Selective inhibition of RANK blocks osteoclast maturation and function and prevents bone loss in mice.
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.
Kim
Hyunsoo
H
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, Republic of Korea.
Choi
Han Kyoung
HK
Shin
Ji Hye
JH
Kim
Kyung Hee
KH
Huh
Ji Young
JY
Lee
Seung Ah
SA
Ko
Chang-Yong
CY
Kim
Han-Sung
HS
Shin
Hong-In
HI
Lee
Hwa Jeong
HJ
Jeong
Daewon
D
Kim
Nacksung
N
Choi
Yongwon
Y
Lee
Soo Young
SY
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001862:Bone Resorption / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D009842:Oligopeptides / Q000235:genetics / Q000494:pharmacology; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D051567:Proto-Oncogene Proteins c-vav / Q000502:physiology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology; D014161:Transduction, Genetic
D009842:Oligopeptides; D051567:Proto-Oncogene Proteins c-vav; D053246:Receptor Activator of Nuclear Factor-kappa B; D011994:Recombinant Proteins; D048029:TNF Receptor-Associated Factor 6; C505687:Tnfrsf11a protein, mouse; C496622:Vav3 protein, mouse; D020559:Monomeric GTP-Binding Proteins