMed  Google Scholar 

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

  4. Yasuda, T. et al. Aberrations of 6q13 mapped to the COL12A1 locus in chondromyxoid fibroma. Mod. Pathol. 22, 1499–1506 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Panoutsopoulou K. et al. Insights into the genetic architecture of osteoarthritis from stage 1 of the arcOGEN study. Ann. Rheum. Dis. 70, 864–867 (2011).

    Article  CAS  PubMed  Google Scholar 

  6. Huang, D. W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).

    Article  CAS  Google Scholar 

  7. National Institute of Allergy and Infectious Disease (NIAID), NIH. DAVID Bioinformatics Resource 6.7 [online], (2010).

  8. Mackie, E. J., Tatarczuch, L. & Mirams, M. The skeleton: a multi-functional complex organ: the growth plate chondrocyte and endochondral ossification. J. Endocrinol. 211, 109–121 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Dreier, R. Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Res. Ther. 12, 216 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  10. 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 

  11. Day-Williams, A. G. et al. A variant in MCF2L is associated with osteoarthritis. Am. J. Hum. Genet. 89, 446–450 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 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 

  13. Geyer, M. et al. Differential transcriptome analysis of intraarticular lesional vs intact cartilage reveals new candidate genes on osteoarthritis pathophysiology. Osteoarthritis Cartilage 17, 328–335 (2009).

    Article  CAS  PubMed  Google Scholar 

  14. Karlsson, C. et al. Genome-wide expression profiling reveals new candidate genes associated with osteoarthritis. Osteoarthritis Cartilage 18, 581–592 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Xu, Y. et al. Identification of the pathogenic pathways in osteoarthritic hip cartilage: commonality and discord between hip and knee OA. Osteoarthritis Cartilage 20, 1029–1038 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Leijten, J. C. et al. Gremlin 1, frizzled-related protein, and Dkk-1 are key regulators of human articular cartilage homeostasis. Arthritis Rheum. 64, 3302–3312 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Provot, S. & Schipani, E. Molecular mechanisms of endochondral bone development. Biochem. Biophys. Res. Commun. 328, 658–665 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Klüppel, M. et al. Maintenance of chondroitin sulfation balance by chondroitin-4-sulfotransferase 1 is required for chondrocyte development and growth factor signaling during cartilage morphogenesis. Development 132, 3989–4003 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Guo, J. et al. PTH/PTHrP receptor delays chondrocyte hypertrophy via both Runx2-dependent and -independent pathways. Dev. Biol. 292, 116–128 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. 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 

  21. Hirata, M. 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. 21, 1111–1123 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Komori, T. Regulation of bone development and extracellular matrix protein genes by RUNX2. Cell Tissue Res. 339, 189–195 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Ueta, C. et al. Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. J. Cell Biol. 153, 87–100 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Enomoto, H. et al. Cbfa1 is a positive regulatory factor in chondrocyte maturation. J. Biol. Chem. 275, 8695–8702 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Fujita, T. et al. Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K–Akt signaling. J. Cell Biol. 166, 85–95 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim, I. S. et al. Regulation of chondrocyte differentiation by Cbfa1. Mech. Dev. 80, 159–170 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Inada, M. et al. Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev. Dyn. 214, 279–290 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Inada, M. et al. Critical roles for collagenase-3 (Mmp13) in development of growth plate cartilage and in endochondral ossification. Proc. Natl Acad. Sci. USA 101, 17192–17197 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fosang, A. J. et al. Degradation of cartilage aggrecan by collagenase-3 (MMP-13). FEBS. Lett. 380, 17–20 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Gelse, K. et al. Molecular differentiation between osteophytic and articular cartilage—clues for a transient and permanent chondrocyte phenotype. Osteoarthritis Cartilage 20, 162–171 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Vortkamp, A. et al. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273, 613–622 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Alvarez, J. et al. TGFβ2 mediates the effects of hedgehog on hypertrophic differentiation and PTHrP expression. Development 129, 1913–1924 (2002).

    CAS  PubMed  Google Scholar 

  33. Kronenberg, H. M. PTHrP and skeletal development. Ann. NY Acad. Sci. 1068, 1–13 (2006).

    Article  CAS  PubMed  Google Scholar 

  34. Wysolmerski, J. J. Parathyroid hormone-related protein: an update. J. Clin. Endocrinol. Metab. 97, 2947–2956 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Mak, K. K., Kronenberg, H. M., Chuang, P. T., Mackem, S. & Yang, Y. Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development 135, 1947–1956 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Lanske, B. et al. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273, 663–666 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Hirai, T. et al. Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life. Proc. Natl Acad. Sci. USA 108, 191–196 (2011).

