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:

To Wnt or not to Wnt: the bone and joint health dilemma

Nature Reviews Rheumatology volume 9, pages 328–339 (2013)Cite this article

Subjects

Abstract

The Wnt signalling cascades have essential roles in development, growth and homeostasis of joints and the skeleton. Progress in basic research, particularly relating to our understanding of intracellular signalling cascades and fine regulation of receptor activation in the extracellular space, has provided novel insights into the roles of Wnt signalling in chronic arthritis. Cartilage and bone homeostasis require finely tuned Wnt signalling; both activation and suppression of the Wnt–β-catenin cascade can lead to osteoarthritis in rodent models. Genetic associations with the Wnt antagonist encoded by FRZB and the transcriptional regulator encoded by Dot1l with osteoarthritis further corroborate the essential part played by Wnts in the joint. In rheumatoid arthritis, inhibition of Wnt signalling has a role in the persistence of bone erosions, whereas Wnts have been associated with the ankylosing phenotype in spondyloarthritis. Together, these observations identify the Wnt pathway as an attractive target for therapeutic intervention; however, the complexity of the Wnt signalling cascades and the potential secondary effects of drug interventions targeting them highlight the need for further research and suggest that our understanding of this exciting pathway is still in its infancy.

Key Points

  • Wnts are lipid-modified glycoproteins that activate a variety of signalling pathways in an autocrine or paracrine manner; target cell activation is dependent on the formation of complex signalling centres

  • Wnts are essential for articular cartilage and bone homeostasis, but excessive Wnt signalling is associated with loss of the stable articular chondrocyte phenotype and can lead to cartilage damage

  • In rheumatoid arthritis, healing of erosions can be inhibited by elevated local concentrations of Wnt antagonists such as Dickkopf-related protein 1 and secreted frizzled-related protein 1

  • Wnts are associated with ankylosis in spondyloarthritis, and data from developmental biology suggest that specific Wnts stimulate direct bone formation and not the initial steps in endochondral ossification

  • Various Wnt antagonists have been proposed as biomarkers in patients with spondyloarthritis, but further validation is required

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: The complex synthesis and signalling properties of Wnt molecules.
Figure 2: Wnt signalling cascades.
Figure 3: The varied roles of Wnts in skeletal development.
Figure 4: The complex roles of Wnts in cartilage homeostasis and disease.

Similar content being viewed by others

References

  1. Clevers, H & Nusse, R. Wnt/β-catenin signaling and disease. Cell 149, 1192–1205 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Kadowaki, T., Wilder, E., Klingensmith, J., Zachary, K. & Perrimon, N. The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing. Genes Dev. 10, 3116–3128 (1996).

    Article  CAS  PubMed  Google Scholar 

  3. Bänziger, C. et al. Wntless, a conserved membrane protein dedicated to the secretion of Wnt proteins from signaling cells. Cell 125, 509–522 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Tabata, T & Takei, Y. Morphogens, their identification and regulation. Development 131, 703–712 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Mii, Y & Taira, M. Secreted Frizzled-related proteins enhance the diffusion of Wnt ligands and expand their signalling range. Development 136, 4083–4088 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Mii, Y & Taira, M. Secreted Wnt “inhibitors” are not just inhibitors: regulation of extracellular Wnt by secreted Frizzled-related proteins. Dev. Growth Differ. 53, 911–923 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Bovolenta, P., Esteve, P., Ruiz, J. M., Cisneros, E. & Lopez-Rios, J. Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease. J. Cell Sci. 121, 737–746 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Sugimura, R & Li, L. Noncanonical Wnt signaling in vertebrate development, stem cells, and diseases. Birth Defects Res. C Embryo Today 90, 243–256 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Li, V. S. et al. Wnt signaling through inhibition of β-catenin degradation in an intact Axin1 complex. Cell 149, 1245–1256 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Wallingford, J. B. & Mitchell, B. Strange as it may seem: the many links between Wnt signaling, planar cell polarity, and cilia. Genes Dev. 25, 201–213 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Clark, C. E., Nourse, C. C. & Cooper, H. M. The tangled web of non-canonical Wnt signalling in neural migration. Neurosignals 20, 202–220 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Minami, Y., Oishi, I., Endo, M. & Nishita M. ROR-family receptor tyrosine kinases in noncanonical Wnt signaling: their implications in developmental morphogenesis and human diseases. Dev. Dyn. 239, 1–15 (2010).

