Revealing mechanism of delayed bone union by glycation stress and development new drug

• Project/Area Number: 16K10896
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Kanazawa University
• Principal Investigator: Hidenori Matsubara 金沢大学, 医学系, 助教 (10507057)
• Research Collaborator: YAMAMOTO YASUHIKO 金沢大学医薬保健研究域 医学系, 血管分子生物学, 教授 (20313637)
• 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: 骨癒合遅延 / AGE / ピリドキサミン / 糖尿病 / 糖化ストレス / 骨折 / MG / RAGE / シグナル伝達 / 遺伝子

Outline of Final Research Achievements

Advanced glycation end-products (AGE) are implicated in diabetic complications. Pyridoxamine (PM) is one of the natural forms of vitamin B6 and is known to inhibit reactive carbonyl intermediates in AGE formation. In this study, we examined whether Metylglyoxal (MGO) was a cause of disturbed bone healing in diabetes and the bone problem was improved by PM treatment. We found that MGO could cause impaired osteoblastic differentiation and delayed bone repair in diabetes. For it, we employed PM in this study. PM treatment did not show any significant effects on blood glucose control. However, the delayed bone healing in diabetes was significantly improved by PM treatment from an early repair stage of day 7. In vitro cellular assays, MGO could inhibit the osteoblastic differentiation of MC3T3 cells. By adding PM, the ALP activity of ST2 cells was not substantially improved at 0.3 mM, but it was not complete at 1 mM, but it was improved.

Academic Significance and Societal Importance of the Research Achievements

Pyrを投与することで，高血糖状態であるDMマウスの血糖コントロールを行わずに，骨癒合遅延の改善をすることができた．これを実臨床に置き換えると，糖尿病が起こす耐糖能異常を全く無視した状態で手術を行い，骨癒合を得られた状態と考える．このメリットは，骨折手術において，血糖コントロールのために延期していた手術を早期に行えることや糖毒性により血糖コントロールが困難な患者の偽関節を予防できることにある．本研究は，今後の糖化ストレスによる骨修復障害の治療の基礎となり，Pyrは糖尿病患者における偽関節や骨癒合遅延といったBone problemを改善する可能性がある．

Research Products

• [Journal Article] 外傷後後遺症に対する創外固定を用いた治療 (2017)
  • Author(s): 松原秀憲, 宇賀治修平, 濱田知, 土屋弘行
  • Journal Title: 臨床整形外科 Volume: 52 Pages: 761-768
  • Peer Reviewed
• [Presentation] 糖化ストレスによる骨修復能障害はピリドキサミン投与により改善される (2019)
  • Author(s): 宇賀治修平，松原秀憲，相川敬男，吉田泰久，濱田知，土屋弘行
  • Organizer: 中部日本整形災害外科
• [Presentation] Delayed bone repair in diabetes is improved by the treatment of pyridoxamine (2018)
  • Author(s): Shuhei Ugaji, Hidenori Matsubara, Yasuhisa Yoshida, Hiroyuki Tsuchiya
  • Organizer: American Academy of Orthopaedic Surgeons 2019
  • Int'l Joint Research
• [Presentation] 糖尿病による骨修復能障害はピリドキサミン投与により改善される (2017)
  • Author(s): 宇賀治修平,松原秀憲,吉田泰久,濱田知,土屋弘行
  • Organizer: 第32回日本整形外科基礎学術集会
• [Presentation] Distraction Osteogenesisを用いた感染性偽関節の治療成績 (2017)
  • Author(s): 松原秀憲, 野村一世, 吉田泰久, 宇賀治修平, 土屋弘行
  • Organizer: 第30回日本創外固定・骨延長学会学術集会
• [Presentation] Deformity Correction and Lengthening for the Treatment of Benign Bone Tumors Using External Fixation (2017)
  • Author(s): Hidenori Matsubara, Shuhei Ugaji, Hiroyuki Tsuchiya
  • Organizer: 3rd World Ortho ReCon ILLRS&ASAMI Congress
• [Presentation] Clinical outcomes of conversion from external fixator to iodine-supported titanium alloy plate (2017)
  • Author(s): Hidenori Matsubara, Toshiharu Shirai, Shuhei Ugaji, Hiroyuki Tsuchiya
  • Organizer: 3rd World Ortho ReCon ILLRS&ASAMI Congress