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J. Biol. Chem., Vol. 283, Issue 7, 3816-3826, February 15, 2008

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BMP-2 Induces Osterix Expression through Up-regulation of Dlx5 and Its Phosphorylation by p38^*

Arnau Ulsamer¹², M^a. José Ortuño¹³, Silvia Ruiz¹, Antonio R. G. Susperregui², Nelson Osses, José Luis Rosa, and Francesc Ventura⁴

From the Departament de Ciències Fisiològiques II, Universitat de Barcelona, IDIBELL, L'Hospitalet de Llobregat, E-08907 Spain and Instituto de Química, Facultad de Ciencias Básicas y Matemáticas, Pontificia Universidad Católica de Valparaíso, 4059 Valparaiso, Chile

Osterix, a zinc-finger transcription factor, is specifically expressed in osteoblasts and osteocytes of all developing bones. Because no bone formation occurs in Osterix null mice, Osterix is thought to be an essential regulator of osteoblast differentiation. We report that bone morphogenetic protein-2 (BMP-2) induces an increase in Osterix expression, which is mediated through a homeodomain sequence located in the proximal region of the Osterix promoter. Our results demonstrate that induction of Dlx5 by BMP-2 mediates Osterix transcriptional activation. First, BMP-2 induction of Dlx5 precedes the induction of Osterix. Second, Dlx5 binds to the BMP-responsive homeodomain sequences both in vitro and in vivo. Third, Dlx5 overexpression and knock-down assays demonstrate its role in activating Osterix expression in response to BMP-2. Furthermore, we show that Dlx5 is a novel substrate for p38 MAPK in vitro and in vivo and that Ser-34 and Ser-217 are the sites phosphorylated by p38. Phosphorylation at Ser-34/217 increases the transactivation potential of Dlx5. Thus, we propose that BMP activates expression of Osterix through the induction of Dlx5 and its further transcriptional activation by p38-mediated phosphorylation.

Received for publication, June 8, 2007 , and in revised form, November 8, 2007.

^* This research was supported by Ministerio de Educación y Ciencia Grants BFU2005-01474 and ISCIII (RETIC RD06/0020) and by the Generalitat de Catalunya (Distinció de la Generalitat a joves investigadors). 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 and 2.

¹ These authors contributed equally to this work.

² Recipients of fellowships from the Ministerio de Educación y Ciencia.

³ Recipient of a fellowship from the University of Barcelona.

⁴ To whom correspondence should be addressed: Departament de Ciències Fisiològiques II, Universitat de Barcelona, IDIBELL. C/Feixa Llarga s/n. E-08907 L'Hospitalet de Llobregat, Spain. Tel.: 34-934024281; Fax: 34-934024268; E-mail: fventura{at}ub.edu.

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