Osteoblast-specific cell-surface antigen regulating recruitment of osteoclasts: Bone regeneration based on the new concept concerning the regulation of bone remodeling

• Project/Area Number: 18K09506
• 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 University
• Principal Investigator: Kukita Toshio 九州大学, 歯学研究院, 教授 (70150464)
• Co-Investigator(Kenkyū-buntansha): 久木田 明子 佐賀大学, 医学部, 准教授 (30153266) ; 久本 由香里 九州大学, 歯学研究院, 助教 (40729026)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 破骨細胞 / 骨芽細胞 / 石灰化 / 骨改造制御 / 血管 / 環境センサー / 骨改造 / 膜表面分子 / 質量分析 / モノクローナル抗体 / 血管内皮細胞 / 骨改造開始点・場の制御 / 免疫シナプス様構造 / 骨芽細胞表面分子 / 破骨細胞誘導 / 免疫シナプス / プロテオミクス

Outline of Final Research Achievements

We have found and analyzed a novel osteoblat-specific cell surface molecule （A7 antigen）involving regulation of bone remodeling and calcification. By use of MASS spectroscopic analysis, we have identified insulin receptor-like molecule (IRLM) as one candidate for A7 antigen. We have obtained lines of evidence showing IRLM is actually expressed on cell surface of primary osteoblasts. We have also obtained strong evidence demonstrating that A7 antigen is highly associated with IRLM itself by use of IP/IB analysis. IRLM is reported as the sensor for a specified culture environment. When primary osteoblasts were treated with the specified culture environment, calcification was significantly stimulated. It was suggested that A7 antigen/IRLM acts as a sensor for the specific environment in bone tissues.

Academic Significance and Societal Importance of the Research Achievements

新規骨芽細胞特異的膜表面分子が骨改造において制御的な役割を果たしており、特定の環境因子のセンサーとして機能する可能性を見出した。本研究から導き出される骨改造制御に関する新しい概念に基づいて、新しい治療法を開発することが可能となる。超高齢化社会に入り骨疾患者が増加する一方にある我国において、本研究は社会的意義が極めて深い研究である。

Research Products

• [Journal Article] Extracellular vesicles from deciduous pulp stem cells recover bone loss by regulating telomerase activity in an osteoporosis mouse model. (2020)
  • Author(s): Sonoda S, Murata S, Nishida K, Kato H, Uehara N, Kyumoto-Nakamura Y, Yamaza H, Takahashi I, Kukita T, Yamaza T.
  • Journal Title: Stem Cell Res Ther Volume: 11 Issue: 1
  • DOI: 10.1186/s13287-020-01818-0
  • Peer Reviewed / Open Access
• [Journal Article] IgG immune complexs with Staphylococcus aureus protein A emhance osteoclast differentiation and bone resorption by stimulating Fc receptors and TLR2. (2020)
  • Author(s): Kamohara A, Hirata H, Xu X, Shiraki M, Yamaza S, Zhang JQ, Kukita T, Toyonaga K, Hara H, Urano Y, Yamashita Y, Miyamoto H, Kukita A.
  • Journal Title: Int Immunol Volume: 32 Pages: 89-104
  • Peer Reviewed
• [Journal Article] IgG immune complexes with Staphylococcus aureus protein A enhance osteoclast differentiation and bone resorption by stimulating Fc receptors and TLR2. (2020)
  • Author(s): Kamohara A, Hirata H, Xu X, Shiraki M, Yamada S, Zhang JQ, Kukita T, Toyonaga K, Hara H, Urano Y, Yamashita Y, Miyamoto H, Kukita A.
  • Journal Title: Int Immunol. 2020 Feb 7;32(2):89-104. Volume: 32 Issue: 2 Pages: 89-104
  • DOI: 10.1093/intimm/dxz063
  • Peer Reviewed
• [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] Acetylsalicylic Acid Treatment and Suppressive Regulation of AKT Accelerate Odontogenic Differentiation of Stem Cells from the Apical Papillla. (2019)
  • Author(s): Tanaka Y, Sonoda S, Yamaza H, Murata S, Nishida K, Kyumoto-Nakamura Y, Uehara N, Nonaka K, Kukita T, Yamaza T.Tanaka Y
  • Journal Title: J Endod. 2019 May;45(5):591-598.e6. Volume: 45 Issue: 5 Pages: 591-598
  • DOI: 10.1016/j.joen.2019.01.016
  • Peer Reviewed
• [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] 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] 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] Pamidronate decreases bilirubin-impaired cell death and improves dentinogenic dysfunction of stem cells from human deciduous teeth. (2018)
  • Author(s): Yamaza H, Sonoda S, Nonaka K, Kukita T, Yamaza T.
  • Journal Title: Stem Cell Res.Ther. Volume: 9 Issue: 1 Pages: 303-314
  • DOI: 10.1186/s13287-018-1042-7
  • Peer Reviewed
• [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] 破骨細胞機能制御に関連する新規破骨細胞特異的膜表面抗原 (2020)
  • Author(s): 顧炯炎,久本由香里,寺町順平,日浦秀暢,張旌旗, 張暁旭,上原範久,山座孝義,久木田明子,久木田敏夫
  • Organizer: 歯科基礎医学会
• [Presentation] 骨芽細胞特異的な骨改造制御膜表面分子の同定と機能解析 (2020)
  • Author(s): 日浦 秀暢, 久本 由香里, Tamer Badawy, 上原 範久, 張 旌旗, 顧 炯炎, 山座 孝義, 久木田 明子, 高橋 一郎, 久木田敏夫
  • Organizer: 歯科基礎医学会
• [Presentation] Osteoblast-specific cell surface antigen regulating osteoclastogenesis and calcification. A possible unique modulator of bone remodeling (2018)
  • Author(s): Tamer Badawy, Yukari Kyumoto-Nakamura, Norihisa Uehara, Akiko Kukita, Toshio Kukita
  • Organizer: American Siciety of Bone and Mineral Research (ASBMR)
  • Int'l Joint Research
• [Presentation] Osteoblast Lineage^Specific Cell Surface Antigen Regulation Osteoclastogenesis and 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] Novel Osteoblast-Lineage Specific Cell-Surface Antigen Possibly Regulating Osteoclastogenesis and Calcification 破骨細胞形成と石灰化を制御する可能性を有する新規骨芽細胞膜表面抗原 (2018)
  • Author(s): Tamer Badawy, 久本由香里、上原範久、久木田明子、久木田敏夫
  • Organizer: 第36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36回 日本骨代謝学会
• [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36回 日本骨代謝学会