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J. Biol. Chem., Vol. 280, Issue 5, 3583-3589, February 4, 2005

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Akt1/Akt2 and Mammalian Target of Rapamycin/Bim Play Critical Roles in Osteoclast Differentiation and Survival, Respectively, Whereas Akt Is Dispensable for Cell Survival in Isolated Osteoclast Precursors^*

Toshifumi Sugatani and Keith A. Hruska

From the Department of Pediatrics, Cell and Molecular Biology Unit, Washington University School of Medicine, St. Louis, Missouri 63110

Akt, also known as protein kinase B, is a serine/threonine protein kinase with antiapoptotic activities; also, it is a downstream target of phosphatidylinositol 3-kinase. Here we show that Akt1/Akt2 play a critical role in osteoclast differentiation but not cell survival and that mammalian target of rapamycin (mTOR) and Bim, a pro-apoptotic Bcl-2 family member, are required for cell survival in isolated osteoclast precursors. To investigate the function of Akt1, Akt2, mTOR, and Bim, we employed a retroviral system for delivery of small interfering RNA into cells. Loss of Akt1 and/or Akt2 protein inhibited osteoclast differentiation due to down-regulation of IB-kinase (IKK) / activity, phosphorylation of IB-, nuclear translocation of nuclear factor-B (NFB) p50, and NFB p50 DNA-binding activity. Surprisingly, deletion of Akt1 and/or Akt2 protein did not stimulate cleaved caspase-3 activity and failed to promote apoptosis. Conversely, loss of mTOR protein induced apoptosis due to up-regulation of cleaved caspase-3 activity. In addition, we found that mTOR is downstream of phosphatidylinositol 3-kinase (but not Akt) and that macrophage colony-stimulating factor regulates Bim expression through mTOR activation for cell survival. These results demonstrate that Akt1/Akt2 are key elements in osteoclast differentiation and that the macrophage colony-stimulating factor stimulation of mTOR leading to Bim inhibition is essential for cell survival in isolated osteoclast precursors.

Received for publication, September 13, 2004 , and in revised form, November 4, 2004.

^* This study was supported by National Institutes of Health Grant AR41677 (to K. A. H.). 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: Dept. of Pediatrics, Washington University School of Medicine, 5th Fl., McDonnell Pediatric Research Bldg., Campus Box 8208, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-286-2772; Fax: 314-286-2894; E-mail: hruska_k{at}kids.wustl.edu.

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