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J. Biol. Chem., Vol. 282, Issue 26, 18676-18685, June 29, 2007

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A Novel Regulatory Role for Stromal-derived Factor-1 Signaling in Bone Morphogenic Protein-2 Osteogenic Differentiation of Mesenchymal C2C12 Cells^*

Wei Zhu¹, Oheneba Boachie-Adjei^¶, Bernard A. Rawlins^¶, Baruch Frenkel^||, Adele L. Boskey, Lionel B. Ivashkiv, and Carl P. Blobel

From the Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, New York 10021, ^¶Spinal Deformity Service, Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, New York 10021, ^||Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, and Musculoskeletal Integrity Program, Hospital for Special Surgery, New York, New York 10021

Stromal-derived factor 1 (SDF-1) is a chemokine with important functions in development and postnatal tissue homeostasis. SDF-1 signaling via the G-protein-coupled receptor CXCR4 regulates the recruitment of stem and precursor cells to support tissue-specific repair or regeneration. In this study we examined the contribution of SDF-1 signaling to osteogenic differentiation of mesenchymal C2C12 cells induced by bone morphogenic protein 2 (BMP2). Blocking SDF-1 signaling before BMP2 stimulation by treatment with siRNA, antibodies against SDF-1 or CXCR4, or the G-protein-coupled receptor inhibitor pertussis toxin strongly suppressed BMP2 induction of osteogenic differentiation in C2C12 cells, as evidenced by an early decrease in the expression of the myogenesis inhibitor Id1, the osteogenic master regulators Runx2 and Osx, the osteoblast-associated transcription factors JunB, Plzf, Msx2, and Dlx5, and later of the bone marker proteins osteocalcin and alkaline phosphatase. Similarly, blocking SDF-1/CXCR4 signaling strongly inhibited BMP2-induced osteogenic differentiation of ST2 bone marrow stromal cells. Moreover, we found that the interaction between SDF-1 and BMP2 signaling was mediated via intracellular Smads and MAPK activation. Our data provide the first evidence for a co-requirement of the SDF-1/CXCR4 signaling axis in BMP2-induced osteogenic differentiation of C2C12 and ST2 cells and, thus, uncover a new potential target for modulation of osteogenesis.

Received for publication, November 1, 2006 , and in revised form, April 9, 2007.

^* This work was supported by a grant from Beatrice and Samuel A. Seaver Foundation and the Surgeon-in-Chief Fund from Hospital for Special Surgery. 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: Arthritis and Tissue Degeneration Program, Caspary Research Bldg., 4th floor, Hospital for Special Surgery, 535 E. 70th St., New York, NY 10021. Tel.: 212-774-7017; Fax: 212-774-2560; E-mail: ZhuW{at}HSS.EDU.

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