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J. Biol. Chem., Vol. 279, Issue 40, 41998-42007, October 1, 2004

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Histone Deacetylase 3 Interacts with Runx2 to Repress the Osteocalcin Promoter and Regulate Osteoblast Differentiation^*

Tania M. Schroeder, Rachel A. Kahler, Xiaodong Li¶||, and Jennifer J. Westendorf¶||**

From the Graduate Program in Biochemistry, Molecular Biology and Biophysics, and the Graduate Program in Microbiology, Immunology and Cancer Biology, ^¶The Cancer Center, and the ^||Department of Orthopaedic Surgery, the University of Minnesota, Minneapolis, Minnesota 55455

The Runt domain transcription factor Runx2 (AML-3, and Cbfa1) is essential for osteoblast development, differentiation, and bone formation. Runx2 positively or negatively regulates osteoblast gene expression by interacting with a variety of transcription cofactor complexes. In this study, we identified a trichostatin A-sensitive autonomous repression domain in the amino terminus of Runx2. Using a candidate approach, we found that histone deacetylase (HDAC) 3 interacts with the amino terminus of Runx2. In transient transfection assays, HDAC3 repressed Runx2-mediated activation of the osteocalcin promoter. HDAC inhibitors and HDAC3-specific short hairpin RNAs reversed this repression. In vivo, Runx2 and HDAC3 associated with the osteocalcin promoter. These data indicate that HDAC3 regulates Runx2-mediated transcription of osteoblast genes. Suppression of HDAC3 in MC3T3 preosteoblasts by RNA interference accelerated the expression of Runx2 target genes, osteocalcin, osteopontin, and bone sialoprotein but did not significantly alter Runx2 levels. Matrix mineralization also occurred earlier in HDAC3-suppressed cells, but alkaline phosphatase expression was not affected. Thus, HDAC3 regulates osteoblast differentiation and bone formation. Although HDAC3 is likely to affect the activity of multiple proteins in osteoblasts, our data show that it actively regulates the transcriptional activity of the osteoblast master protein, Runx2.

Received for publication, April 2, 2004 , and in revised form, July 22, 2004.

^* This work was supported by National Institutes of Health Grants AR48147 and AR050938, The V Foundation for Cancer Research, and The Cancer Center at the University of Minnesota. 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.

^** To whom correspondence should be addressed: The Cancer Center, University of Minnesota, MMC 806, 420 Delaware St. SE, Minneapolis, MN 55455. Tel.: 612-626-3365; Fax: 612-626-4915; E-mail: weste047{at}umn.edu.

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