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

Hyunsoo Kim, Kyoung Choi Han, Hye Shin Ji, Hee Kim Kyung, Young Huh Ji, Ah Lee Seung, Chang Yong Ko, Han Sung Kim, Hong In Shin, Jeong Lee Hwa, Daewon Jeong, Nacksung Kim, Yongwon Choi, Young Lee Soo

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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.

Original languageEnglish
Pages (from-to)813-825
Number of pages13
JournalJournal of Clinical Investigation
Volume119
Issue number4
DOIs
Publication statusPublished - 2009 Apr 1

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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    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. (2009). Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice. Journal of Clinical Investigation, 119(4), 813-825. https://doi.org/10.1172/JCI36809