HDAC3 and HDAC7 Have Opposite Effects on Osteoclast Differentiation

Lan Pham; Bria Kaiser; Amanda Romsa; Toni Schwarz; Raj Gopalakrishnan; Eric D. Jensen; Kim C. Mansky

doi:10.1074/jbc.M110.216853

HDAC3 and HDAC7 Have Opposite Effects on Osteoclast Differentiation*

From the Departments of ^‡Developmental and Surgical Science and
^§Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, Minnesota 55455

1↵ To whom correspondence may be addressed: Dept. of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, 16-108B Moos Tower, 515 Delaware St. SE, Minneapolis, MN 55455. Tel.: 612-624-0986; E-mail: jens0709{at}umn.edu.
2↵ To whom correspondence may be addressed: Dept. of Developmental and Surgical Science, University of Minnesota School of Dentistry, 6-320 Moos Tower, 515 Delaware St. SE, Minneapolis, MN 55455. Tel.: 612-626-5582; Fax: 612-626-2571; E-mail: kmansky{at}umn.edu.

Abstract

Histone deacetylases (HDACs) are negative regulators of transcription. Endochondral bone formation including chondrocyte and osteoblast maturation is regulated by HDACs. Very little is known about the role HDACs play in osteoclast differentiation. It has been previously reported that HDAC inhibitors, trichostatin A and sodium butyrate, suppress osteoclast differentiation through multiple mechanisms. In this study, we report that suppression of HDAC3 expression similar to HDAC inhibitors inhibits osteoclast differentiation, whereas osteoclasts suppressed for HDAC7 expression had accelerated differentiation when compared with control cells. Mitf, a transcription factor, is necessary for osteoclast differentiation. We demonstrate that Mitf and HDAC7 interact in RAW 264 cells and osteoclasts. The transcriptional activity of Mitf is repressed by HDAC7. Lastly, we show that either the amino or the carboxyl terminus of HDAC7 is sufficient for transcriptional repression and that the repression of HDAC7 is insensitive to trichostatin A, indicating that HDAC7 represses Mitf at least in part by deacetylation-independent mechanism.

Footnotes

↵* This work was supported, in whole or in part, by National Institutes of Health Grants R03 DE020117 (to E. D. J.) and R01 AR056642 (to R. G.) and MinnCResT Grant T32 DE007288 from the NIDCR (to L. P.).