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J. Biol. Chem., Vol. 279, Issue 7, 5329-5337, February 13, 2004

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Parathyroid Hormone Induction of the Osteocalcin Gene

REQUIREMENT FOR AN OSTEOBLAST-SPECIFIC ELEMENT 1 SEQUENCE IN THE PROMOTER AND INVOLVEMENT OF MULTIPLE SIGNALING PATHWAYS^*

Di Jiang, Renny T. Franceschi, Heidi Boules, and Guozhi Xiao¶

From the Department of Periodontics, Prevention, and Geriatrics, School of Dentistry and Department of Biological Chemistry, School of Medicine, University of Michigan, Ann Arbor, Michigan 48109-1078

Parathyroid hormone (PTH) is an important peptide hormone regulator of bone formation and osteoblast activity. However, its mechanism of action in bone cells is largely unknown. This study examined the effect of PTH on mouse osteocalcin gene expression in MC3T3-E1 preosteoblastic cells and primary cultures of bone marrow stromal cells. PTH increased the levels of osteocalcin mRNA 4–5-fold in both cell types. PTH also stimulated transcriptional activity of a 1.3-kb fragment of the mouse osteocalcin gene 2 (mOG2) promoter. Inhibitor studies revealed a requirement for protein kinase A, protein kinase C, and mitogen-activated protein kinase pathways in the PTH response. Deletion of the mOG2 promoter sequence from –1316 to –116 caused no loss in PTH responsiveness whereas deletion from –116 to –34 completely prevented PTH stimulation. Interestingly, this promoter region does not contain the RUNX2 binding site shown to be necessary for PTH responsiveness in other systems. Nuclear extracts from PTH-treated MC3T3-E1 cells exhibited increased binding to OSE1, a previously described osteoblast-specific enhancer in the mOG2 promoter. Furthermore, mutation of OSE1 in DNA transfection assays established the requirement for this element in the PTH response. Collectively, these studies establish that actions of PTH on the osteocalcin gene are mediated by multiple signaling pathways and require OSE1 and associated nuclear proteins.

Received for publication, October 21, 2003 , and in revised form, November 18, 2003.

^* This work was supported by National Institutes of Health Grants DE14454 (to G. X.) and DE13386, DE 11723, and DE12211 (to R. T. F.). 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: Dept. of Periodontics, Prevention, and Geriatrics, School of Dentistry, University of Michigan, 1011 N. University Ave., Ann Arbor, MI 48109-078. Tel.: 734-763-5487; Fax: 734-763-5503; E-mail: xiaogz{at}umich.edu.

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