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

破骨细胞分化需要RANK（NF-κB的受体激活剂）及其配体RANKL（分别为TNF受体和TNF家族的保守成员）的相互作用。我们测试了TNF受体上关键接触位点的肽模拟物（WP 9 QY）抑制RANKL诱导的破骨细胞形成和活化的能力。该肽以剂量依赖性方式抑制RANKL处理的骨髓细胞中的破骨细胞生成，以及RANKL诱导的分离破骨细胞的骨吸收。该肽还阻断了RANKL的下游信号传导。此外，WP 9 QY不仅在骨代谢疾病模型如卵巢切除术和低钙饮食模型中，而且在炎性骨吸收模型如胶原诱导的关节炎（CIA）模型和牙周病模型中防止体内破骨细胞生成和骨丢失的增加。WP 9 QY还抑制CIA模型中诱导的炎症。这些结果表明，TNF α和TNF受体（I）结构域3第一环之间的接触位点在RANK/RANKL相互作用中至少部分保守，并且对于诱导破骨细胞及其前体中RANK的信号传导具有重要功能。对这一关键环的识别可能会导致炎症性骨破坏（如RA和牙周病）治疗药物的开发。

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.