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J. Biol. Chem., Vol. 283, Issue 10, 6509-6518, March 7, 2008

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NOTCH1 Regulates Osteoclastogenesis Directly in Osteoclast Precursors and Indirectly via Osteoblast Lineage Cells^*

Shuting Bai, Raphael Kopan, Wei Zou, Matthew J. Hilton^¶, Chin-tong Ong, Fanxin Long^¶, F. Patrick Ross, and Steven L. Teitelbaum¹

From the Departments of Pathology and Immunology, Molecular Biology and Pharmacology, and ^¶Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

NOTCH signaling is a key regulator of cell fate decisions in prenatal skeletal development and is active during adult tissue renewal. In addition, its association with neoplasia suggests that it is a candidate therapeutic target. We find that attenuated NOTCH signaling enhances osteoclastogenesis and bone resorption in vitro and in vivo by a combination of molecular mechanisms. First, deletion of Notch1-3 in bone marrow macrophages directly promotes their commitment to the osteoclast phenotype. These osteoclast precursors proliferate more rapidly than the wild type in response to macrophage colony-stimulating factor and are sensitized to RANKL and macrophage colony-stimulating factor, undergoing enhanced differentiation in response to low doses of either cytokine. Conforming with a role for NOTCH in this process, presentation of the NOTCH ligand JAGGED1 blunts the capacity of wild-type bone marrow macrophages to become osteoclasts. Combined, these data establish that NOTCH suppresses osteoclastogenesis via ligand-mediated receptor activation. Although NOTCH1 and NOTCH3 collaborate in regulating osteoclast formation, NOTCH1 is the dominant paralog. In addition, NOTCH1 deficiency promotes osteoclastogenesis indirectly by enhancing the ability of osteoblast lineage cells to stimulate osteoclastogenesis. This is achieved by decreasing the osteoprotegerin/RANKL expression ratio. Thus, NOTCH1 acts as a net inhibitor of bone resorption, exerting its effect both directly in osteoclast precursors and indirectly via osteoblast lineage cells. These observations raise caution that therapeutic inhibition of NOTCH signaling may adversely accelerate bone loss in humans.

Received for publication, August 21, 2007 , and in revised form, December 18, 2007.

^* This work was supported by National Institutes of Health Grants HD044056 (to R. K.), DK065789 (to F. L.), AR46852 and AR48812 (to F. P. R.), and AR32788, AR46523, and AR48853 (to S. L. T.). 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: Dept. of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Ave., St. Louis, MO 63110. Tel.: 314-454-8463; Fax: 314-454-5505; E-mail: teitelbs{at}wustl.edu.

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