The epoch-making drug development of the inhibitor blocking inflammatory bone destruction in alveolar bones.

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Osteoclast differentiation requires the interaction of RANK (receptor activator of NF-κB) and its ligand RANKL, conserved members of the TNF receptor and TNF families, respectively. We tested the ability of a peptide mimic (WP9QY) of a critical contact site on the TNF receptor to inhibit RANKL-induced osteoclast formation and activation. The peptide dose-dependently inhibited osteoclastogenesis in RANKL-treated bone marrow cells, as well as RANKL-induced bone resorption by isolated osteoclasts. This peptide also blocked the downstream signalings of RANKL. Furthermore, WP9QY prevented the increased in vivo osteoclastogenesis and bone loss not only in the bone metabolic disease models such as ovariectomy and a low calcium diet models but also in the inflammatory bone resorption models such as collagen-induced arthritis (CIA) model and periodontal disease model. WP9QY also inhibited the inflammation induced in CIA model. These results suggest that the contact site between TNFa and the first loop of domain 3 of the TNF receptor (I) is at least partially conserved in the RANK/RANKL interaction and is functionally important for the induction of signaling from RANK in osteoclasts and their precursors. This identification of this critical loop could lead to the development of the therapeutic drug for inflammatory bone destruction such as RA and periodontal disease.