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J. Biol. Chem., Vol. 278, Issue 44, 43121-43129, October 31, 2003

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Runx2 Integrates Estrogen Activity in Osteoblasts^*

Thomas L. McCarthy, Wei-Zhong Chang, Yuan Liu, and Michael Centrella

From the Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520-8041

Steroids significantly effect skeletal integrity. For example, bone mass decreases with glucocorticoid excess or with estrogen depletion after menopause. Glucocorticoid suppresses gene expression by an essential skeletal tissue transcription factor, Runx2, in rat osteoblasts. We now report that estrogen enhances Runx2 activity in dose- and estrogen receptor-dependent ways independently of changes in Runx2 levels or its DNA binding potential. Estrogen receptor and Runx2 can be collected by co-immunoprecipitation. By two-hybrid gene expression analysis, high affinity complex formation involves portions of Runx2 outside of its own DNA binding domain and the DNA binding domain of the estrogen receptor. Consistent with this interaction, the stimulatory effect of estrogen on Runx2 activity is lost when the DNA binding domain of the estrogen receptor is eliminated. Unlike the stimulatory effect of estrogen and the inhibitory effect of glucocorticoid, androgen fails to increase Runx2 activity, whereas Runx2 potently suppresses gene expression induced by all three steroids. Finally, estrogen increases gene transcription by the transforming growth factor- type I receptor gene promoter, which contains several Runx binding sequences, and enhances Smad dependent gene expression by transforming growth factor- in osteoblasts. These results reveal that Runx2 can integrate complex effects on gene transcription in hormone-, growth factor-, and tissue-restricted ways.

Received for publication, June 19, 2003 , and in revised form, August 27, 2003.

^* This work was supported by United States Public Health Service awards AR39201 from NIAMS, National Institutes of Health, and DK56310 from NIDDK, National Institutes of Health, and the Arthritis Foundation Basic Science research program. 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 may be addressed: 333 Cedar St., P.O. Box 208041, New Haven, CT 06520-8041. Tel.: 203-785-4927; Fax: 203-785-5714; E-mail: thomas.mccarthy{at}yale.edu.

To whom correspondence may be addressed: 333 Cedar St., P.O. Box 208041, New Haven, CT 06520-8041. Tel.: 203-785-4927; Fax: 203-785-5714; E-mail: michael.centrella{at}yale.edu

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