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Research Article
A novel role for suppressor of cytokine signaling 3 in cartilage destruction via induction of chondrocyte desensitization toward insulin-like growth factor
Article first published online: 27 APR 2006
DOI: 10.1002/art.21752
Copyright © 2006 by the American College of Rheumatology
1529-0131/asset/cover.gif?v=1&s=104d5c2bb8ef72deba26790b855af7ab80697a0e "Arthritis & Rheumatism")
Additional Information
How to Cite
Smeets, R. L., Veenbergen, S., Arntz, O. J., Bennink, M. B., Joosten, L. A. B., van den Berg, W. B. and van de Loo, F. A. J. (2006), A novel role for suppressor of cytokine signaling 3 in cartilage destruction via induction of chondrocyte desensitization toward insulin-like growth factor. Arthritis & Rheumatism, 54: 1518–1528. doi: 10.1002/art.21752
Publication History
- Issue published online: 27 APR 2006
- Article first published online: 27 APR 2006
- Manuscript Accepted: 5 JAN 2006
- Manuscript Received: 19 JUL 2005
Funded by
- Dutch Arthritis Association. Grant Number: 01-1-304
- VIDI fellowship from the Dutch Organization for Scientific Research. Grant Number: 917.46.363
- Abstract
- Article
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- Cited By
Abstract
Objective
An important mechanism contributing to cartilage destruction in arthritis is chondrocyte desensitization toward its main anabolic factor, insulin-like growth factor 1 (IGF-1). In this study, we sought to determine the role of suppressor of cytokine signaling 3 (SOCS-3) in the induction of IGF-1 desensitization of murine chondrocytes.
Methods
Chondrocyte responsiveness to IGF-1 was assessed by 35S-sulfate incorporation into proteoglycans (PGs), via aggrecan messenger RNA expression, using quantitative real-time polymerase chain reaction or insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation (Western blot analysis). IGF-1 desensitization of patellar chondrocytes was studied in zymosan-induced arthritis. IGF-1 desensitization was induced in patellar cartilage explants or the H4 chondrocyte cell line, exposed to interleukin-1α (IL-1α). SOCS-3 protein expression was assessed by immunohistochemistry or by Western blot analysis of protein extracts. The role of SOCS-3 in IGF-1 signaling was elucidated by adenoviral overexpression.
Results
Exposure of murine articular cartilage to IL-1 caused a significant decrease in IGF-1–induced PG synthesis. This effect also occurred in inducible nitric oxide synthase–knockout mice, revealing the involvement of a secondary IL-1–induced factor other than nitric oxide. We showed that IL-1 significantly up-regulated SOCS-3 transcription and protein synthesis in H4 chondrocytes. In contrast, IL-18 was unable to induce SOCS-3 expression and failed to induce chondrocyte IGF-1 desensitization. Histologic analysis of samples from arthritic knee joints revealed high expression of SOCS-3 in chondrocytes. Through adenoviral overexpression of SOCS-3, we obtained direct evidence that SOCS-3 inhibits IGF-1–mediated cell signaling, since IRS-1 phosphorylation was reduced.
Conclusion
This study demonstrates that IL-1–induced SOCS-3 expression is a novel mechanism of IGF-1 desensitization in chondrocytes; in conjunction with nitric oxide it can contribute to cartilage damage during arthritis.