    CAS  PubMed  Google Scholar 

  13. Matthews, H. K. et al. Directional migration of neural crest cells in vivo is regulated by Syndecan-4/Rac1 and non-canonical Wnt signaling/RhoA. Development 135, 1771–1780 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Cruciat, C. M. & Niehrs, C. Secreted and transmembrane Wnt inhibitors and activators. Cold Spring Harb. Perspect. Biol. http://dx.doi.org/10.1101/cshperspect.a015081.

  15. Niehrs, C. The complex world of WNT receptor signalling. Nat. Rev. Mol. Cell Biol. 13, 767–779 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Leucht, P., Minear, S., Ten Berge, D., Nusse, R. & Helms, J. A. Translating insights from development into regenerative medicine: the function of Wnts in bone biology. Semin. Cell Dev. Biol. 19, 434–443 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Monroe, D. G., McGee-Lawrence, M. E., Oursler, M. J. & Westendorf, J. J. Update on Wnt signaling in bone cell biology and bone disease. Gene 492, 1–18 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Lefebvre, V. & Bhattaram, P. Vertebrate skeletogenesis. Curr. Top. Dev. Biol. 90, 291–317 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Barrow, J. R. et al. Ectodermal Wnt3/β-catenin signaling is required for the establishment and maintenance of the apical ectodermal ridge. Genes Dev. 17, 394–409 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kawakami, Y. et al. WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo. Cell 104, 891–900 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Nam, J. S. et al. Mouse R-spondin2 is required for apical ectodermal ridge maintenance in the hindlimb. Dev. Biol. 311, 124–135 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gros, J. et al. Wnt5a/JNK and FGF/MAPK pathways regulate the cellular events shaping the vertebrate limb bud. Curr. Biol. 20, 1993–2002 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rudnicki, J. A. & Brown, A. M. Inhibition of chondrogenesis by Wnt gene expression in vivo and in vitro. Dev. Biol. 185, 104–118 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Witte, F., Dokas, J., Neuendorf, F., Mundlos, S. & Stricker, S. Comprehensive expression analysis of all Wnt genes and their major secreted antagonists during mouse limb development and cartilage differentiation. Gene Expr. Patterns 9, 215–223 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Day, T. F., Guo, X., Garrett-Beal, L. & Yang, Y. Wnt/β-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev. Cell 8, 739–750 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Akiyama, H. et al. Interactions between SOX9 and β-catenin control chondrocyte differentiation. Genes Dev. 18, 1072–1087 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hill, T. P., Später, D., Taketo, M. M., Birchmeier, W. & Hartmann, C. Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev. Cell 8, 727–738 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Church, V., Nohno, T., Linker, C., Marcelle, C. & Francis-West, P. Wnt regulation of chondrocyte differentiation. J. Cell Sci. 115, 4809–4818 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Dong, Y. F., Soung do, Y., Schwarz, E. M., O'Keefe, R. J. & Drissi, H. Wnt induction of chondrocyte hypertrophy through the Runx2 transcription factor. J. Cell. Physiol. 208, 77–86 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Guo, X., Mak, K. K., Taketo, M. M. & Yang, Y. The Wnt/β-catenin pathway interacts differentially with PTHrP signaling to control chondrocyte hypertrophy and final maturation. PLoS ONE 4, e6067 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Tamamura, Y. et al. Developmental regulation of Wnt/β-catenin signals is required for growth plate assembly, cartilage integrity, and endochondral ossification. J. Biol. Chem. 280, 19185–19195 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Dao, D. Y. et al. Cartilage-specific β-catenin signaling regulates chondrocyte maturation, generation of ossification centers, and perichondrial bone formation during skeletal development. J. Bone Miner. Res. 27, 1680–1694 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bradley, E. W. & Drissi, M. H. Wnt5a regulates chondrocyte differentiation through differential use of the CaN/NFAT and IKK/NF-κB pathways. Mol. Endocrinol. 24, 1581–1593 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bradley, E. W. & Drissi, M. H. Wnt5b regulates mesenchymal cell aggregation and chondrocyte differentiation through the planar cell polarity pathway. J. Cell. Physiol. 226, 1683–1693 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Hu, H. et al. Sequential roles of Hedgehog and Wnt signaling in osteoblast development. Development 132, 49–60 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Hartmann, C. & Tabin, C. J. Wnt-14 plays a pivotal role in inducing synovial joint formation in the developing appendicular skeleton. Cell 104, 341–351 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Später, D., Hill, T. P., Gruber, M. & Hartmann, C. Role of canonical Wnt-signalling in joint formation. Eur. Cell. Mater. 12, 71–80 (2006).

