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J. Biol. Chem., Vol. 280, Issue 14, 13720-13727, April 8, 2005

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Negative Regulation of RANKL-induced Osteoclastic Differentiation in RAW264.7 Cells by Estrogen and Phytoestrogens^*

Verónica García Palacios, Lisa J. Robinson, Christopher W. Borysenko, Thomas Lehmann, Sara E. Kalla, and Harry C. Blair¶

From the Departments of Pathology and Cell Biology and Physiology, University of Pittsburgh and the Veterans Affairs Medical Center, Pittsburgh, Pennsylvania 15243

We studied estrogen effects on osteoclastic differentiation using RAW264.7, a murine monocytic cell line. Differentiation, in response to RANKL and colony-stimulating factor 1, was evaluated while varying estrogen receptor (ER) stimulation by estradiol or nonsteroidal ER agonists was performed. The RAW264.7 cells were found to express ER but not ER. In contrast to RANKL, which decreased ER expression and induced osteoclast differentiation, 10 nM estradiol, 3 µM genistein, or 3 µM daidzein all increased ER expression, stimulated cell proliferation, and decreased multinucleation, with the effects of estrogen daidzein > genistein. However, no estrogen agonist reduced RANKL stimulation of osteoclast differentiation markers or its down-regulation of ER expression by more than 50%. Genistein is also an Src kinase antagonist in vitro, but it did not decrease Src phosphorylation in RAW264.7 cells relative to other estrogen agonists. However, both phytoestrogens and estrogen inhibited RANKL-induced IB degradation and NF-B nuclear localization with the same relative potency as seen in proliferation and differentiation assays. This study demonstrates, for the first time, the direct effects of estrogen on osteoclast precursor differentiation and shows that, in addition to effecting osteoblasts, estrogen may protect bone by reducing osteoclast production. Genistein, which activates ERs selectively, inhibited osteoclastogenesis less effectively than the nonselective phytoestrogen daidzein, which effectively reproduced effects of estrogen.

Received for publication, September 24, 2004 , and in revised form, January 3, 2005.

^* This work was supported by National Institutes of Health Grants AG12951 and AR47700 and by the Department of Veterans Affairs. 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 material.

^¶ To whom correspondence should be addressed: 705 Scaife Hall, University of Pittsburgh, Pittsburgh, PA 15261. E-mail: hcblair{at}imap.pitt.edu.

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