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Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice

Title
Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice
Authors
Kim H.Han K.C.Ji H.S.Kyung H.K.Ji Y.H.Seung A.L.Ko C.-Y.Kim H.-S.Shin H.-I.Hwa J.L.Jeong D.Kim N.Choi Y.Soo Y.L.
Ewha Authors
이수영이화정김현수
SCOPUS Author ID
이수영scopus; 이화정scopus
Issue Date
2009
Journal Title
Journal of Clinical Investigation
ISSN
0021-9738JCR Link
Citation
vol. 119, no. 4, pp. 813 - 825
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
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.
DOI
10.1172/JCI36809
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자연과학대학 > 생명과학전공 > Journal papers
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