Development of a new anabolic peptide on bone by the identification

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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.