Elucidation of a novel regulatory mechanism of bone metabolism by cellular senescence regulators and its therapeutic application

• Project/Area Number: 18K09034
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Saga University
• Principal Investigator: Kukita Akiko 佐賀大学, 医学部, 准教授 (30153266)
• Co-Investigator(Kenkyū-buntansha): 馬渡 正明 佐賀大学, 医学部, 教授 (80202357) ; 久木田 敏夫 九州大学, 歯学研究院, 教授 (70150464)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 骨代謝 / 骨芽細胞 / 骨細胞 / 老化 / 骨粗鬆症 / 転写因子 / 核蛋白質 / 老化細胞 / オートファジー / 骨形成 / アポトーシス / 細胞・組織 / 破骨細胞

Outline of Final Research Achievements

We analyzed the role of basic HLH-type transcription factors involved in cellular senescence in bone metabolism and bone aging. bHLH-1 knockout (KO) mice showed increased bone mass and bone formation in femurs, and osteoblasts showed increased proliferation and differentiation of progenitor cells, and increased number of osteocytes. On the other hand, autophagy in osteoblasts was increased whereas apoptosis in osteoblasts and osteocytes was decreased. The bone mass of bHLH-1 KO mice was higher than that of wild type (WT) mice even in old age, and the bone loss due to aging was also reduced. Furthermore, the expression of senescent marker genes was decreased in osteoblasts and osteocytes of bHLH-1 KO mice, suggesting that bHLH-1 may be involved in the accumulation of senescent cells and age-related bone loss.

Academic Significance and Societal Importance of the Research Achievements

超高齢化社会に伴い骨粗鬆症や変形性関節症などの骨・関節疾患の患者数が増加している。近年、このような加齢に関連する疾患において、複製やストレスなどの刺激で形成した老化細胞の蓄積が病態の原因となることが報告されている。本研究では老化細胞の制御機能が知られているbHLH型転写因子が、老化した骨で老化細胞の蓄積に関わる可能性を初めて明らかにした。本研究で得た知見は、骨・関節疾患の治療法の開発などの研究に将来的に寄与するものと考えられる。

