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  • Review Article
  • Published:

Cushioning the cartilage: a canonical Wnt restricting matter

Nature Reviews Rheumatology volume 13, pages 670–681 (2017)Cite this article

Subjects

Key Points

  • Wnt signalling is essential for joint health: loss of and excessive activation of the canonical signalling pathway are both deleterious for articular cartilage

  • In cartilage, Wnt ligands have distinct effects on the activation of downstream cascades; Wnt16 seems to be a partial agonist that protects against excessive cascade activation

  • Ligand–receptor, ligand–antagonist and receptor–antagonist interactions, as well as the establishment of concentration gradients by cell surface and extracellular matrix molecules, all contribute to the regulation of Wnt pathway activation

  • Intracellularly, β-catenin forms complexes with the T cell factor and lymphoid enhancer-binding factor family of transcription factors, and the composition of these complexes determines the resulting transcriptional response

  • Histone modifications further regulate the activity of canonical Wnt signalling in cartilage; DOT1L limits excessive activation of Wnt signalling and protects the cartilage against osteoarthritis

  • Increasing insights into specific mechanisms that regulate Wnt signalling in the joint such as histone modification might reveal unexpected opportunities in achieving tissue-specific effects and developing targeted therapies

Abstract

Wnt signalling pathways have key roles in joint development, homeostasis and disease, particularly in osteoarthritis. New data is starting to reveal the importance of tightly regulating canonical Wnt signalling pathway activation to maintain homeostasis and health in articular cartilage. In addition to the presence of different Wnt antagonists that limit pathway activation in articular cartilage, the reciprocal crosstalk between the canonical and non-canonical cascades and competitive antagonism between different Wnt ligands seem to be critical in restraining excessive Wnt pathway activation. Changes in transcriptional complex assembly upon Wnt pathway activation, epigenetic modulation of target gene transcription, in particular through histone modifications, and complex interactions between the Wnt signalling pathway and other signalling pathways, are also instrumental in adjusting Wnt signalling. In this Review, the cellular and molecular mechanisms involved in fine-tuning canonical Wnt signalling in the joint are updated, with a focus on the articular cartilage. The interventions for preventing or treating osteoarthritis are also discussed, which should aim to limit disease-associated excessive canonical Wnt activity to avoid joint damage.

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Figure 1: Ligand-dependent activation of the Wnt signalling cascade.
Figure 2: Tight regulation of canonical Wnt signalling is critical to maintaining cartilage health.
Figure 3: Diverse effects of secreted frizzled-related proteins sFRP1 and sFRP3.
Figure 4: Transcriptional and epigenetic regulation of Wnt signalling in articular cartilage.

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Acknowledgements

Original research on Wnt signalling in the Laboratory of Tissue Homeostasis and Disease is supported by grants from the Flanders Research Foundation (FWO Vlaanderen), a C1 grant from KU Leuven and an unrestricted grant from Celgene (to S.M.). S.M. was the recipient of a Marie-Curie fellowship named “DOTOS”.

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Authors and Affiliations

  1. Department of Development and Regeneration, Laboratory for Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Centre, Katholieke Universiteit Leuven, Herestraat 49, Leuven, B-3000, Belgium

    Silvia Monteagudo & Rik J. Lories

  2. Division of Rheumatology, University Hospitals Leuven, Herestraat 49, Leuven, B-3000, Belgium

    Rik J. Lories

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  1. Silvia Monteagudo
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Both authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Rik J. Lories.

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Glossary

Canonical Wnt signalling pathway

The best-characterized signalling cascade triggered by Wnts that functions through regulation of intracellular β-catenin levels.

Non-canonical Wnt signalling pathways

Alternatively activated signalling cascades that function via Wnt–frizzled receptor interactions resulting in activation of mitogen activated protein kinases such as c-Jun N-terminal kinase and in intracellular calcium release.

Joint interzone

The area in the developing limb where the joints will be formed; joint interzone cells are progenitors of the cells of the synovium, articular cartilage and ligaments.

Superficial zone chondrocytes

Flat-appearing lubricin-producing cells in the superficial zone of the articular cartilage.

Articular chondrocytes

A unique population of chondrocytes in the articular cartilage, embedded in a self-produced water-rich extracellular matrix.

Kyphosis

Abnormal curvature of the spine.

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Monteagudo, S., Lories, R. Cushioning the cartilage: a canonical Wnt restricting matter. Nat Rev Rheumatol 13, 670–681 (2017). https://doi.org/10.1038/nrrheum.2017.171

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