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J. Biol. Chem., Vol. 282, Issue 2, 1080-1086, January 12, 2007

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Heparan Sulfate Proteoglycans (HSPGs) Modulate BMP2 Osteogenic Bioactivity in C2C12 Cells^*

Xiangyang Jiao, Paul C. Billings, Michael P. O'Connell, Frederick S. Kaplan^¶, Eileen M. Shore^||, and David L. Glaser¹

From the Center For Research in Fibrodysplasia Ossificans Progressiva (FOP) and Related Disorders and the Departments of Orthopaedics, ^¶Medicine and ^||Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Cell surface heparan sulfate proteoglycans (HSPGs) have been implicated in bone morphogenetic protein (BMP)-mediated morphogenesis by regulating BMP activity and gradient formation. However, the direct role of HSPGs in BMP signaling is poorly understood. Here we show that HSPGs directly regulate BMP2-mediated transdifferentiation of C2C12 myoblasts into osteoblasts. HSPGs sequester BMP2 at the cell surface and mediate BMP2 internalization. Depletion of cell surface HSPGs by heparinase III treatment or decreased glycosaminoglycan chain sulfation with sodium chlorate enhances BMP2 morpho-genetic bioactivity. The addition of exogenous heparin, a widely used anticoagulant, reduced BMP2 signaling. Our results suggest that cell surface HSPGs mediate BMP2 internalization and modulate BMP2 osteogenic activity.

Received for publication, December 16, 2005 , and in revised form, September 7, 2006.

^* This work was supported by grants from the International Fibrodysplasia Ossificans Progressiva Association (IFOPA), The Ian Cali Endowment, The Center for Research on FOP and Related Disorders, The Isaac and Rose Nassau Professorship of Orthopaedic Molecular Medicine, and the National Institutes of Health (Grant R01 AR19160841) and the Orthopaedic Research and Education Foundation Clinician-Scientist award. 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, Hospital of the University of Pennsylvania, Two Silverstein, 3400 Spruce St., Philadelphia, PA 19104. Tel.: 215-662-3350; Fax: 215-349-5928; E-mail: david.glaser{at}uphs.upenn.edu.

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