    Article  PubMed  Google Scholar 

  38. Später, D. et al. Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis. Development 133, 3039–3049 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Li, X. et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J. Biol. Chem. 280, 19883–19887 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Robling, A. G. et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J. Biol. Chem. 283, 5866–5875 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Baker-Lepain, J. C. et al. Variant alleles of the Wnt antagonist FRZB are determinants of hip shape and modify the relationship between hip shape and osteoarthritis. Arthritis Rheum. 64, 1457–1465 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  42. 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  Google Scholar 

  43. 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 

  44. Min, J. L. et al. Association of the Frizzled-related protein gene with symptomatic osteoarthritis at multiple sites. Arthritis Rheum. 52, 1077–1080 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. 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 

  46. 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  Google Scholar 

  47. Mahmoudi, T. et al. The leukemia-associated Mllt10/Af10-Dot1l are TCF4/β-catenin coactivators essential for intestinal homeostasis. PLoS Biol. 8, e1000539 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 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: Wnt-16 expression and signaling after injury and in osteoarthritis. Arthritis Rheum. 58, 1410–1421 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Blom, A. B. et al. Involvement of the Wnt signaling pathway in experimental and human osteoarthritis: prominent role of Wnt-induced signaling protein 1. Arthritis Rheum. 60, 501–512 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Sen, M. et al. Expression and function of wingless and frizzled homologs in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 97, 2791–2796 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Nakamura, Y., Nawata, M. & Wakitani, S. Expression profiles and functional analyses of Wnt-related genes in human joint disorders. Am. J. Pathol. 167, 97–105 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Imai, K. et al. Differential expression of Wnts and FRPs in the synovium of rheumatoid arthritis and osteoarthritis. Biochem. Biophys. Res. Commun. 345, 1615–1620 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Sen, M. et al. Regulation of fibronectin and metalloproteinase expression by Wnt signaling in rheumatoid arthritis synoviocytes. Arthritis Rheum. 46, 2867–2877 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Sen, M., Chamorro, M., Reifert, J., Corr, M. & Carson, D. A. Blockade of Wnt-5a/frizzled 5 signaling inhibits rheumatoid synoviocyte activation. Arthritis Rheum. 44, 772–781 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Zhu, M. et al. Inhibition of β-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthritis Rheum. 58, 2053–2064 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhu, M. 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. 24, 12–21 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Yuasa, T. et al. Transient activation of Wnt/β-catenin signaling induces abnormal growth plate closure and articular cartilage thickening in postnatal mice. Am. J. Pathol. 175, 1993–2003 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lodewyckx, L., Luyten, F. P. & Lories R. J. Genetic deletion of low-density lipoprotein receptor-related protein 5 increases cartilage degradation in instability-induced osteoarthritis. Rheumatology (Oxford) 51, 1973–1978 (2012).

