Chondrocyte and Disc Biology
A Wnt/β-catenin negative feedback loop inhibits interleukin-1–induced matrix metalloproteinase expression in human articular chondrocytes
Version of Record online: 27 JUL 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 8, pages 2589–2600, August 2012
How to Cite
Ma, B., van Blitterswijk, C. A. and Karperien, M. (2012), A Wnt/β-catenin negative feedback loop inhibits interleukin-1–induced matrix metalloproteinase expression in human articular chondrocytes. Arthritis & Rheumatism, 64: 2589–2600. doi: 10.1002/art.34425
- Issue online: 27 JUL 2012
- Version of Record online: 27 JUL 2012
- Accepted manuscript online: 10 FEB 2012 04:40PM EST
- Manuscript Accepted: 2 FEB 2012
- Manuscript Received: 25 AUG 2011
- BioMedical Materials Institute (for program project P2.02 OAcontrol)
- Dutch Ministry of Economic Affairs, Agriculture, and Innovation
The results of 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, for instance, the expression of matrix metalloproteinases (MMPs). The aim of this study was to investigate the role of Wnt/β-catenin signaling in interleukin-1β (IL-1β)–induced MMP expression in human chondrocytes.
Primary cultures of human, murine, and bovine articular chondrocytes as well as human mesenchymal stem cells and mouse embryonic fibroblasts were used in the experiments. Multiple strategies for the activation and inhibition of signaling pathways were utilized. Reporter assays and coimmunoprecipitation were performed to study the interaction between β-catenin and NF-κB.
In contrast to the role of Wnt/β-catenin in animal chondrocytes, in human chondrocytes it was a potent inhibitor of MMP-1, MMP-3, and MMP-13 expression and generic MMP activity both in basal conditions and after IL-1β stimulation. This effect was independent of the T cell factor/lymphoid enhancer factor family of transcription factors but rather was attributable to an inhibitory protein–protein interaction between β-catenin and NF-κB. IL-1β indirectly activated β-catenin signaling by inducing canonical Wnt-7B expression and by inhibiting the expression of canonical Wnt antagonists.
Wnt/β-catenin signaling in human chondrocytes had an unexpected anticatabolic role by counteracting NF-κB–mediated MMP expression induced by IL-1β in a negative feedback loop.