Development for low side effect anti-bone resorption medicines of pediatric steroidal osteoporosis

• Project/Area Number: 17K11968
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthodontics/Pediatric dentistry
• Research Institution: Kyushu Dental College
• Principal Investigator: Maki Kenshi 九州歯科大学, 歯学部, 教授 (60209400)
• Co-Investigator(Kenkyū-buntansha): 松原 琢磨 九州歯科大学, 歯学部, 准教授 (00423137) ; 古株 彰一郎 九州歯科大学, 歯学部, 教授 (30448899) ; 青木 和広 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (40272603) ; 自見 英治郎 九州大学, 歯学研究院, 教授 (40276598)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 骨代謝 / 骨芽細胞 / 破骨細胞 / Bif-1 / Endophilin B1 / SH3GLB1 / Bax相互作用因子 / Bif-1欠損マウス / p130cas / μCT / 骨密度 / ステロイド / p130Cas / 小児 / 骨吸収

Outline of Final Research Achievements

Bif-1-deficient (Bif-1 -/- ) mice showed increased trabecular bone volume and trabecular number. Histological analyses indicated that the osteoclast numbers increased in Bif-1 -/- mice. Consistent with the in vivo results, osteoclastogenesis induced by RANKL was accelerated in Bif-1 -/- mice without affecting RANKL-induced activation of RANK downstream signals, such as NF-κB and MAPKs, CD115/RANK expression in osteoclast precursors, osteoclastic bone-resorbing activity and the survival rate. Unexpectedly, both the bone formation rate and osteoblast surface substantially increased in Bif-1 -/- mice. Osteoblastic differentiation and mineralization were enhanced in Bif-1 -/- mice. Finally, bone marrow cells from Bif-1 -/- mice showed a significantly higher colony-forming efficacy, suggesting that cells from Bif-1 -/- mice had higher clonogenicity and self-renewal activity than those from WT mice.

Academic Significance and Societal Importance of the Research Achievements

Bif-1欠損マウスでは骨梁の数と骨量が増加する。そのメカニズムが解明できたことにより、Bif-1をターゲットにした新たな骨代謝治療薬創出につながる可能性がある。

Research Products

• [Journal Article] Bif-1/Endophilin B1/SH3GLB1 regulates bone homeostasis (2019)
  • Author(s): Touyama K, Khan M, Aoki K, Matsuda M, Hiura F, Takakura N, Matsubara T, Harada Y, Hirohashi Y, Tamura Y, Gao J, Mori K, Kokabu S, Yasuda H, Fujita Y, Watanabe K, Takahashi Y, Maki K, Jimi E
  • Journal Title: J Cell Biochem Volume: 120 Pages: 18793-18804
  • Peer Reviewed
• [Journal Article] Ameloblastin attenuates RANKL-mediated osteoclastogenesis by suppressing activation of nuclear factor of activated T cells cytoplasmic1 (NFATc1) (2019)
  • Author(s): Chaweewannakorn W, Ariyoshi W, Okinaga T, Fujita Y, Maki K, Nishihara T
  • Journal Title: J Cell Physiol Volume: 234 Issue: 2 Pages: 1745-1757
  • DOI: 10.1002/jcp.27045
  • Peer Reviewed / Open Access / Int'l Joint Research