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J. Biol. Chem., Vol. 278, Issue 28, 25386-25394, July 11, 2003

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Inhibitory Effects of Insulin-like Growth Factor-1 and Osteogenic Protein-1 on Fibronectin Fragment- and Interleukin-1-stimulated Matrix Metalloproteinase-13 Expression in Human Chondrocytes^*

Hee-Jeong Im , Carol Pacione , Susan Chubinskaya  , Andre J. van Wijnen ¶, Yubo Sun || and Richard F. Loeser   **

From the Departments of Biochemistry and Internal Medicine, Section of Rheumatology, Rush Medical College, Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612, the ^¶Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, and the ^||Department of Medicine, University of Miami School of Medicine, Miami, Florida 33101

Matrix metalloproteinase-13 (collagenase-3), a member of the family of matrix metalloproteinases (MMPs), plays a major pathological role in the cartilage destruction of arthritis. A dramatic up-regulation of MMP-13 by inflammatory cytokines such as interleukin (IL)-1 or by fibronectin fragments has been observed in chondrocytes. In this study, we investigated the inhibitory effects of insulin-like growth factor-1 (IGF-1) and osteogenic protein-1 (OP-1) on the expression of MMP-13, which was induced by fibronectin fragment or IL-1 in human immortalized or human primary chondrocytes. IGF-1 and OP-1 each significantly reduced the basal level as well as fibronectin fragment- or IL-1-stimulated transcription of the MMP-13 gene in a dose-dependent fashion with the corresponding decreases in the protein level of MMP-13. The most prominent suppressive effect was observed by the combination of IGF-1 and OP-1, which decreased the basal promoter activity by 60% and almost completely abrogated the fibronectin fragment-stimulated MMP-13 promoter activity. OP-1 was found to enhance mRNA levels of IGF-1 and the IGF-1 receptor, the latter of which appeared to be responsible for the combined effect of IGF-1 and OP-1. The suppressive effect of IGF-1 and OP-1 on MMP-13 expression was due in part to down-regulation of the expression of pro-inflammatory cytokines and the activity of their intermediate molecules, including NF-B and AP-1 factors. We propose that IGF-1 and OP-1 could be key physiological regulators of MMP-13 gene expression and that the combination of IGF-1 and OP-1 may be useful in controlling the excess catabolic activity in arthritis.

Received for publication, February 26, 2003 , and in revised form, May 2, 2003.

^* This work was supported by National Institutes of Health Grants AG16697 (to R. F. L.), AG47654 (to S. C.), and AR49003 (to R. F. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Rheumatology, Rush-Presbyterian-St. Luke's Medical Center, 1725 W. Harrison, Suite 1017, Chicago, IL 60612. Tel.: 312-942-8994; Fax: 312-942-3053; E-mail: rloeser{at}rush.edu.

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