Elucidation of the molecular mechanism of the bone matrix protein osteocalcin in protecting brain function

• Project/Area Number: 18K09510
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57010:Oral biological science-related
• Research Institution: Kyushu Dental College
• Principal Investigator: Higashi Sen 九州歯科大学, 歯学部, 助教 (40228705)
• Co-Investigator(Kenkyū-buntansha): 竹内 弘 九州歯科大学, 歯学部, 教授 (70304813)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 神経細胞 / 骨 / オステオカルシン / 脳 / GPRC6A / Gpr158 / 受容体 / 細胞内シグナル / 骨代謝 / 糖代謝 / osteocalcin

Outline of Final Research Achievements

The bone protein osteocalcin (OC) improves systemic sugar and energy metabolism via the receptor GPRC6A. On the other hand, it was reported that OC passes through the blood-brain barrier and placenta followed by migrating into the brain, thus maintains cognitive function, exerts antidepressant action, and supports fetal brain development and learning / memory ability based on the experiments using mice. However, the direct action of OC on nerve cells has not been elucidated. In this study, we showed that OC acts directly on neurons via the receptor GPR158, promotes cell proliferation and differentiation, and suppresses oxidative stress-induced apoptotic cell death. This result is expected to contribute to the development of new preventive and therapeutic strategies for cognitive and developmental disorders targeting OC and GPR158.

Academic Significance and Societal Importance of the Research Achievements

骨タンパク質オステオカルシン（OC）による認知機能の維持・抗うつ作用や、胎児の脳の発達と学習・記憶能力の支持する効果が報告されたが、神経細胞に対するOCの直接作用は不明であった。本研究でOCが受容体GPR158を介して神経細胞に直接作用し、脳機能保護につながる様々な効果を発揮することが示された。社会問題となっている認知障害や発達障害に対する新たな予防・治療戦略の開発に寄与することが期待される。

