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J. Biol. Chem., Vol. 283, Issue 36, 24546-24553, September 5, 2008

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Defective Osteoclastogenesis by IKKβ-null Precursors Is a Result of Receptor Activator of NF-B Ligand (RANKL)-induced JNK-dependent Apoptosis and Impaired Differentiation^*

Jesse E. Otero, Simon Dai, Domenica Foglia, Muhammad Alhawagri, Jean Vacher, Manolis Pasparakis^¶, and Yousef Abu-Amer^||1

From the Department of Orthedic Surgery and ^||Department of Cell Biology and Physiology, Washington University School of Mede, St. Louis, Missouri 63110, the Institut de Recherches Cliniques de Montreal, Montreal, Quebec H2W 1R7, Canada, and the ^¶University of Cologne, Cologne D-50674, Germany

It has been reported previously that inhibitory B kinase (IKK) supports osteoclastogenesis through NF-B-mediated prevention of apoptosis. This finding suggests that the ligand for receptor activator of NF-B (RANKL), the master osteoclastogenic cytokine, induces apoptosis of osteoclast precursors (OCPs) in the absence of IKKβ/NF-B competency. To validate this hypothesis, we sought to determine the pro-apoptotic signaling factors induced by RANKL in IKKβ-null osteoclast OCPs and to rescue osteoclast differentiation in the absence of IKKβ through their inhibition. To accomplish this, we generated mice that lack IKKβ in multiple hematopoietic lineages, including OCPs. We found that these mice possess both in vitro and in vivo defects in osteoclast generation, in concurrence with previous reports, and that this defect is a result of susceptibility to RANKL-mediated apoptosis as a result of gain-of-function of JNK activation. We demonstrate that differentiation of OCPs depends on IKKβ because reduced IKKβ mRNA expression correlates with impaired induction of osteoclast differentiation markers in response to RANKL stimulation. We further show that fine-tuned inhibition of JNK activation in these cells inhibits RANKL-induced apoptosis and restores the ability of IKKβ-null OCPs to become mature osteoclasts. Our data highlight the pro-osteoclastogenic and anti-apoptotic roles of IKKβ in OCPs and identify a pro-apoptotic mechanism activated within the RANK signalosome.

Received for publication, January 17, 2008 , and in revised form, June 13, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AR049192 and AR054326 (to Y. A.-A.). This work was also supported by Ruth L. Kirschstein Predoctoral National Research Service Award AR055392-01 (to J. E. O.) and Shriners Hospital for Children Grants 8510 and 8570 (to Y. A.-A). 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 To whom correspondence should be addressed: Washington University Orthopedics, One Barnes-Jewish Hospital Plaza, Suite 11300, Box 8233, St. Louis, MO 63110. Fax: 314-362-0334; E-mail: abuamery{at}wudosis.wustl.edu.

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