Send to

Choose Destination
J Bone Miner Metab. 2012 Sep;30(5):543-53. doi: 10.1007/s00774-012-0353-5. Epub 2012 Apr 28.

Identification and characterization of anti-osteoclastogenic peptides derived from the cytoplasmic tail of receptor activator of nuclear factor kappa B.

Author information

Division of Cellular and Molecular Biology, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo, 108-8639, Japan.


Pathological bone resorption by osteoclasts is primarily treated with bisphosphonates. Because the administration of bisphosphonates is associated with a risk for multiple adverse symptoms, a precise understanding of the mechanisms underlying osteoclastogenesis is required to develop drugs with minimal side-effects. Osteoclastogenesis depends on receptor activator of nuclear factor kappa B (RANK) signaling mediated by TRAF6. We previously identified a highly conserved domain in the cytoplasmic tail of RANK (HCR), which did not share any significant homology with other proteins and was essential for osteoclastogenesis. HCR acts as a platform for the formation of Gab2- and Vav3-containing signal complexes, and ectopic expression of the HCR peptide inhibits osteoclastogenesis. Here, we uncover the mechanisms of HCR peptide-mediated inhibition of osteoclastogenesis. Expression of either the amino- or carboxyl-terminal half of the HCR peptide (N- or C-peptide) independently inhibited RANK signaling prior to cell-cell fusion. In contrast, expression of the GY-peptide, which is a part of the C-peptide, did not significantly affect prefusion RANK signaling, but did inhibit cell-cell fusion to prevent formation of multinucleated mature osteoclasts. Moreover, Gab2, which is involved in RANK signaling by binding TRAF6, bound the C-peptide but not the N-peptide, suggesting that the C- and the N-peptides sequester TRAF6 in a Gab2-dependent and Gab2-independent manner, respectively. In contrast, the GY-peptide did not bind Gab2 but could bind Vav3, which mediates signaling for cell-cell fusion. Collectively, we propose that the HCR peptide inhibits osteoclastogenesis through two modes of action-inhibition of (1) prefusion RANK signaling and (2) cell-cell fusion by blocking TRAF6- and Vav3-mediated signaling, respectively.

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center