Elucidation of molecular regulation mechanism of low turnover diabetic osteoporosis via advanced glycation end products and its therapeutic application

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17995
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: Tanaka Kenichi 産業医科大学, 医学部, 助教 (90596686)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 終末糖化産物 / 破骨細胞 / 糖尿病 / 低骨代謝回転

Outline of Final Research Achievements

Diabetic patients are at high risk for osteoporosis and bone fractures, which have been attributed to endogenous glycation products (AGEs) produced by chronic hyperglycemia and the low-turnover bone metabolism abnormalities characterized in diabetes mellitus. Although AGEs inhibit osteoblast functions, little is known about their roles in regulation of human osteoclast differentiation. In addition, the mechanism of the low bone metabolism observed in diabetes mellitus is unknown. Glyceraldehyde-modified AGEs inhibited human osteoclast differentiation from human monocytes through induction of IL-10 expression via NF-κB. Serum AGE levels were significantly higher in patients with diabetes, and serum AGE levels were negatively correlated with bone metabolism markers. It can be assumed that AGE bioaccumulation in diabetic patients increases the risk of bone fracture, through inhibition of osteoclast differentiation, reduction of bone turnover, and disruption of bone remodeling.

Free Research Field

内分泌代謝糖尿病

Academic Significance and Societal Importance of the Research Achievements

糖尿病患者は心血管疾患のみならず、骨粗鬆症や骨折リスクが高いことが問題である。糖尿病で特徴とされる低回転型の骨代謝異常のメカニズムとして、グリコールアルデヒド由来AGEのIL-10産生を介したヒト単球から破骨細胞への分化作用が関与している可能性が示され、AGEの新たな分子基盤が明らかにされた。また糖尿病患者の高AGE血症と低回転型の骨代謝異常との関連が示唆された。
現在の高齢社会において糖尿病、骨粗鬆症患者が増加し続けることで今後さらに医療費が増大することが予想される。糖尿病患者の高AGE血症をターゲットとした治療法の確立が、糖尿病のみならず糖尿病性骨粗鬆症に対しても有用となることが期待される。