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J. Biol. Chem., Vol. 280, Issue 46, 38544-38555, November 18, 2005

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A Novel Role for GADD45 as a Mediator of MMP-13 Gene Expression during Chondrocyte Terminal Differentiation^*

Kosei Ijiri1, Luiz F. Zerbini, Haibing Peng, Ricardo G. Correa, Binfeng Lu¶, Nicole Walsh, Yani Zhao¶, Noboru Taniguchi||, Xu-Ling Huang, Hasan Otu, Hong Wang, Jian Fei Wang, Setsuro Komiya||, Patricia Ducy**, Mahboob U. Rahman2, Richard A. Flavell, Ellen M. Gravallese, Peter Oettgen, Towia A. Libermann, and Mary B. Goldring3

From the Beth Israel Deaconess Medical Center, New England Baptist Bone and Joint Institute and Beth Israel Deaconess Medical Center Genomics Center, and Harvard Medical School, Boston, Massachusetts 02115, Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, the ^¶Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, the ^||Department of Neuro-Musculoskeletal Disorders, Orthopaedic Surgery, Graduate School of Medicine and Dentistry, Kagoshima University, Kagoshima 890-8520, Japan, the ^**Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520-8011

The growth arrest and DNA damage-inducible 45 (GADD45) gene product has been implicated in the stress response, cell cycle arrest, and apoptosis. Here we demonstrated the unexpected expression of GADD45 in the embryonic growth plate and uncovered its novel role as an essential mediator of matrix metalloproteinase-13 (MMP-13) expression during terminal chondrocyte differentiation. We identified GADD45 as a prominent early response gene induced by bone morphogenetic protein-2 (BMP-2) through a Smad1/Runx2-dependent pathway. Because this pathway is involved in skeletal development, we examined mouse embryonic growth plates, and we observed expression of Gadd45 mRNA coincident with Runx2 protein in pre-hypertrophic chondrocytes, whereas GADD45 protein was localized prominently in the nucleus in late stage hypertrophic chondrocytes where Mmp-13 mRNA was expressed. In Gadd45^-/- mouse embryos, defective mineralization and decreased bone growth accompanied deficient Mmp-13 and Col10a1 gene expression in the hypertrophic zone. Transduction of small interfering RNA-GADD45 in epiphyseal chondrocytes in vitro blocked terminal differentiation and the associated expression of Mmp-13 and Col10a1 mRNA in vitro. Finally, GADD45 stimulated MMP-13 promoter activity in chondrocytes through the JNK-mediated phosphorylation of JunD, partnered with Fra2, in synergy with Runx2. These observations indicated that GADD45 plays an essential role during chondrocyte terminal differentiation.

Received for publication, April 18, 2005 , and in revised form, August 19, 2005.

^* This work was supported in part by National Institutes of Health Grants R01-AR45378 and R01-AG22021 (to M. B. G.) and R01-AI49527 (to T. A. L.) and a Biomedical Science Grant from the Arthritis Foundation (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.

The on-line version of this article (available at http://www.jbc.org) contains Fig. S1.

¹ Present address: Dept. of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.

² Present address: Centocor, Inc., 200 Great Valley Pkwy., Malvern, PA 19355-1307.

³ To whom correspondence should be addressed: Harvard Institutes of Medicine, HIM246, 4 Blackfan Circle, Boston, MA 02115-5713. Tel.: 617-667-0742; Fax: 617-975-5299; E-mail: mgoldrin{at}bidmc.harvard.edu.

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