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

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 7

The RRI peptide suppresses LPS- or RANKL-induced OC formation and bone destruction.

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The RRI peptide suppresses LPS- or RANKL-induced OC formation and bone d...
Inhibition of LPS- or RANKL-induced (12.5 mg LPS or 2 mg RANKL/kg body weight) bone destruction after injection of the RANK inhibitor peptide (20 mg peptide/kg body weight). TRAP staining was performed on sections of calvaria bone (A). Scale bar: 100 μm. (B) Fold differences of bone cavity (left) and the number of OCs (right) were analyzed. *P < 0.01; †P < 0.05. Data represent mean ± SD. n = 7. (C) Effect of the RANK inhibitor peptide on pre-OC formation. Mouse calvaria were injected once with RANKL (2 mg/kg body weight) or PBS, induced for OC formation for 2 days, and then treated with Mt-1 or WT-1 peptide for 2 more days. (C) After TRAP staining of calvaria bone, the numbers of pre-OCs (left) and mature OCs (right) were determined. *P < 0.01. Data represent mean ± SD. n = 4.