Research Products

• [Journal Article] PMEPA1 and NEDD4 control proton production of osteoclasts by regulating vesicular trafficking (2021)
  • Author(s): 75.Hirata H, Xu X, Nishioka K, Matsuhisa F, Kitajima S, Kukita T, Murayama M, Urano Y, Miyamoto H, Mawatari M, Kukita A
  • Journal Title: FASEB J. Volume: 35 Issue: 2
  • DOI: 10.1096/fj.202001795r
  • Peer Reviewed
• [Journal Article] Prostate transmembrane protein androgen induced 1 is induced by activation of osteoclasts and regulates bone resorption (2019)
  • Author(s): Xu Xianghe、Hirata Hirohito、Shiraki Makoto、Kamohara Asana、Nishioka Kenichi、Miyamoto Hiroshi、Kukita Toshio、Kukita Akiko
  • Journal Title: The FASEB Journal Volume: 33 Issue: 3 Pages: 4365-4375
  • DOI: 10.1096/fj.201801573r
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Osteoblast lineage-specific cell-surface antigen (A7) regulates osteoclast recruitment and calcification during bone remodeling (2019)
  • Author(s): Badawy Tamer、Kyumoto-Nakamura Yukari、Uehara Norihisa、Zhang Jingqi、Sonoda Soichiro、Hiura Hidenobu、Yamaza Takayoshi、Kukita Akiko、Kukita Toshio
  • Journal Title: Laboratory Investigation Volume: 印刷中 Issue: 6 Pages: 1-19
  • DOI: 10.1038/s41374-018-0179-4
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Deficiency of stress-associated gene Nupr1 increases bone volume by attenuating differentiation of osteoclasts and enhancing differentiation of osteoblasts. (2019)
  • Author(s): Shiraki M, Xu X, Iovanna JL, Kukita T, Hirata H, Kamohara A, Kubota Y, Miyamoto H, Mawatari M, Kukita A.
  • Journal Title: FASEB J. Volume: 33 Issue: 8 Pages: 8836-8852
  • DOI: 10.1096/fj.201802322rr
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IL-1beta induce pathologically activated osteoclasts bearing extremely high level of resorption activity imaged by pH-sensitive fluorescence probes: A possible pathological subpopulation of osteoclasts, accompanied with suppressed expression of integrin regulating molecule kindling-3 and talin-1. (2018)
  • Author(s): Shiratori T., Kyumoto-Nakamura Y., Kukita A., Uehara N., Zhang J., Koda K., Kamiya M., Badawy T., Tomoda E., Xu X., Yamaza T., Urano Y., Koyano K., Kukita T.
  • Journal Title: J. Immunology Volume: 200 Issue: 1 Pages: 218-228
  • DOI: 10.4049/jimmunol.1602035
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IL-1β induce pathologically activated osteoclasts bearing extremely high level of resorption activity imaged by pH-sensitive fluorescence probes: A possible pathological subpopulation of osteoclasts, accompanied with suppressed expression of integrin regulating molecule kindling-3 and talin-1. (2018)
  • Author(s): Shiratori T., Kyumoto-Nakamura Y., Kukita A., Uehara N., Zhang J., Koda K., Kamiya M., Badawy T., Tomoda E., Xu X., Yamaza T., Urano Y., Koyano K., Kukita T.
  • Journal Title: J. Immunology Volume: 200 Issue: 4 Pages: 218-228
  • DOI: 10.1002/jcp.26147
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Pmepa1は小胞輸送に関わり骨吸収中の破骨細胞で酸の分泌を制御する (2020)
  • Author(s): 平田寛人、村山雅俊、白木誠、久木田敏夫、馬渡正明、久木田明子
  • Organizer: 第38回 日本骨代謝学会
• [Presentation] Pmepa1は骨吸収中の破骨細胞で小胞輸送に関わり酸の分泌を制御する (2020)
  • Author(s): 平田寛人,村山雅俊,白木誠,久木田敏夫,久木田明子,馬渡正明
  • Organizer: 第35回 日本整形外科学会基礎学術集会
• [Presentation] Prostate transmembrane protein androgen induced-1 Is Localized to Lysosome with Nedd4 and Vacuolar ATPase subunits in Osteoclasts, and Regulates Bone Resorption (2020)
  • Author(s): Hirohito Hirata, Xianghe Xu, Masatoshi Murayama, Makoto Shiraki, Toshio Kukita, Mawatari Masaaki, Akiko Kukita
  • Organizer: American Society for Bone and Mineral Research(ASBMR) 2020 Annual Meeting
  • Int'l Joint Research
• [Presentation] Pmepa1は破骨細胞でNedd4とLAMP２と共局在し骨吸収を制御する (2019)
  • Author(s): 平田寛人、徐祥赫、白木誠、蒲原麻菜、久木田敏夫、馬渡正明、久木田明子
  • Organizer: 第37回 日本骨代謝学会