    Article  PubMed  Google Scholar 

  38. Li, T. F. et al. Parathyroid hormone-related peptide (PTHrP) inhibits Runx2 expression through the PKA signaling pathway. Exp. Cell Res. 299, 128–136 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Kozhemyakina, E. et al. Parathyroid hormone-related peptide represses chondrocyte hypertrophy through a protein phosphatase 2A/histone deacetylase 4/MEF2 pathway. Mol. Cell Biol. 29, 5751–5762 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhang, M. et al. PTHrP prevents chondrocyte premature hypertrophy by inducing cyclin-D1-dependent Runx2 and Runx3 phosphorylation, ubiquitylation and proteasomal degradation. J. Cell Sci. 122, 1382–1389 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jiang, J. et al. Interaction between zonal populations of articular chondrocytes suppresses chondrocyte mineralization and this process is mediated by PTHrP. Osteoarthritis Cartilage 16, 70–82 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Kafienah, W. et al. Three-dimensional cartilage tissue engineering using adult stem cells from osteoarthritis patients. Arthritis Rheum. 56, 177–187 (2007).

    Article  PubMed  Google Scholar 

  43. Petersson, M. et al. Effects of arginine-vasopressin and parathyroid hormone-related protein (1–34) on cell proliferation and production of YKL-40 in cultured chondrocytes from patients with rheumatoid arthritis and osteoarthritis. Osteoarthritis Cartilage 14, 652–659 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Becher, C. et al. Decrease in the expression of the type 1 PTH/PTHrP receptor (PTH1R) on chondrocytes in animals with osteoarthritis. J. Orthop. Surg. Res. 5, 28 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Kim, S. Y. & Im, G. I. The expression of SOX trio, PTHrP (parathyroid hormone-related peptide)/IHH (Indian hedgehog protein) in surgically induced osteoarthritis of the rat. Cell Biol. Int. 35, 529–535 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Serra, R., Karaplis, A. & Sohn, P. Parathyroid hormone-related peptide (PTHrP)-dependent and -independent effects of transforming growth factor beta (TGF-β) on endochondral bone formation. J. Cell Biol. 145, 783–794 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chen, C. G. et al. Chondrocyte-intrinsic Smad3 represses Runx2-indicible matrix metalloproteinase 13 expression to maintain articular cartilage and prevent osteoarthritis. Arthritis Rheum. 64, 3278–3289 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Blaney Davidson, E. N. et al. Increase in ALK1/ALK5 ratio as a cause for elevated MMP-13 expression in osteoarthritis in humans and mice. J. Immunol. 182, 7937–7945 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Yang, X. et al. TGF-β/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J. Cell Biol. 153, 35–46 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wu, Q. et al. Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum. 58, 3132–3144 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 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 

  52. Valdes, A. M. et al. Genetic variation in the SMAD3 gene is associated with hip and knee osteoarthritis. Arthritis Rheum. 62, 2347–2352 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. 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 

  54. Southam, L. et al. A SNP in the 5′-UTR of GDF5 is associated with osteoarthritis in Europeans and with in vivo differences in allelic expression in articular cartilage. Hum. Mol. Genet. 16, 2226–2232 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Settle, S. H. et al. Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes. Dev. Biol. 254, 116–130 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Tsumaki, N. et al. Role of CDMP-1 in skeletal morphogenesis: promotion of mesenchymal cell recruitment and chondrocyte differentiation. J. Cell Biol. 144, 161–173 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Coleman, C. M. et al. Growth differentiation factor-5 enhances in vitro mesenchymal stromal cell chondrogenesis and hypertrophy. Stem Cells Dev. 22, 1968–1976 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Luyten, F. P. Cartilage-derived morphogenetic protein-1. Int. J. Biochem. Cell Biol. 29, 1241–1244 (1997).

    Article  CAS  PubMed  Google Scholar 

  59. Bobacz, K. et al. Differentially regulated expression of growth differentiation factor 5 and bone morphogenetic protein 7 in articular cartilage and synovium in murine chronic arthritis: potential importance for cartilage breakdown and synovial hypertrophy. Arthritis Rheum. 58, 109–118 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Egli, R. et al. Functional analysis of the osteoarthritis susceptibility-associated GDF5 regulatory polymorphism. Arthritis Rheum. 60, 2055–2064 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Daans, M., Luyten, F. P. & Lories, R. J. GDF5 deficiency in mice is associated with instability-driven joint damage, gait and subchondral bone changes. Ann. Rheum. Dis. 70, 208–213 (2011).

    Article  PubMed  Google Scholar 

  62. Okuda, T. et al. Molecular cloning, expression, and chromosomal mapping of human chondroitin 4-sulfotransferase, whose expression pattern in human tissues is different from that of chondroitin 6-sulfotransferase. J. Biochem. 128, 763–770 (2000).

