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Wnt–β-catenin signaling in the pathogenesis of osteoarthritis

Nature Clinical Practice Rheumatology volume 4, pages 550–556 (2008)Cite this article

Abstract

Osteoarthritis (OA) is a progressively degenerative joint condition that is influenced by various metabolic and structural factors. The canonical Wnt–frizzled–β-catenin pathway has been implicated in the pathogenesis of OA. Products of the Wnt, frizzled, secreted frizzled-related protein (sFRP), Dickkopf and LDL-receptor-related protein gene families have crucial roles in the development and maintenance of bone, cartilage and joints. Increased levels of β-catenin have been observed in degenerative cartilage, suggesting that a diminished capacity to limit Wnt signaling might contribute to cartilage loss. Polymorphisms in genes involved in Wnt signaling—particularly in the gene encoding sFRP-3—are associated with an increased susceptibility to the development of OA. At least one of these polymorphisms in the gene encoding sFPR-3 is associated with a reduced ability to limit β-catenin signaling. In addition, the canonical Wnt signaling pathway is influenced by local factors, including alterations in glycosaminoglycan sulfation, cartilage matrix content, transforming growth factor β and vitamin D. A higher circulating level of the Wnt inhibitor Dickkopf-1, for instance, is associated with slowed progression of hip OA. Hence, the sum of local and systemic factors contributes to the outcome of the Wnt–frizzled pathways. Further investigation is needed to fully define the role of Wnt signaling in OA.

Key Points

  • Wnt–frizzled–β-catenin signaling influences skeletal development and homeostasis of adult bone mass

  • Single nucleotide polymorphisms in LRP5 and FRZB have been associated with OA in population studies

  • Wnt and FRZB gene expression are increased in cartilage in response to mechanical trauma

  • An increase in β-catenin expression is seen in degenerated cartilage

  • Elevated circulating levels of the Wnt antagonist Dickkopf-1 seem to be associated with reduced progression of radiographic hip OA in elderly women

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Figure 1: The canonical Wnt signaling pathway and its inhibitors.

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Acknowledgements

This work was supported by a grant from the NIH (5U01AR50901-02).

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  1. Department of Medicine, Division of Rheumatology, Allergy and Rheumatology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0663, USA mcorr@ucsd.edu

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  1. M Corr is a Professor of Medicine in the Department of Medicine, Division of Rheumatology, Allergy and Rheumatology, at the University of California at San Diego, La Jolla, CA, USA.,

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Corr, M. Wnt–β-catenin signaling in the pathogenesis of osteoarthritis. Nat Rev Rheumatol 4, 550–556 (2008). https://doi.org/10.1038/ncprheum0904

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