    Article  CAS  Google Scholar 

  59. 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 

  60. Miclea, R. L. et al. Inhibition of GSK3β in cartilage induces osteoarthritic features through activation of the canonical Wnt signaling pathway. Osteoarthritis Cartilage 19, 1363–1372 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Weng, L. H., Wang, C. J., Ko, J. Y., Sun, Y. C. & Wang, F. S. Control of Dkk-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees. Arthritis Rheum. 62, 1393–1402 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Oh, H., Chun, C. H. & Chun, J. S. Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice. Arthritis Rheum. 64, 2568–2578 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Leijten, J. C. et al. Gremlin 1, frizzled-related protein, and Dkk-1 are key regulators of human articular cartilage homeostasis. Arthritis Rheum. 64, 3302–3012 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Lodewyckx, L., Cailotto, F., Thysen, S., Luyten, F. P. & Lories, R. J. Tight regulation of wingless-type signaling in the articular cartilage–subchondral bone biomechanical unit: transcriptomics in Frzb-knockout mice. Arthritis Res. Ther. 14, R16 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nalesso, G. et al. Wnt-3a modulates articular chondrocyte phenotype by activating both canonical and noncanonical pathways. J. Cell Biol. 193, 551–564 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cailotto, F., Sebillaud, S., Netter, P., Jouzeau, J. Y. & Bianchi, A. The inorganic pyrophosphate transporter ANK preserves the differentiated phenotype of articular chondrocyte. J. Biol. Chem. 285, 10572–10582 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ma, B., van Blitterswijk, C. A. & Karperien, M. A Wnt/β-catenin negative feedback loop inhibits interleukin-1-induced matrix metalloproteinase expression in human articular chondrocytes. Arthritis Rheum. 64, 2589–2600 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Matzelle, M. M. et al. Resolution of inflammation induces osteoblast function and regulates the Wnt signaling pathway. Arthritis Rheum. 64, 1540–1550 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Walsh, N. C. et al. Osteoblast function is compromised at sites of focal bone erosion in inflammatory arthritis. J. Bone Miner. Res. 24, 1572–1585 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Li, X. et al. Dkk2 has a role in terminal osteoblast differentiation and mineralized matrix formation. Nat. Genet. 37, 945–952 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. de Rooy, D. P. et al. Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2012-202184.

  72. Glass, D. A. 2nd et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev. Cell 8, 751–764 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Diarra, D. et al. Dickkopf-1 is a master regulator of joint remodeling. Nat. Med. 13, 156–163 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Maiti, G., Naskar, D. & Sen, M. The Wingless homolog Wnt5a stimulates phagocytosis but not bacterial killing. Proc. Natl Acad. Sci. USA 109, 16600–16605 (2012).

    Article  PubMed  Google Scholar 

  75. Kim, J. et al. Wnt5a induces endothelial inflammation via β-catenin-independent signaling. J. Immunol. 185, 1274–1282 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. Maeda, K. et al. Wnt5a–ROR2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat. Med. 18, 405–412 (2012).

    Article  CAS  PubMed  Google Scholar 

  77. Lee, Y. S. et al. The Wnt inhibitor secreted frizzled-related protein 1 (sFRP1) promotes human TH17 differentiation. Eur. J. Immunol. 42, 2564–2573 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Dougados, M. & Baeten, D. Spondyloarthritis. Lancet 377, 2127–2137 (2011).

    Article  PubMed  Google Scholar 

  79. Lories, R. J., Luyten, F. P. & de Vlam, K. Progress in spondylarthritis. Mechanisms of new bone formation in spondyloarthritis. Arthritis Res. Ther. 11, 221 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Machado, P. et al. Both structural damage and inflammation of the spine contribute to impairment of spinal mobility in patients with ankylosing spondylitis. Ann. Rheum. Dis. 69, 1465–1470 (2010).

    Article  PubMed  Google Scholar 

  81. Wanders, A. et al. Nonsteroidal anti-inflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum. 52, 1756–1765 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Poddubnyy, D. et al. Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the German Spondyloarthritis Inception Cohort. Ann. Rheum. Dis. 71, 1616–1622 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. van der Heijde, D. et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum. 58, 1324–1331 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Uderhardt, S. et al. Blockade of Dickkopf (Dkk)-1 induces fusion of sacroiliac joints. Ann. Rheum. Dis. 69, 592–597 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Haynes, K. R. et al. Excessive bone formation in a mouse model of ankylosing spondylitis is associated with decreases in Wnt pathway inhibitors. Arthritis Res. Ther. 14, R253 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Heiland, G. R. et al. High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann. Rheum. Dis. 71, 572–574 (2012).