Research Products

• [Journal Article] Phospholipase C-related but catalytically inactive protein acts as a positive regulator of insulin signalling in adipocytes. (2022)
  • Author(s): Gao, J., Mizokami, A., Takeuchi, H., Li, A., Huang, F., Nagano, H., Kanematsu, T., Jimi, E., Hirata, M.
  • Journal Title: J. Cell. Sci. Volume: 135 Issue: 1
  • DOI: 10.1242/jcs.258584
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Osteocalcin promotes proliferation, differentiation, and survival of PC12?cells (2021)
  • Author(s): Ando Eika、Higashi Sen、Mizokami Akiko、Watanabe Seiji、Hirata Masato、Takeuchi Hiroshi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 557 Pages: 174-179
  • DOI: 10.1016/j.bbrc.2021.03.146
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of aging on bone metabolism: the involvement of complement C1q (2021)
  • Author(s): Aonuma Fumiko、Higashi Sen、Tsuka Shintaro、Ohsumi Tomoko、Masaki Chihiro、Hosokawa Ryuji、Takeuchi Hiroshi
  • Journal Title: Journal of Prosthodontic Research Volume: 65 Issue: 3 Pages: 393-399
  • DOI: 10.2186/jpr.JPOR_2019_644
  • NAID: 130008076958
  • ISSN: 1883-1958, 1883-9207
  • Peer Reviewed / Open Access
• [Journal Article] Volume-regulated chloride channel regulates cell proliferation and is involved in the possible interaction between TMEM16A and LRRC8A in human metastatic oral squamous cell carcinoma cells (2021)
  • Author(s): Yoshimoto Shohei、Matsuda Miho、Kato Kenichi、Jimi Eijiro、Takeuchi Hiroshi、Nakano Shuji、Kajioka Shunichi、Matsuzaki Etsuko、Hirofuji Takao、Inoue Ryuji、Hirata Masato、Morita Hiromitsu
  • Journal Title: European Journal of Pharmacology Volume: 895 Pages: 173881-173881
  • DOI: 10.1016/j.ejphar.2021.173881
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Substituent effects of cyclic naphthalene diimide on G-quadruplex binding and the inhibition of cancer cell growth. (2021)
  • Author(s): Fukuda, H., Sato, S., Zou, T., Higashi, S., Takahashi, O., Habu, M., Sasaguri, M., Tominaga, K., Takenaka, S., Takeuchi, H.
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 50 Pages: 128323-128323
  • DOI: 10.1016/j.bmcl.2021.128323
  • Peer Reviewed / Open Access
• [Journal Article] GLP-1 signaling is required for improvement of glucose tolerance by osteocalcin. J. Endocrinol. (2020)
  • Author(s): Mizokami, A., Mukai, S., Gao, J., Kawakubo-Yasukochi, T., Otani, T., Takeuchi, H., Jimi, E., Hirata, M.
  • Journal Title: Journal of Endocrinology Volume: 244 Issue: 2 Pages: 285-296
  • DOI: 10.1530/joe-19-0288
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Modification of TRPV4 activity by acetaminophen. (2020)
  • Author(s): Nakagawa, F., Higashi, S., Ando, E., Ohsumi, T., Watanabe, S., Takeuchi, H.
  • Journal Title: Heliyon Volume: 6 Issue: 1 Pages: e03301-e03301
  • DOI: 10.1016/j.heliyon.2020.e03301
  • Peer Reviewed / Open Access
• [Journal Article] Osteocalcin triggers Fas/FasL-mediated necroptosis in adipocytes regulated by the activation of p300. (2018)
  • Author(s): Otani, T., Matsuda, M., Mizokami, A., Kitagawa, N., Takeuchi, H., Jimi, E.,Inai, T., and Hirata, M.
  • Journal Title: Cell Death Disease Volume: 9 Issue: 12 Pages: 1194-1210
  • DOI: 10.1038/s41419-018-1257-7
  • Peer Reviewed / Open Access
• [Presentation] 骨基質タンパク質オステオカルシンによる PC12 の形態的・機能的修飾 (2022)
  • Author(s): 2.東泉、安藤瑛香、溝上顕子、渡邉誠之、平田雅人、竹内弘
  • Organizer: 第95回日本薬理学会年会
• [Presentation] PC12の細胞増殖と神経様分化に対する骨基質タンパク質オステオカルシンの影響 (2020)
  • Author(s): 安藤瑛香，東泉，溝上顕子，渡邉誠之，平田雅人，竹内弘
  • Organizer: 第73回日本薬理学会西南部会
• [Presentation] 骨基質タンパク質オステオカルシンが PC12 細胞に及ぼす影響 (2020)
  • Author(s): 安藤瑛香，東泉，溝上顕子，渡邉誠之，平田雅人，竹内弘
  • Organizer: 第62回歯科基礎医学会学術大会
• [Presentation] Effect of bone matrix protein osteocalcin on proliferation and neuronal differentiation of PC12 cells (2020)
  • Author(s): 安藤瑛香、東泉、溝上顕子、大住伴子、渡邉誠之、平田雅人、竹内弘
  • Organizer: 第93回日本薬理学会年会
• [Presentation] Effect of acetaminophen on TRPV4 (2019)
  • Author(s): 中川文雄, 安藤瑛香, 東泉, 大住伴子, 渡邉誠之, 竹内弘
  • Organizer: 第66回日本麻酔科学会学術集会
• [Presentation] Anti-cancer effects of newly developed G-quadruplex binders (2019)
  • Author(s): Fukuda, H., Sato, S., Higashi, S., Habu, M., Tominaga, K., Takenaka, S., Takeuchi, H.
  • Organizer: 12th JKBT
• [Presentation] テロメアDNA構造を標的とする新規化合物の抗腫瘍効果と有害作用に関する検討 (2019)
  • Author(s): 福田晃、竹内弘
  • Organizer: 第56回 日本口腔組織培養学会
• [Presentation] テロメア構造結合性新規化合物の抗癌効果の検討 (2019)
  • Author(s): 福田晃、東泉、大住伴子、竹内弘
  • Organizer: 第61回歯科基礎医学会学術大会
• [Presentation] テロメアDNA構造結合性化合物の癌細胞特異的増殖抑制効果の検討 (2019)
  • Author(s): 福田晃、土生学、笹栗正明、冨永和宏、竹内弘
  • Organizer: 第73回日本口腔科学会学術集会
• [Presentation] 骨基質オステオカルシンによる膵α細胞の性状変化. (2019)
  • Author(s): 東泉、溝上顕子、大住伴子、平田雅人、竹内弘
  • Organizer: 第92回日本薬理学会年会
• [Presentation] 細胞外糖濃度によるマクロファージ極性化の調節. (2018)
  • Author(s): 工藤崇裕、臼井通彦、東泉、大住伴子、中島啓介、竹内弘
  • Organizer: 第71回日本薬理学会西南部会
• [Presentation] 培地グルコース濃度はAMPKを介してマクロファージ極性化に影響する. (2018)
  • Author(s): 工藤崇裕、臼井通彦、東泉、大住伴子、竹内弘
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] 培地グルコース濃度がマクロファージの性質に与える影響について. (2018)
  • Author(s): 工藤崇裕、臼井通彦、東泉、大住伴子、中島啓介、竹内弘
  • Organizer: 第78回九州歯科学会
• [Presentation] Effect of extracellular glucose concentration on macrophage polarization. (2018)
  • Author(s): Kudo, T., Usui, M., Higashi, S., Ohsumi, T., Nakashima, K., Takeuchi, H.
  • Organizer: Asia-pacific Conference in Fukuoka 2018
  • Int'l Joint Research
• [Remarks] 九州歯科大学 口腔応用薬理学分野 Web ページ
  • URL: https://www.kyu-dent.ac.jp/research/lecture/oral_pharmacological