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J. Biol. Chem., Vol. 279, Issue 9, 8269-8277, February 27, 2004

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Disabling of Receptor Activator of Nuclear Factor-B (RANK) Receptor Complex by Novel Osteoprotegerin-like Peptidomimetics Restores Bone Loss in Vivo^*

Xin Cheng, Masa Kinosaki, Masamichi Takami, Yongwon Choi, Hongtao Zhang, and Ramachandran Murali¶

From the Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute for Cancer Research, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104

The tumor necrosis factor family ligand, tumor necrosis factor-related activation-induced cytokine (TRANCE), and its receptors, receptor activator of nuclear factor-B (RANK) and osteoprotegerin (OPG), are known to be regulators of development and activation of osteoclasts in bone remodeling. Sustained osteoclast activation that occurs through TRANCE-RANK causes osteopenic disorders such as osteoporosis and contributes to osteolytic metastases. Here, we report a rationally designed small molecule mimic of osteoprotegerin to inhibit osteoclast formation in vitro and limit bone loss in an animal model of osteoporosis. One of the mimetics, OP3-4, significantly inhibited osteoclast formation in vitro (IC₅₀ = 10 µM) and effectively inhibited total bone loss in ovariectomized mice at a dosage of 2 mg/kg/day. Unlike soluble OPG receptors, which preclude TRANCE binding to RANK, OP3-4 shows the ability to modulate RANK-TRANCE signaling pathways and alters the biological functions of the RANK-TRANCE receptor complex by facilitating a defective receptor complex. These features suggest that OPG-derived small molecules can be used as a probe to understand complex biological functions of RANK-TRANCE-OPG receptors and also can be used as a platform to develop more useful therapeutic agents for inflammation and bone disease.

Received for publication, September 2, 2003 , and in revised form, November 7, 2003.

^* The work was supported by grants from the Abramson Family Institute for Cancer Research Foundation and the NCI, National Institutes of Health. 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.

Present address: 55-1-201, Shimotogari Nagaizumi-cho, Suntohgun, Shizuoka 411-0941, Japan.

Present address: Dept. of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawaku, Tokyo 142-8555, Japan.

^¶ To whom correspondence should be addressed: Dept. of Pathology and Laboratory Medicine, 252 John Morgan Bldg., University of Pennsylvania, Philadelphia, PA 19104-6082. E-mail: murali{at}xray.med.upenn.edu.

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