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J. Biol. Chem., Vol. 282, Issue 15, 11347-11355, April 13, 2007

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Cartilage Oligomeric Matrix Protein Associates with Granulin-Epithelin Precursor (GEP) and Potentiates GEP-stimulated Chondrocyte Proliferation^*

Ke Xu, Yan Zhang, Kirill Ilalov, Cathy S. Carlson, Jian Q. Feng^¶, Paul E. Di Cesare^||, and Chuan-ju Liu^||**1

From the Department of Orthopaedic Surgery, New York University Hospital for Joint Diseases, New York, New York 10003, the ^||Department of Cell Biology, New York University School of Medicine, New York, New York 10016, the Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota 55108, the ^¶Department of Biomedical Sciences, Baylor College of Dentistry, Texas A & M University System Health Science Center, Dallas, Texas 75246, and the ^**Institute of Pathogenic Biology, Shandong University School of Medicine, Jinan, Shandong 250012, China

Mutations in human cartilage oligomeric matrix protein (COMP) have been linked to the development of pseudoachondroplasia and multiple epiphyseal dysplasia; however, the functions of both wild-type and mutant COMP in the skeletogenesis remain unknown. In an effort to define the biological functions of COMP, a functional genetic screen based on the yeast two-hybrid system was performed. This led to the identification of granulin-epithelin precursor (GEP), an autocrine growth factor, as a COMP-associated partner. COMP directly binds to GEP both in vitro and in vivo, as revealed by in vitro pull down and co-immunoprecipitation assays. GEP selectively interacts with the epidermal growth factor repeat domain of COMP but not with the other three functional domains of COMP. The granulin A repeat unit of GEP is required and sufficient for association with COMP. COMP co-localizes with GEP predominantly in the pericellular matrix of transfected rat chondrosarcoma cell and primary human chondrocytes. Staining of musculoskeletal tissues of day 19 mouse embryo with antibodies to GEP is restricted to chondrocytes in the lower proliferative and upper hypertrophic zones. Overexpression of GEP stimulates the proliferation of chondrocytes, and this stimulation is enhanced by COMP. In addition, COMP appears to be required for GEP-mediated chondrocyte proliferation, since chondrocyte proliferation induced by GEP is dramatically inhibited by an anti-COMP antibody. These findings provide the first evidence linking the association of COMP and GEP and identifying a previously unrecognized growth factor (i.e. GEP) in cartilage.

Received for publication, September 11, 2006 , and in revised form, January 16, 2007.

^* This study was supported by National Institutes of Health Research Grants AR052022 (to C. L.), AR050620 (to C. L.), and RR14099 (to C. C.) and a Young Scholar Award from the Arthritis Foundation (to C. 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.

¹ To whom correspondence should be addressed: Dept. of Orthopaedic Surgery, New York University School of Medicine, 301 E. 17th St., New York, NY 10003. Tel.: 212-598-6103; Fax: 212-598-6096; E-mail: Chuanju.liu{at}med.nyu.edu.

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