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

2018 Fiscal Year Final Research Report

• 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
• Keywords: 骨癒合遅延 / AGE / ピリドキサミン / 糖尿病

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.

Free Research Field

整形外科

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．