A Wnt/ß-catenin negative feedback loop inhibits IL-1-induced MMP expression in human articular chondrocytes.

Bin Ma, Clemens van Blitterswijk, Hermanus Bernardus Johannes Karperien

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Abstract

Objective: Recent animal studies suggest that activation of Wnt/β-catenin signaling in articular chondrocytes might be a driving factor in the pathogenesis of osteoarthritis (OA) by stimulating amongst others the expression of matrix metalloproteinases (MMPs). This study aimed to investigate the role of Wnt/β-catenin signaling in IL-1β-induced MMP expression in human chondrocytes. Methods: Primary cultures of human, mouse and bovine articular chondrocytes as well as human mesenchymal stem cells (hMSCs) and mouse embryonic fibroblasts (MEFs) were used. Multiple strategies for activation and inhibition of signaling pathways were used. Reporter assays and co-immunoprecipitations were used to study the interaction between β-catenin and NF-κB. Results: In contrast to animal chondrocytes, in human chondrocytes Wnt/β-catenin is a potent inhibitor of MMP1, -3 and -13 expression and generic MMP activity both in basal conditions and after IL-1β stimulation. This effect is independent of TCF/LEF transcription factors but is due to an inhibitory protein-protein interaction between β-catenin and NF-κB. Furthermore we show that IL-1β indirectly activates β-catenin signaling by inducing canonical Wnt7B expression and by inhibiting the expression of canonical Wnt antagonists. Conclusion: Our data reveal an unexpected anti-catabolic role of Wnt/β-catenin signaling in human chondrocytes by counteracting NF-κB-mediated MMP expression induced by IL-1β in a negative feedback loop.
Original languageEnglish
Pages (from-to)2589-2600
Number of pages33
JournalArthritis & rheumatism
Volume64
Issue number8
DOIs
Publication statusPublished - 2012

Keywords

  • METIS-286521
  • IR-80573

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