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J. Biol. Chem., Vol. 282, Issue 1, 39-48, January 5, 2007

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The LIM Protein, LIMD1, Regulates AP-1 Activation through an Interaction with TRAF6 to Influence Osteoclast Development^*

Yunfeng Feng¹, Haibo Zhao^¶1, Hilary F. Luderer, Holly Epple, Roberta Faccio, F. Patrick Ross^¶, Steven L. Teitelbaum^¶, and Gregory D. Longmore²

From the Departments of Medicine, Cell Biology, ^¶Pathology, and Orthopedic Surgery, Washington University, St. Louis, Missouri 63110

Increasingly a number of proteins important in the regulation of bone osteoclast development have been shown primarily influence osteoclastogenesis under conditions of physiologic or pathologic stress. Why basal osteoclastogenesis is normal and how these proteins regulate stress osteoclastogenic responses, as opposed to basal osteoclastogenesis, is unclear. LIM proteins of the Ajuba/Zyxin family localize to cellular sites of cell adhesion where they contribute to the regulation of cell adhesion and migration, translocate into the nucleus where they can affect cell fate, but are also found in the cytoplasm where their function is largely unknown. We show that one member of this LIM protein family, Limd1, is uniquely up-regulated during osteoclast differentiation and interacts with Traf6, a critical cytosolic regulator of RANK-L-regulated osteoclast development. Limd1 positively affects the capacity of Traf6 to activate AP-1, and Limd1^–/– osteoclast precursor cells are defective in the activation of AP-1 and thus induction of NFAT2. Limd1^–/– mice, although having normal basal bone osteoclast numbers and bone density, are resistant to physiological and pathologic osteoclastogenic stimuli. These results implicate Limd1 as a potentially important regulator of osteoclast development under conditions of stress.

Received for publication, August 3, 2006 , and in revised form, October 23, 2006.

^* This work was supported by National Institutes of Health Grant CA75315 and the Washington University/Pfizer biomedical research program (to G. D. L) and National Institutes of Health Grants AR032788, AR046523, and AR048853 (to S. L. T.) and AR046852 and AR048812 (to F. P. R.). 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 Figs. S1–S4.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Division of Hematology, Washington University, School of Medicine, 660 South Euclid Ave., St. Louis MO 63110. Tel.: 314-362-8834; Fax: 314-362-8826; E-mail: glongmor{at}im.wustl.edu.

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