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J. Biol. Chem., Vol. 282, Issue 50, 36240-36249, December 14, 2007

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Runx2- and Histone Deacetylase 3-mediated Repression Is Relieved in Differentiating Human Osteoblast Cells to Allow High Bone Sialoprotein Expression^*

Virginie Lamour, Cédric Detry, Christelle Sanchez¹, Yves Henrotin, Vincent Castronovo, and Akeila Bellahcène²

From the Metastasis Research Laboratory, Center of Experimental Cancer Research and Bone and Cartilage Metabolism Research Unit, University of Liège, 4000 Liège, Belgium

Bone sialoprotein (BSP) is a bone matrix glycoprotein whose expression coincides with terminal osteoblastic differentiation and the onset of mineralization. In this study we show that BSP expression is considerably increased in confluent Saos-2 human osteosarcoma cells and in differentiating normal human osteoblasts, concomitantly with the decrease of Runx2, a key transcription factor controlling bone formation. Therefore, we investigated the role of Runx2 in the regulation of BSP expression in Saos-2 cells. Using a mobility shift assay, we demonstrated that Runx2 binds to the BSP promoter only in preconfluent cells. Histone deacetylase 3 (HDAC3) has been recently shown to act as a Runx2 co-repressor. Chromatin immunoprecipitation assays demonstrated that both Runx2 and HDAC3 are detectable at the BSP promoter in preconfluent Saos-2 cells but not when they are confluent and overexpress BSP. Consistently, nuclear Runx2 protein level is down-regulated, whereas Saos-2 cells became increasingly confluent. Finally, the suppression of HDAC3, Runx2, or both by RNA interference induced the expression of BSP at both mRNA and protein levels in Saos-2 cells. Our data demonstrate that Runx2 and HDAC3 repress BSP gene expression and that this repression is suspended upon osteoblastic cell differentiation. Both the nuclear disappearance of Runx2 and the non-recruitment of HDAC3 represent new means to relieve Runx2-mediated suppression of BSP expression, thus allowing the acquisition of a fully differentiated and mineralization-competent phenotype by osteoblast cells.

Received for publication, July 16, 2007 , and in revised form, October 12, 2007.

^* This work was supported by grants from the National Fund for Scientific Research (NFSR) (Belgium), the Inter-University Attraction Pole (IAP-P5/31), and the University of Liège (Fonds Spéciaux), Belgium. We acknowledge the support of the European Commission through METABRE Contract CEE LSHC-CT-2004-503049. 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 A postdoctoral researcher at NFSR.

² A Research Associate of the NFSR. To whom correspondence should be addressed: Metastasis Research Laboratory, University of Liège, Tour de Pathologie, Bât B23, Sart-Tilman, 4000 Liège, Belgium. Tel.: 3243662557; Fax: 3243662975; E-mail: a.bellahcene{at}ulg.ac.be.

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