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Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice
Hyunsoo Kim, … , Yongwon Choi, Soo Young Lee
Hyunsoo Kim, … , Yongwon Choi, Soo Young Lee
Published March 2, 2009
Citation Information: J Clin Invest. 2009;119(4):813-825. https://doi.org/10.1172/JCI36809.
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Research Article Bone biology Article has an altmetric score of 3

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

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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.

Authors

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

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Figure 6

The RRI peptide blocks Vav3 and small GTPase signaling.

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The RRI peptide blocks Vav3 and small GTPase signaling.
(A) Biotinylated...
(A) Biotinylated 10-mer peptides were incubated with the pre-OC lysates, and the precipitates were immunoblotted with the indicated antibodies. (B) Association of Vav3 with RANK through the IVVY motif. 293T cells were cotransfected with the expression vectors as indicated. Protein complexes were precipitated with glutathione-Sepharose and analyzed by immunoblot analysis using the corresponding antibody. GST–RANK WT, the cytoplasmic tail of RANK WT (aa 235-625) fused to GST; GST–RANK Mt, identical to GST–RANK WT except for 2 mutations at I535L/V536A; FLAG-Vav3, FLAG-tagged Vav3 DNA. (C) Vav3 phosphorylation in pre-OCs was assayed in the presence of WT or Mt peptides at the indicated times of RANKL stimulation. A parallel blot with equal loading was used to assess total Vav3 protein. (D) Pre-OCs were stimulated with RANKL for the indicated times, and the activated forms of Rac1 and Cdc42 were detected by GST pull-down assays. (E) Rescue of TRAP+ MNC formation by retrovirus-mediated expression of constitutive active Rac1 or Cdc42 in the presence of RRI peptides. A representative TRAP staining is shown. TRAP+ MNCs were counted. *P < 0.001. Data represent mean ± SD. Scale bar: 100 μm. Mock, empty vector; RhoA, RhoAV14; Rac1, Rac1V12; Cdc42, Cdc42V12. Rac1, Cdc42, and RhoA expression were confirmed by immunoblot analysis using the corresponding antibody.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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