    Article  CAS  PubMed  Google Scholar 

  87. Daoussis, D. et al. Evidence that Dkk-1 is dysfunctional in ankylosing spondylitis. Arthritis Rheum. 62, 150–158 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Appel, H. et al. Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum. 60, 3257–3262 (2009).

    Article  PubMed  Google Scholar 

  89. Saad, C. G. et al. Low sclerostin levels: a predictive marker of persistent inflammation in ankylosing spondylitis during anti-tumor necrosis factor therapy? Arthritis Res. Ther. 14, R216 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lane, N. E. et al. Wnt signaling antagonists are potential prognostic biomarkers for the progression of radiographic hip osteoarthritis in elderly Caucasian women. Arthritis Rheum. 56, 3319–3325 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Padhi, D. A. et al. The effects of multiple doses of sclerostin antibody AMG 785 in healthy men and postmenopausal women with low bone mass [abstract OP0044]. Ann. Rheum. Dis. 71 (Suppl. 3), 67–68 (2012).

    Google Scholar 

  92. Andrade, A. C., Nilsson, O., Barnes, K. M. & Baron, J. Wnt gene expression in the post-natal growth plate: regulation with chondrocyte differentiation. Bone 40, 1361–1369 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Kengaku, M. et al. Distinct Wnt pathways regulating AER formation and dorsoventral polarity in the chick limb bud. Science 280, 1274–1277 (1998).

    Article  CAS  PubMed  Google Scholar 

  94. Guo, X. et al. Wnt/β-catenin signaling is sufficient and necessary for synovial joint formation. Genes Dev. 18, 2404–2417 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hartmann, C. & Tabin, C. J. Dual roles of Wnt signaling during chondrogenesis in the chicken limb. Development 127, 3141–3159 (2000).

    CAS  PubMed  Google Scholar 

  96. Yang, Y., Topol, L., Lee, H. & Wu, J. Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation. Development 130, 1003–1015 (2003).

    Article  CAS  PubMed  Google Scholar 

  97. Pasold, J. et al. Reduced expression of Sfrp1 during chondrogenesis and in articular chondrocytes correlates with osteoarthritis in STR/ort mice. Exp. Cell Res. http://dx.doi.org/10.1016/j.yexcr.2012.12.012.

  98. Ladher, R. K. et al. Cloning and expression of the Wnt antagonists Sfrp-2 and Frzb during chick development. Dev. Biol. 218, 183–198 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Kusu, N. et al. Sclerostin is a novel secreted osteoclast-derived bone morphogenetic protein antagonist with unique ligand specificity. J. Biol. Chem. 278, 24113–24117 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Chan, B. Y. et al. Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis. Osteoarthritis Cartilage 19, 874–885 (2011).

    Article  CAS  PubMed  Google Scholar 

  101. Roudier, M. et al. Sclerostin is expressed in articular cartilage but loss or inhibition does not affect cartilage remodeling during aging or following mechanical injury. Arthritis Rheum. http://dx.doi.org/10.1002/art.37802.

Download references

Author information

Authors and Affiliations

  1. Department of Development and Regeneration, Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven, Herestraat 49, Leuven, B3000, Belgium

    Rik J. Lories

  2. Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, San Diego, 92093-0663, CA, USA

    Maripat Corr

  3. Department of Medicine, Center for Musculoskeletal Diseases, University of California at Davis School of Medicine, 4625 2nd Avenue, Suite 1002, Sacramento, 95817, CA, USA

    Nancy E. Lane

Authors
  1. Rik J. Lories
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maripat Corr
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nancy E. Lane
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally to each stage of the preparation of this manuscript for publication.

Corresponding author

Correspondence to Rik J. Lories.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lories, R., Corr, M. & Lane, N. To Wnt or not to Wnt: the bone and joint health dilemma. Nat Rev Rheumatol 9, 328–339 (2013). https://doi.org/10.1038/nrrheum.2013.25

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2013.25

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