한빛사논문
Abstract
1Division of Life and Pharmaceutical Sciences, Center for Cell Signaling and Drug Discovery Research, Department of Life Science, College of Natural Sciences, Ewha Womans University, Seoul, Republic of Korea.
2Nano-Biomaterials Science Laboratory, Division of Applied Life Sciences (BK21), Graduate School of Gyeongsang National University, Jinju, Republic of Korea.
3Department of Biomedical Engineering, College of Health Science, Institute of Medical Engineering, Yonsei University, Wonju, Republic of Korea.
4IHBR, Department of Oral Pathology, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea.
5College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea.
6Department of Microbiology and the Aging-associated Disease Research Center, Yeungnam University College of Medicine, Daegu, Republic of Korea.
7Medical Research Center for Gene Regulation, Chonnam National University Medical School, Gwangju, Republic of Korea.
8Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Address correspondence to: Soo Young Lee, Division of Life and Pharmaceutical Sciences, Center for Cell Signaling and Drug Discovery Research, Department of Life Science, College of Natural Sciences, Ewha Womans University, Seoul 120-750, Republic of Korea. Phone: 82-2-3277-3770; Fax: 82-2-3277-3760.
Published March 2, 2009
Received for publication July 17, 2008, and accepted in revised form January 13, 2009.
Regulation of the formation and function of bone-resorbing osteoclasts (OCs) is a key to understanding the pathogenesis of skeletal disorders. Gene-targeting studies have shown that the RANK signaling pathway plays a critical role in OC differentiation and function. Although pharmaceutical blockade of RANK may be a viable strategy for preventing bone destruction, RANK is implicated in multiple biological processes. Recently, a cytoplasmic motif of RANK was identified that may be specifically involved in OC differentiation. Here, we developed a cell-permeable inhibitor termed the RANK receptor inhibitor (RRI), which targets this motif. The RRI peptide blocked RANKL-induced OC formation from murine bone marrow-derived macrophages. Furthermore, RRI inhibited the resorptive function of OCs and induced OC apoptosis. Treatment with the peptide impaired downstream signaling of RANK linked to Vav3, Rac1, and Cdc42 and resulted in disruptions of the actin cytoskeleton in differentiated OCs. In addition, RRI blocked inflammation-induced bone destruction and protected against ovariectomy-induced bone loss in mice. These data may be useful in the development of selective therapeutic agents for the treatment of osteoporosis and other bone diseases.논문정보
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