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J. Biol. Chem., Vol. 283, Issue 28, 19359-19370, July 11, 2008

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Bone Morphogenetic Protein 2 Mediates Dentin Sialophosphoprotein Expression and Odontoblast Differentiation via NF-Y Signaling^*

Shuo Chen, Jelica Gluhak-Heinrich, Marcos Martinez, Tong Li, Yimin Wu^¶, Hui-Hsiu Chuang, Lei Chen^||, Juan Dong^**, Isabel Gay^**, and Mary MacDougall^**1

From the Department of Pediatric Dentistry, Department of Orthodontics, and ^¶Department of Neurosurgery, University of Texas Health Science Center, San Antonio, Texas 78229-3900, the ^||Department of Orthodontics, Fujian Medical University, Fujian 350005, China, and the ^**Department of Oral/Maxillofacial Surgery, University of Alabama at Birmingham School of Dentistry, Birmingham, Alabama 35294-0007

Dentin sialophosphoprotein (DSPP), an important odontoblast differentiation marker, is necessary for tooth development and mineralization. Bone morphogenetic protein 2 (BMP2) plays a vital role in odontoblast function via diverse signal transduction systems. We hypothesize that BMP2 regulates DSPP gene transcription and thus odontoblast differentiation. Here we report that expression of BMP2 and DSPP is detected during mouse odontogenesis by in situ hybridization assay, and BMP2 up-regulates DSPP mRNA and protein expression as well as DSPP-luciferase promoter activity in mouse preodontoblasts. By sequentially deleting fragments of the mouse DSPP promoter, we show that a BMP2-response element is located between nucleotides –97 and –72. By using antibody and oligonucleotide competition assays in electrophoretic mobility shift analysis and chromatin immunoprecipitation experiments, we show that the heterotrimeric transcription factor Y (NF-Y) complex physically interacts with the inverted CCAAT box within the BMP2-response element. BMP2 induces NF-Y accumulation into the nucleus increasing its recruitment to the mouse DSPP promoter in vivo. Furthermore, forced overexpression of NF-Y enhances promoter activity and increases endogenous DSPP protein levels. In contrast, mutations in the NF-Y-binding motif reduce BMP2-induced DSPP transcription. Moreover, inhibiting BMP2 signaling by Noggin, a BMP2 antagonist, results in significant inhibition of DSPP gene expression in preodontoblasts. Taken together, these results indicate that BMP2 mediates DSPP gene expression and odontoblast differentiation via NF-Y signaling during tooth development.

Received for publication, November 19, 2007 , and in revised form, April 8, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants PO1 DE113221 and DE01448401A2 from NIDCR. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3.

¹ To whom correspondence should be addressed: Dept. of Oral/Maxillofacial Surgery, University of Alabama, School of Dentistry, 1919 7th Ave. South, SDB 702, Birmingham, AL 35294-0007. Tel.: 205-996-5122; Fax: 205-996-5104; E-mail: MacDougall{at}uab.edu.

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