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J. Biol. Chem., Vol. 282, Issue 25, 18245-18253, June 22, 2007

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NF-B p50 and p52 Regulate Receptor Activator of NF-B Ligand (RANKL) and Tumor Necrosis Factor-induced Osteoclast Precursor Differentiation by Activating c-Fos and NFATc1^*

Teruhito Yamashita¹, Zhenqiang Yao¹, Fang Li, Qian Zhang, I. Raul Badell, Edward M. Schwarz, Sunao Takeshita^¶, Erwin F. Wagner^||, Masaki Noda^**, Koichi Matsuo, Lianping Xing, and Brendan F. Boyce²

From the Department of Pathology and Laboratory Medicine and Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York 14642, the ^¶Department of Bone and Joint Disease, Research Institute, National Center for Geriatrics and Gerontology, Obu 474-8522, Japan, the ^||Research Institute of Molecular Pathology, A-1030 Vienna, Austria, the ^**Tokyo Medical and Dental University, Tokyo 101-0062, Japan, and the Department of Microbiology and Immunology, School of Medicine, Keio University, Tokyo 160-8582, Japan

Postmenopausal osteoporosis and rheumatoid joint destruction result from increased osteoclast formation and bone resorption induced by receptor activator of NF-B ligand (RANKL) and tumor necrosis factor (TNF). Osteoclast formation induced by these cytokines requires NF-B p50 and p52, c-Fos, and NFATc1 expression in osteoclast precursors. c-Fos induces NFATc1, but the relationship between NF-B and these other transcription factors in osteoclastogenesis remains poorly understood. We report that RANKL and TNF can induce osteoclast formation directly from NF-B p50/p52 double knockout (dKO) osteoclast precursors when either c-Fos or NFATc1 is expressed. RANKL- or TNF-induced c-Fos up-regulation and activation are abolished in dKO cells and in wild-type cells treated with an NF-B inhibitor. c-Fos expression requires concomitant RANKL or TNF treatment to induce NFATc1 activation in the dKO cells. Furthermore, c-Fos expression increases the number and resorptive capacity of wild-type osteoclasts induced by TNF in vitro. We conclude that NF-B controls early osteoclast differentiation from precursors induced directly by RANKL and TNF, leading to activation of c-Fos followed by NFATc1. Inhibition of NF-B should prevent RANKL- and TNF-induced bone resorption.

Received for publication, November 17, 2006 , and in revised form, May 2, 2007.

^* This work is supported by National Institutes of Health Grants AR43510 (to B. F. B.) and AR48697 (to L. X.). 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.

¹ These authors contributed equally to the work.

² To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, 601 Elmwood Ave., Box 626, Rochester, NY 14642. Tel.: 585-275-5837; Fax: 585-273-3637; E-mail: Brendan_Boyce{at}urmc.rochester.edu.

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