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J. Biol. Chem., Vol. 281, Issue 29, 20160-20170, July 21, 2006

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Concerted Action of Smad and CREB-binding Protein Regulates Bone Morphogenetic Protein-2-stimulated Osteoblastic Colony-stimulating Factor-1 Expression^*

Nandini Ghosh-Choudhury¹, Prajjal K. Singha, Kathleen Woodruff, Patricia St Clair, Sameer Bsoul^¶, Sherry L. Werner, and Goutam Ghosh Choudhury^||**2

From the Departments of Pathology, ^||Medicine, and ^¶Dental Diagnostic Science, University of Texas Health Science Center, the South Texas Veterans Health Care System, and the ^**Geriatrics Research, Education and Clinical Center, San Antonio, Texas 78229

Bone remodeling depends upon proper osteoblast and osteoclast function. Bone morphogenetic protein-2 (BMP-2) stimulates differentiation of osteoblasts from pluripotent precursors. Osteoclast formation depends on the concerted action of osteoblast-derived receptor activator of NF-B ligand and colony-stimulating factor-1 (CSF-1). BMP-2 stimulates receptor activator of NF-B ligand expression. However, the effect of BMP-2 on CSF-1 expression has not been studied. We investigated the role of BMP-2 in CSF-1 expression in osteogenic C2C12 cells. Incubation of C2C12 cells with BMP-2 supported osteoclastogenesis of spleen cells with a concomitant increase in expression of CSF-1 mRNA and protein. To determine the mechanism, we identified a BMP-responsive element between –627 bp and –509 bp in the CSF-1 promoter. DNase I footprint analysis revealed the presence of consensus Smad binding motif in this region. Electrophoretic mobility shift assay showed BMP-2-stimulated binding of proteins to this motif. Mutation of core sequence as well as its 5'- and 3'-flanking sequences abolished the DNA-protein interaction resulting in inhibition of CSF-1 transcription. Supershift analysis detects the presence of Smads 1, 5, and 4 and the transcriptional coactivator CREB-binding protein in the BMP-responsive element-protein complex. In addition, Smads 1 and 5 alone or in combination with Smad 4 increased CSF-1 transcription. Furthermore, CREB-binding protein markedly increased transcription of CSF-1. These data represent the first evidence that BMP-2 increases the osteoclastogenic CSF-1 expression by a transcriptional mechanism using the canonical Smad pathway and provide a mechanism for BMP-2-induced osteoclast differentiation.

Received for publication, October 11, 2005 , and in revised form, March 29, 2006.

^* This work was supported in part by grants from the National Institutes of Health (Grant RO1-AR52425 to N. G.-C.); by American Heart Association Western Affiliate (to N. G.-C.); by Veterans Affairs Medical Research Service VISN award (to N. G.-C.); by Veterans Integrated Service Network Review Award (to N. G.-C.); by Cancer Therapy and Research Center (to N. G.-C.); by Veterans Affairs Medical Research Service Merit Review Award (to G. G. C.); by National Institutes of Health Grants RO1 DK 50190, DK 55815, and P50 DK061597 (to G. G. C.); and by a Juvenile Diabetes Research Foundation regular research grant (to G. G. C.). 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.

² A Veterans Affairs Medical Research Service Career Scientist.

¹ To whom correspondence should be addressed: Dept. of Pathology, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229. Tel.: 210-567-3108; Fax: 210-567-2303; E-mail: choudhury{at}uthscsa.edu.

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