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J. Biol. Chem., Vol. 280, Issue 1, 548-555, January 7, 2005

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Activation of the Discoidin Domain Receptor 2 Induces Expression of Matrix Metalloproteinase 13 Associated with Osteoarthritis in Mice^*

Lin Xu, Haibing Peng¶, Dongying Wu||, Kenpan Hu||, Mary B. Goldring¶, Bjorn R. Olsen||, and Yefu Li||**

From the Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, the ^¶Division of Rheumatology, Beth Israel Deaconess Medical Center and New England Baptist Bone and Joint Institute, Harvard Institutes of Medicine, Boston, Massachusetts 02115, and the ^||Department of Oral and Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts 02115

Human genetic studies indicate that mutations in type IX and XI collagens result in early-onset osteoarthritis (OA) with a wide spectrum of osteochondrodysplasia. However, a convincing causal chain of events underlying the role of these collagen mutations in the pathogenesis of OA has not been elucidated. Here we show that the expression of a cell surface collagen receptor, discoidin domain receptor 2 (DDR2), is increased in chondrocytes of the articular cartilage of knee joints in mice that develop OA as a result of a heterozygous mutation in type XI collagen. At the same time point, 6 months, we also found increased expression and activity of matrix metalloproteinase 13 (MMP-13) in the mutant mouse knee cartilage. The expression of both DDR2 and MMP-13 was increased in chondrocytes cultured on plates coated with native type II collagen but not on gelatin, and overexpression of DDR2, but not of a truncated form, was found to induce the expression of MMP-13 when chondrocytes were cultured on type II collagen but not on plastic. The DDR2-induced expression of MMP-13 appears to be specific, since we did not observe induction of MMP-1, MMP-3, MMP-8, ADAMTS-4, ADAMTS-5, and IL-1 transcripts in human chondrocytes or Mmp-3, Mmp-8, Adamts-4, Adamts-5, and Il-1 in mouse chondrocytes. Our data suggest that the defect in the cartilage matrix of mice that are heterozygous for a type XI collagen mutation (cho/+) permits activation and up-regulation of DDR2 in chondrocytes. This could be due to increased exposure of chondrocytes to type II collagen as a result of the decreased amount of type XI collagen in the mutant cartilage. The specific induction of MMP-13 by DDR2 in response to its cartilage-specific ligand, type II collagen, may contribute to cartilage damage in hereditary OA.

Received for publication, September 24, 2004 , and in revised form, October 25, 2004.

^* This work was supported by National Institutes of Health Grants P01-AR050245 (to Y. L.), R01-AR36819 (to B. R. O. and L. X.), and R01-AR45378 and R01-AG22021 (to M. B. G.). 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.

This article was selected as a Paper of the Week.

These authors contributed equally to this work.

^** To whom correspondence should be addressed: 188 Longwood Ave., Boston, MA 02115. Tel.: 617-432-1835; Fax: 617-432-3221; E-mail: yefu_li{at}hms.harvard.edu.

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