2023 Fiscal Year Final Research Report

Development of a revolutionary bone anabolic reagent by optimizing the RANKL reverse signaling to stimulate bone formation.

Research Project

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Project/Area Number	19H01068
Research Category	Grant-in-Aid for Scientific Research (A)
Allocation Type	Single-year Grants
Section	一般
Review Section	Medium-sized Section 57:Oral science and related fields
Research Institution	Tokyo Medical and Dental University
Principal Investigator	AOKI Kazuhiro 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (40272603)
Co-Investigator(Kenkyū-buntansha)	林智広東京工業大学, 物質理工学院, 准教授 (30401574) 本間雅東京大学, 医学部附属病院, 講師 (60401072) 秋吉一成京都大学, 工学研究科, 教授 (90201285) 宇田川信之松本歯科大学, 歯学部, 教授 (70245801)
Project Period (FY)	2019-04-01 – 2023-03-31
Keywords	骨形成促進薬 / RANKL逆シグナル / RANKL結合ペプチド / LassoGraft Technology / RaPID法 / プロテオリポソーム技術 / 原子間力顕微鏡
Outline of Final Research Achievements	A signal was identified in which Runx2 is activated via membrane-bound RANKL on osteoblast membranes. The vesicles expressing RANK, whose secretion increases when osteoclasts begin resorbing bone, accelerate osteoblast differentiation by binding to membrane RANKL(Ikebuchi et al., Nature 2018). Although a detailed description is not possible due to patent-related information, various local anabolic drug candidates have been discovered with the help of research collaborator Professor Hiroaki Suga; screening of drug candidates using in vivo models has yielded good results. On the other hand, RANK liposomes were prepared using the proteoliposome method but did not exhibit osteogenic activity. The reasons for this were explored by measuring the morphology of RANK liposomes and investigating their adhesive properties using atomic force microscopy (AFM).
Free Research Field	硬組織薬理学
Academic Significance and Societal Importance of the Research Achievements	骨芽細胞上の膜型RANKLが骨形成促進薬の新たな標的になると2018年のNature誌に掲載されたが、本基盤研究はその提唱された仮説を実証したことになる。代表的な局所の骨形成促進薬としてbone morphogenetic protein(BMP)-2があげられるが、本研究の成果により、BMP-2とは別の経路で局所の骨形成を促進させる薬剤が生まれたことになる。歯科領域でも整形外科領域でも局所の骨造成は日々の臨床において行われており、本基盤研究の研究成果による新規薬剤の創生は、患者の治療と転帰を改善する可能性を秘めており、社会的意義が大きい。