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

Taguchi, Yuu; Kiga, Yoko; Gohda, Jin; Inoue, Jun-ichiro
September 2012
Journal of Bone & Mineral Metabolism;Sep2012, Vol. 30 Issue 5, p543
Academic Journal
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.


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