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Cushioning the cartilage: a canonical Wnt restricting matter
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Journal Article
Cushioning the cartilage: a canonical Wnt restricting matter
2017
Overview
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
In this Review, the role of canonical Wnt signalling in articular cartilage is discussed, along with the regulatory mechanisms that exist to fine-tune Wnt signalling and the rationale for developing drugs that modulate Wnt signalling for the treatment of joint diseases such as osteoarthritis.
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
