Molecular pharmacological analyses of a potential drug target regulating the clock gene in bone

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K11495
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Aichi Gakuin University
• Principal Investigator: HIRAI Takao 愛知学院大学, 薬学部, 准教授 (80389072)
• Co-Investigator(Kenkyū-buntansha): 浜村 和紀 愛知学院大学, 歯学部, 准教授 (00422767) ; 近藤 久貴 愛知学院大学, 歯学部, 講師 (40469002)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 時計遺伝子 / 骨代謝

Outline of Final Research Achievements

Recent studies demonstrated that the bone metabolic functions are closely related to an intrinsic biological rhythm, named the circadian clock. Previous reports have demonstrated that adrenergic receptor (AR) signaling in osteoblasts up-regulated the basic leucine zipper transcriptional factor nuclear factor IL-3 (Nfil3)/e4 promoter binding protein 4 (E4BP4).
In the present study, we determined whether Nfil3/E4BP4 contributed to regulating the cellular function of osteoblasts. To evaluate the functionality of Nfil3/E4BP4 on bone metabolism, we compared the bone phenotype of Nfil3 null mice with that of WT littermates. The results suggest that Nfil3/E4BP4 plays a key role in bone formation. Since the circadian clock regulates key molecules in the cellular functions in osteoblasts, this system may be closely involved in the cellular functions associated with bone remodeling, indicating the potential of this clock system in the treatment of bone disorders.

Free Research Field

骨代謝学、分子薬理学

Academic Significance and Societal Importance of the Research Achievements

近年、概日時計制御系による骨代謝制御の可能性が示唆されている。本研究は、時計遺伝子Nfil3/E4BP4の骨リモデリングにおける役割を明らかにするなど、体内時計と骨代謝を直接結びつける分子機構の一部を明らかにした。また、骨芽細胞におけるNfil3/E4BP4と時計遺伝子Bmal1, Rev-erbとの関連についても検討した結果、Nfil3/E4BP4はRev-erbによって負に制御されることが明らかとなった。これらの研究成果は時間薬理学の観点に基づいた新たな治療法や予防法の開発、時計遺伝子を標的とした骨粗鬆症に対する新たな治療理論の構築につながるものと期待される。