    Article  CAS  PubMed  Google Scholar 

  63. Gandhi, N. S. & Mancera, R. L. The structure of glycosaminoglycans and their interactions with proteins. Chem. Biol. Drug Des. 72, 455–482 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Klüppel, M. The roles of chondroitin-4-sulfotransferase-1 in development and disease. Prog. Mol. Biol. Transl. Sci. 93, 113–132 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Cortes, M., Baria, A. T. & Schwartz, N. B. Sulfation of chondroitin sulfate proteoglycans is necessary for proper Indian hedgehog signaling in the developing growth plate. Development 136, 1697–1706 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 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 

  67. Bos, S. D. et al. Increased type II deiodinase protein in OA-affected cartilage and allelic imbalance of OA risk polymorphism rs225014 at DIO2 in human OA joint tissues. Ann. Rheum. Dis. 71, 1254–1258 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Shao, Y. Y., Wang, L. & Ballock, R. T. Thyroid hormone and the growth plate. Rev. Endocr. Metab. Disord. 7, 265–271 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Wang, L., Shao, Y. Y. & Ballock, R. T. Thyroid hormone interacts with the Wnt/β-catenin signaling pathway in the terminal differentiation of growth plate chondrocytes. J. Bone Miner. Res. 22, 1988–1995 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Williams, A. J. et al. Iodothyronine deiodinase enzyme activities in bone. Bone 43, 126–134 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Bassett, J. H. et al. Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase is osteoblasts. Proc. Natl Acad. Sci. USA 107, 7604–7609 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Nagase, H. et al. Deiodinase 2 upregulation demonstrated in osteoarthritis patients cartilage causes cartilage destruction in tissue-specific transgenic rats. Osteoarthritis Cartilage 21, 514–523 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Roemer, K. Notch and the p53 clan of transcription factors. Adv. Exp. Med. Biol. 727, 223–240 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Guerrini, L, Costanzo, A. & Merlo, G. R. A symphony of regulators centered on p63 to control development of ectoderm-derived structures. J. Biomed. Biotechnol. 2011, 864904 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Barter, M. J., Bui, C. & Young, D. A. Epigenetic mechanisms in cartilage and osteoarthritis: DNA methylation, histone modifications and microRNAs. Osteoarthritis Cartilage 20, 339–349 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Nguyen, A. T. & Zhang, Y. The diverse functions of Dot1 and H3K79 methylation. Genes Dev. 25, 1345–1358 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Castaño Betancourt, M. C. et al. Genome-wide association and functional studies identify the DOT1L gene to be involved in cartilage thickness and hip osteoarthritis. Proc. Natl Acad. Sci. USA 109, 8218–8223 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Evangelou, E. et al. The DOT1L rs12982744 polymorphism is associated with osteoarthritis of the hip with genome-wide statistical significance in males. Ann. Rheum. Dis. 72, 1264–1265 (2013).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  80. Eyre, S. et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat. Genet. 44, 1336–1340 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Brennan, P., Donev, R. & Hewamana, S. Targeting transcription factors for therapeutic benefit. Mol. Biosyst. 4, 909–919 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Borgatti, M. et al. Decoy molecules based on PNA-DNA chimeras and targeting Sp1 transcription factors inhibit the activity of urokinase-type plasminogen activator receptor (uPAR) promoter. Oncol. Res. 15, 373–383 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Syddall, C. M., Reynard, L. N., Young, D. A. & Loughlin, J. The identification of trans-acting factors that regulate the expression of GDF5 via the osteoarthritis susceptibility SNP rs143383. PLoS Genet. 9, e1003557 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Estrada, K. et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat. Genet. 44, 491–501 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ermakov, S. et al. Family-based association study of polymorphisms in the RUNX2 locus with hand bone length and hand BMD. Ann. Hum. Genet. 72, 510–518 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Bustamante, M. et al. Promoter 2 −1025 T/C polymorphism in the RUNX2 gene is associated with femoral neck BMD in Spanish postmenopausal women. Calcif. Tissue Int. 81, 327–332 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Lee, H. J. et al. Association of a RUNX2 promoter polymorphism with bone mineral density in postmenopausal Korean women. Calcif. Tissue Int. 84, 439–445 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Plöger, F. et al. Brachydactyly type A2 associated with a defect in proGDF5 processing. Hum. Mol. Genet. 17, 1222–1233 (2008).

    Article  CAS  PubMed  Google Scholar 

  89. Polinkovsky, A. et al. Mutations in CDMP1 cause autosomal dominant brachydactyly type C. Nat. Genet. 17, 18–19 (1997).

    Article  CAS  PubMed  Google Scholar 

  90. Thomas, J. T. et al. A human chondrodysplasia due to a mutation in TGF-β superfamily member. Nat. Genet. 12, 315–317 (1996).

