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J. Biol. Chem., Vol. 283, Issue 17, 11526-11534, April 25, 2008

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The Tec Family Tyrosine Kinase Btk Regulates RANKL-induced Osteoclast Maturation^*

Seoung Hoon Lee¹, Taesoo Kim¹, Daewon Jeong¹, Nacksung Kim^¶, and Yongwon Choi²

From the Departments of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, Department of Microbiology and the Aging-associated Disease Research Center, Yeungnam University College of Medicine, Daegu 705-717, Korea, and the ^¶National Research Laboratory for Regulation of Bone Metabolism and Disease, Chonnam National University Medical School, Gwangju 501-746, Korea

A spontaneous mutation in Bruton's tyrosine kinase (Btk) induces a defect in B-cell development that results in the immunodeficiency diseases X-linked agammaglobulinemia in humans and X-linked immunodeficiency (Xid) in mice. Here we show an unexpected role of Btk in osteoclast formation. When bone marrow cells derived from Xid mice were stimulated with receptor activator of NF-B ligand, an osteoclast differentiation factor, they did not completely differentiate into mature multinucleated osteoclasts. Moreover, we found that the defects appeared to occur at the stage in which mononuclear preosteoclasts fuse to generate multinucleated cells. Supporting this notion, macrophages from Xid mice also failed to form multinucleated foreign body giant cells. The fusion defect of the Xid mutant osteoclasts was caused by decreased expression of nuclear factor of activated T cells c1 (NFATc1), a master regulator of osteoclast differentiation, as well as reduced expression of various osteoclast fusion-related molecules, such as the d2 isoform of vacuolar H⁺-ATPase V0 domain and the dendritic cell-specific transmembrane protein. This deficiency was completely rescued by the introduction of a constitutively active form of NFATc1 into bone marrow-derived macrophages. Our data provide strong evidence that Btk plays a critical role in osteoclast multinucleation by modulating the activity of NFATc1.

Received for publication, October 30, 2007 , and in revised form, January 15, 2008.

^* This work was supported in part by grants from the National Institutes of Health (to Y. C.), from the National Research Laboratory of Korea (R0A-2007-000-20025-0) (to N. K.), and from the Korea Science and Engineering Foundation (R13-2005-005-01004-0) and Yeungnam University for research in 2006 (to D. J.). 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 Fig. S1.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Rm. 308, BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-746-6404; Fax: 215-573-0888; E-mail: ychoi3{at}mail.med.upenn.edu.

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