Article
Wnt/β-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: its possible role in joint degeneration

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Abstract

A fine balance between anabolic and catabolic mechanisms maintains extracellular matrix homeostasis in articular cartilage, and shifts toward degradation are associated with joint conditions such as osteoarthritis. To test the possible involvement, relevance and significance of the Wnt/β-catenin-signaling pathway in those catabolic shifts, rabbit articular chondrocyte cultures were subjected to experimental activation of β-catenin signaling by Wnt3A treatment or forced expression of constitutive-active β-catenin (CA-β-catenin). Both interventions provoked strong gelatinase activity and stimulated gene expression of matrix metalloprotease-3 and -13 and a disintegrin-like and metalloprotease with thrombospondin motif (ADAMTS)-4 and -5 proteases. Furthermore, Wnt3A treatment additively enhanced the effects of intereukin-1β, a well-known catabolic culprit of proteoglycan matrix loss. To determine whether Wnt/β-catenin signaling is associated with age-associated osteoarthritic changes in articular cartilage in vivo, we analyzed the presence and intracellular distribution of β-catenin in a spontaneous guinea pig osteoarthritis model. Healthy articular chondrocytes in young guinea pig knees contained barely detectable levels of β-catenin. In contrast, the protein was highly abundant in osteoarthritic-like chondrocytes present in older guinea pig joints, and was localized not only in the cytoplasm but also the nucleus, a clear reflection of activated Wnt signaling. These and other data suggest that Wnt/β-catenin signaling is a powerful stimulator of chondrocyte matrix catabolic action and may be part of mechanisms leading to excessive remodeling and degradation of cartilage matrix in age-associated joint pathologies.

Keywords

articular cartilage
chondrocyte
Wnt
β-catenin signaling
MMP
osteoarthritis

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An erratum to this article is available online at https://doi.org/10.1038/labinvest.2008.26.