Drs. Sharpe, Newham, and Clements, Ms Langham, and Ms Barker own stock or stock options in AstraZeneca.
Dual regulation of metalloproteinase expression in chondrocytes by Wnt-1–inducible signaling pathway protein 3/CCN6
Article first published online: 26 JUN 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 7, pages 2289–2299, July 2012
How to Cite
Baker, N., Sharpe, P., Culley, K., Otero, M., Bevan, D., Newham, P., Barker, W., Clements, K. M., Langham, C. J., Goldring, M. B. and Gavrilović, J. (2012), Dual regulation of metalloproteinase expression in chondrocytes by Wnt-1–inducible signaling pathway protein 3/CCN6. Arthritis & Rheumatism, 64: 2289–2299. doi: 10.1002/art.34411
- Issue published online: 26 JUN 2012
- Article first published online: 26 JUN 2012
- Accepted manuscript online: 31 JAN 2012 10:36AM EST
- Manuscript Accepted: 24 JAN 2012
- Manuscript Received: 14 OCT 2010
- NIH. Grant Numbers: R01-AG-022021, RC4-AR-060546
- Arthritis Foundation Postdoctoral Fellowship
- Biotechnology and Biological Sciences Research Council Industrial Partnership CASE Studentship
- Action Arthritis grant
Wnt-1–inducible signaling pathway protein 3 (WISP-3)/CCN6 is mutated in progressive pseudorheumatoid dysplasia and may have effects on cartilage homeostasis. The aim of this study was to ascertain additional roles for WISP-3/CCN6 by determining its expression in osteoarthritic (OA) cartilage and by investigating its effects on cartilage-relevant metalloproteinase expression in immortalized (C-28/I2) and primary chondrocytes.
Cartilage steady-state levels of WISP-3/CCN6 messenger RNA and protein production were determined by real-time quantitative reverse transcription–polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. WISP-3/CCN6 was overexpressed in C-28/I2 cells, and the resultant clones were analyzed by quantitative RT-PCR. The stable clones were analyzed by RT-PCR for metalloproteinase expression, and the signaling pathways involved were investigated using pharmacologic inhibition. The effects of WISP-3/CCN6 on metalloproteinase expression in primary chondrocytes were investigated using a small interfering RNA approach.
WISP-3/CCN6 was highly expressed in OA cartilage compared with undamaged cartilage, at both the RNA and protein levels. WISP-3/CCN6 overexpression in C-28/I2 cells resulted in unexpected dual regulation of metalloproteinases; expression of the potent aggrecanase ADAMTS-5 was down-regulated 9-fold, while expression of MMP-10 was up-regulated 14-fold, and these responses were accentuated in the WISP-3/CCN6 clones grown in suspension. MMP-10 up-regulation was dependent on several MAPKs, but WISP-3/CCN6–mediated ADAMTS-5 repression was independent of these pathways and was partially relieved by activation of β-catenin signaling. WISP-3/CCN6 also suppressed ADAMTS-5 expression in C-28/I2 cells treated with cytokines. In cytokine-treated primary chondrocytes, gene silencing of WISP-3/CCN6 resulted in enhanced ADAMTS-5 expression, while MMP-10 expression was suppressed.
WISP-3/CCN6 was highly expressed in end-stage OA cartilage, suggesting a role for this growth factor in cartilage homeostasis. WISP-3/CCN6–induced repression of ADAMTS-5 expression and regulation of MMP-10 expression suggest complex and context-dependent roles for WISP-3/CCN6 in cartilage biology.