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J. Biol. Chem., Vol. 280, Issue 33, 29964-29970, August 19, 2005

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Fas Binding to Calmodulin Regulates Apoptosis in Osteoclasts^*

Xiaojun Wu, Eun-Young Ahn, Margaret A. McKenna, Hyeonju Yeo, and Jay M. McDonald¶

From the Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294 and the Veterans Affairs Medical Center, Birmingham, Alabama 35233

Promotion of osteoclast apoptosis is one therapeutic approach to osteoporosis. Calmodulin, the major intracellular Ca²⁺ receptor, modulates both osteoclastogenesis and bone resorption. The calmodulin antagonist, trifluoperazine, rescues bone loss in ovariectomized mice (Zhang, L., Feng, X., and McDonald, J. M. (2003) Endocrinology 144, 4536-4543). We show here that a 3-h treatment of mouse osteoclasts with either of the calmodulin antagonists, tamoxifen or trifluoperazine, induces osteoclast apoptosis dose-dependently. Tamoxifen, 10 µM, and trifluoperazine, 10 µM, induce 7.3 ± 1.8-fold and 5.3 ± 0.9-fold increases in osteoclast apoptosis, respectively. In Jurkat cells, calmodulin binds to Fas, the death receptor, and this binding is regulated during Fas-mediated apoptosis (Ahn, E. Y., Lim, S. T., Cook, W. J., and McDonald, J. M. (2004) J. Biol. Chem. 279, 5661-5666). In osteoclasts, calmodulin also binds Fas. When osteoclasts are treated with 10 µM trifluoperazine, the binding between Fas and calmodulin is dramatically decreased at 15 min and gradually recovers by 60 min. A point mutation of the Fas death domain in the Lpr^-cg mouse renders Fas inactive. Using glutathione S-transferase fusion proteins, the human Fas cytoplasmic domain is shown to bind calmodulin, whereas a point mutation (V254N) comparable with the Lpr^-cg mutation in mice has markedly reduced calmodulin binding. Osteoclasts derived from Lpr^-cg mice have diminished calmodulin/Fas binding and are more sensitive to calmodulin antagonist-induced apoptosis than those from wild-type mice. Both tamoxifen- and trifluoperazine-induced apoptosis are increased 1.6 ± 0.2-fold in Lpr^-cg-derived osteoclasts compared with osteoclasts derived from wild-type mice. In summary, calmodulin antagonists induce apoptosis in osteoclasts by a mechanism involving interference with calmodulin binding to Fas. The effects of calmodulin/Fas binding on calmodulin antagonist-induced apoptosis may open a new avenue for therapy for osteoporosis.

Received for publication, January 20, 2005 , and in revised form, June 8, 2005.

^* This work was supported by National Institutes of Health Grant (NIH)/NIAMS Grant RO1 AR 43225 and NIH/NIAMS Grant P30AR46031 (to J. M. M.). 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 should be addressed: University of Alabama at Birmingham, 509 LHRB, 1530 3rd Ave. S., Birmingham, AL 35294-0007. Tel.: 205-934-6666; Fax: 205-975-9927; E-mail: mcdonald{at}uab.edu.

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