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

• 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
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 時計遺伝子 / 骨代謝 / 生体分子

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.

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。

Research Products

• [Journal Article] Baicalein stimulates fibroblast growth factor 21 expression by up-regulating retinoic acid receptor-related orphan receptor α in C2C12 myotubes (2019)
  • Author(s): Takao Hirai, Kohei Nomura, Rie Ikai, Ken-ichi Nakashima, Makoto Inoue
  • Journal Title: Biomedicine & Pharmacotherapy Volume: 109 Pages: 503-510
  • DOI: 10.1016/j.biopha.2018.10.154
  • Peer Reviewed / Open Access
• [Journal Article] Regulation of Clock Genes by Adrenergic Receptor Signaling in Osteoblasts (2018)
  • Author(s): Takao Hirai
  • Journal Title: Neurochemical Research Volume: 43(1) Issue: 1 Pages: 120-126
  • DOI: 10.1007/s11064-017-2365-y
  • Peer Reviewed
• [Journal Article] Bidirectional communication between sensory neurons and osteoblasts in an in vitro coculture system. (2017)
  • Author(s): Kodama Daisuke, Hirai Takao, Kondo Hisataka, Hamamura Kazunori, Togari Akifumi.
  • Journal Title: FEBS Letters Volume: 591(3) Issue: 3 Pages: 527-539
  • DOI: 10.1002/1873-3468.12561
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Baicalein regulates FGF21 expression through RORα-mediated transcriptional activity (2018)
  • Author(s): Kohei Nomura, Takao Hirai, Ken-ichi Nakashima, Makoto Inoue
  • Organizer: 第91回日本薬理学会年会、第18回国際薬理学・臨床薬理学会議
  • Int'l Joint Research
• [Presentation] 骨代謝における時計遺伝子の関与 (2016)
  • Author(s): 平居 貴生
  • Organizer: 第58回歯科基礎医学会学術大会
  • Place of Presentation: 札幌コンベンションセンター（北海道札幌市）
  • Year and Date: 2016-08-26
  • Invited
• [Presentation] 交感神経による骨代謝制御 (2016)
  • Author(s): 平居 貴生，戸苅 彰史
  • Organizer: 第18回応用薬理シンポジウム
  • Place of Presentation: 名古屋大学医学部（愛知県名古屋市）
  • Year and Date: 2016-08-05
  • Invited