    Article  CAS  PubMed  Google Scholar 

  91. Thomas, J. T. et al. Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Nat. Genet. 17, 58–64 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. Szczaluba, K. et al. Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene. Am. J. Med. Genet. A. 138, 379–383 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Dawson, K. et al. GDF5 is a second locus for multiple-synostosis syndrome. Am. J. Hum. Genet. 78, 708–712 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Klopocki, E. et al. Deletion and point mutations of PTHLH cause brachydactyly type E. Am. J. Hum. Genet. 86, 434–439 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Celli, J. et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 99, 143–153 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. van Bokhoven, H. et al. p63 gene mutations in EEC syndrome, limb-mammary syndrome, and isolated split hand–split foot malformation suggest a genotype–phenotype correlation. Am. J. Hum. Genet. 69, 481–492 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ianakiev, P. et al. Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27. Am. J. Hum. Genet. 67, 59–66 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mundlos, S. et al. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell 89, 773–779 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Lango Allen, H. et al. Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature 467, 832–838 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lettre, G. et al. Identification of ten loci associated with height highlights new biological pathways in human growth. Nat. Genet. 40, 584–591 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhao, J. et al. The role of height-associated loci identified in genome wide association studies in the determination of pediatric stature. BMC Med. Genet. 11, 96 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sanna, S. et al. Common variants in the GDF5–UQCC region are associated with variation in human height. Nat. Genet. 40, 198–203 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Mendizabal, I, Marigorta, U. M., Lao, O. & Comas, D. Adaptive evolution of loci covarying with the human African Pygmy phenotype. Hum. Genet. 131, 1305–1317 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Gudbjartsson, D. F. et al. Many sequence variants affecting diversity of adult human height. Nat. Genet. 40, 609–615 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Ermakov, S., Malkin, I., Kobyliansky, E. & Livshits, G. Variation in femoral length is associated with polymorphism in RUNX2 gene. Bone 38, 199–205 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Kim, J. J. et al. Identification of 15 loci influencing height in a Korean population. J. Hum. Genet. 55, 27–31 (2010).

    Article  PubMed  Google Scholar 

  107. Elliott, K. S. et al. Evaluation of the genetic overlap between osteoarthritis with body mass index and height using genome-wide association scan data. Ann. Rheum. Dis. 72, 935–941 (2013).

    Article  PubMed  Google Scholar 

  108. Posthumus, M. et al. The association between the COL12A1 gene and anterior cruciate ligament ruptures. Br. J. Sports Med. 44, 1160–1165 (2010).

    Article  PubMed  Google Scholar 

  109. Williams, F. M. et al. GDF5 single-nucleotide polymorphism rs143383 is associated with lumbar disc degeneration in Northern European women. Arthritis Rheum. 63, 708–712 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 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 

  111. Posthumus, M. et al. Components of the transforming growth factor-β family and the pathogenesis of human Achilles tendon pathology—a genetic association study. Rheumatology (Oxford) 49, 2090–2097 (2010).

    Article  CAS  Google Scholar 

  112. Liu, Y. et al. RUNX2 polymorphisms associated with OPLL and OLF in the Han population. Clin. Orthop. Relat. Res. 468, 3333–3341 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  113. National Center for Biotechnology Information, US National Library of Medicine. Online Mendelian Inheritance in Man (OMIM) [online], (2009).

  114. GWAS Central. GWAS Central 7.0 [online], (2012).

  115. NIH. Genetic Association Database [online], (2011).

  116. National Center for Biotechnology Information, US National Library of Medicine. PubMed [online], (2009).

Download references

Acknowledgements

L. Reynard and J. Loughlin acknowledge research support from Arthritis Research UK, the UK Medical Research Council, the JGW Patterson Foundation, the Oliver Bird Rheumatism Program of the Nuffield Foundation, the Dr William Harker Foundation, the NIHR Newcastle Biomedical Research Centre, and the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no 305815 (D-BOARD).

Author information

Authors and Affiliations

  1. Musculoskeletal Research Group, Institute of Cellular Medicine, 4th Floor Catherine Cookson Building, The Medical School, Framlington Place, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

    Louise N. Reynard & John Loughlin

Authors
  1. Louise N. Reynard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John Loughlin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors researched the data for the article and provided a substantial contribution to discussions of the content and contributed equally to writing the article and to review/editing of the manuscript before submission.

Corresponding author

Correspondence to John Loughlin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Reynard, L., Loughlin, J. Insights from human genetic studies into the pathways involved in osteoarthritis. Nat Rev Rheumatol 9, 573–583 (2013). https://doi.org/10.1038/nrrheum.2013.121

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2013.121

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