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

J Clin Invest. 2009 Apr;119(4):813-25. doi: 10.1172/JCI36809. Epub 2009 Mar 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Bone Resorption / pathology
  • Bone Resorption / physiopathology
  • Bone Resorption / prevention & control*
  • Female
  • Mice
  • Mice, Inbred C57BL
  • Monomeric GTP-Binding Proteins / physiology
  • Mutagenesis, Site-Directed
  • Oligopeptides / genetics
  • Oligopeptides / pharmacology
  • Osteoclasts / cytology
  • Osteoclasts / drug effects*
  • Osteoclasts / physiology
  • Proto-Oncogene Proteins c-vav / physiology
  • Receptor Activator of Nuclear Factor-kappa B / antagonists & inhibitors*
  • Receptor Activator of Nuclear Factor-kappa B / genetics
  • Receptor Activator of Nuclear Factor-kappa B / physiology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction / drug effects
  • TNF Receptor-Associated Factor 6 / physiology
  • Transduction, Genetic


  • Oligopeptides
  • Proto-Oncogene Proteins c-vav
  • Receptor Activator of Nuclear Factor-kappa B
  • Recombinant Proteins
  • TNF Receptor-Associated Factor 6
  • Tnfrsf11a protein, mouse
  • Vav3 protein, mouse
  • Monomeric GTP-Binding Proteins