Development of a new anabolic peptide on bone by the identification

NF-κ B B受体激活因子配体（RANKL）促进树突状细胞和破骨细胞的分化和功能.近年来的研究也揭示了RANKL在哺乳动物腺体发育、体温调节等方面的广泛生理作用。我们在这项研究中发现，RANKL结合肽促进骨形成，导致一个重要的发现，以澄清RANKL的生理作用。这项研究产生了重要的发现，即骨形成的合成代谢活性依赖于RANKL反向信号强度。两种RANKL结合肽之间的骨形成活性的比较引导我们得出这一结论。在本研究开始时，我们假设两种合成代谢肽之间RANKL结合位点的差异可能导致两种肽之间骨形成活性的差异。由于成骨细胞分化的刺激作用只有在100 μ M及以上的肽浓度时才出现，我们认为RANKL在成骨细胞膜表面的聚集可能是RANKL反向信号的触发。进一步的研究是必要的，以引导这项研究朝着新的治疗药物的发展，如澄清RANKL分子之间的适当距离，可以打开骨形成活性，和配体的发展，这可以使RANKL集群。最后，我们感谢Masashi Honma博士（东京大学医学部附属医院药学部）对RANKL反向信号传导的骨形成肽的分析。

Receptor activator of NF-〓B ligand (RANKL) promotes dendritic celldifferentiation and osteoclast differentiation and function. Recent findings also revealedthe wide-ranging physiological roles of RANKL such as the mammalian gland developmentand the thermoregulation. We found in this study that RANKL binding peptides promotebone formation, leading to a significant finding to clarify the physiological roles of RANKL. This study yields the important finding that anabolic activity on bone formationwas dependent on the RANKL-reverse-signaling intensity. The comparison of boneformation activities between two RANKL-binding peptides guided us to this conclusion. Atthe beginning of this study, we hypothesized that the differences of RANKL binding sitesbetween two anabolic peptides might induce the differences of bone formation activitiesbetween the two peptides. Since the stimulatory effects of osteoblast differentiation wasappeared only when the peptide concentration was higher around100 〓M and over, wethought that making a RANKL clustering on the surface of osteoblast membrane might bea trigger of the RANKL-reverse-signaling. Further studies are necessary for leading this study toward the development of anew therapeutic agent, such as clarification of an appropriate distance between RANKLmolecules that can switch on the bone formation activity, and the development of a ligand,which can make a RANKL clustering. Finally we thank Dr. Masashi Honma (Department of Pharmacy, TheUniversity of Tokyo Hospital, Faculty of Medicine) for analyses of the bone formationpeptides on the RANKL-reverse-signaling.