• [Presentation] 骨転移性乳癌細胞由来細胞外小胞に内包されるmicroRNAと破骨細胞間コミュニケーション (2019)
  • Author(s): 上原範久、久本由香里、久木田明子、久木田敏夫
  • Organizer: 第37回 日本骨代謝学会
• [Presentation] Deficiency of stress-associated gene Nupr1/p8 increased bone volume by enhancing differentiation of osteoblasts (2019)
  • Author(s): Shiraki M, Xu X, Iovanna JL, Kukita T, Hirata H, Kamohara A, Kubota Y, Miyamoto H, Mawatari M, Kukita A.
  • Organizer: 第42回 日本分子生物学会
• [Presentation] Prostate transmembrane protein androgen induced-1 is localized to lysosome with Nedd4 in osteoclasts, and regulates bone resorption (2019)
  • Author(s): H.Hirata, X. Xu, M. Shiraki, M. Murayama, A. Kamohara, K. Nishioka, F. Matsuhisa, S. Kitajima, Y. Urano, H. Miyamoto, T. Kukita, M. Mawatari, A. Kukita
  • Organizer: 第42回 日本分子生物学会
• [Presentation] Galectin-9/Tim-3シグナルを介した破骨細胞分化制御メカニズムの解明 (2019)
  • Author(s): 久本由香里、上原範久、久木田明子、山座孝義、久木田敏夫
  • Organizer: 第42回 日本分子生物学会
• [Presentation] Prostate transmembrane protein androgen induced-1 and nuclear protein ｐlay novel roles in bone methabolism (2019)
  • Author(s): 久木田明子
  • Organizer: 第42回 日本分子生物学会 Satellite symposium:Cutting Edge of Bone and Minerak Research
• [Presentation] 黄色ブドウ球菌のプロテインAとIgG複合体による骨破壊促進機構 (2018)
  • Author(s): 蒲原 麻菜，徐 祥赫，白木 誠 ，平田 寛人, 久木田敏夫, 久木田明子
  • Organizer: 第34回 日本骨代謝学会
• [Presentation] 破骨細胞分化制御におけるGalectin-9/Tim-3シグナルの関与 (2018)
  • Author(s): 久本由香里、上原範久、久木田明子、久木田敏夫
  • Organizer: 第34回 日本骨代謝学会
• [Presentation] Novel osteoblast-lineage specific cell-surface antigen possibly regulateing osteoclastogenesis and calcification (2018)
  • Author(s): Tamer Badawy, Yukari Kyumoto－Nakamura, Norihisa Uehara, Jingqi Zhang, Hidenobu Hiura, Akiko Kukita, Toshio Kukita
  • Organizer: 第34回 日本骨代謝学会
• [Presentation] 黄色ブドウ球菌はプロテインAを介してIgG複合体を形成し破骨細胞の分化と骨吸収を促進する (2018)
  • Author(s): 蒲原 麻菜, 久木田敏夫, 久木田明子
  • Organizer: 第60回歯科基礎医学会
• [Presentation] ラット破骨細胞培養系により明らかになった破骨細胞の骨吸収を制御する新たなタンパク質 (2018)
  • Author(s): 久木田明子，蒲原 麻菜, 久木田敏夫,
  • Organizer: 第60回歯科基礎医学会
  • Invited
• [Presentation] Osteoblast lineage-specific cell-surface antigen regulating osteoclastogenesis an calcification: A possible new player in bone remodeling (2018)
  • Author(s): Badawy Tamer, 久本由香里、上原範久、張旌旗、山座孝義、久木田明子、久木田敏夫
  • Organizer: 第60回歯科基礎医学会
• [Presentation] Deletion of the gene encoding Nupr1/p8, a regulator of autophagy, attenuates osteoclastogenesis but increases trabecular bone mass by enhancing osteoblast differentiation (2018)
  • Author(s): Makoto Shiraki, Hiroto Hirata, Asana Kamohara, Juan Iovanna, Toshio Kukita, Masaaki Mawatari, Akiko Kukita
  • Organizer: 41th Annual Meeting of American Society for Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] IgG complex with protein A of Staphylococcus aureus enhance the differentiation and bone resorption of osteoclasts. (2018)
  • Author(s): Asana Kamohara, Xianghe Xu, Makoto Shiraki, Hiroto Hirata, Toshio Kukita, Akiko Kukita
  • Organizer: 41th Annual Meeting of American Society for Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] Novel Osteoblast-lineage Specific Cell-Surface Antigen possibly regulating Osteoclastogenesis and Calcification (2018)
  • Author(s): Tamer Abdelhadi Badawy, Yukari Kyumoto-Nakamura, Norihisa Uehara, Jingqi Zhang, Hidenobu Hiura, Akiko Kukita, Toshio Kukita
  • Organizer: 41th Annual Meeting of American Society for Bone and Mineral Research
  • Int'l Joint Research
• [Presentation] 黄色ブドウ球菌のプロテインAとIgG複合体による骨破壊促進機構 (2018)
  • Author(s): 蒲原 麻菜, 徐 祥赫, 白木 誠, 平田 寛人, 張旌旗, 久木田敏夫，山田 作夫, 豊永 憲司, 原 博満, 菖蒲池 健夫, 宮本 比呂志, 久木田明子
  • Organizer: 第71回日本細菌学会九州支部会
• [Presentation] IgG complex with protein A of Staphylococcus aureus enhance the differentiation and bone resorption of osteoclasts. (2018)
  • Author(s): Asana Kamohara, Xianghe Xu, Kenji Toyonaga, Hiromitsu Hara, Yoshio Yamashita, Akiko Kukita
  • Organizer: 第47回日本免疫学会