Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume, Japan.
Curr Drug Targets. 2011 Dec;12(14):2096-102. doi: 10.2174/138945011798829456.
Recent meta-analyses have revealed that the risk of bone fracture is increased in both type 1 and type 2 diabetic patients. Low bone mineral density (BMD) can not necessarily explain the link, because BMD is increased rather than decreased in type 2 diabetes, while it is consistently low in type 1 diabetes subjects. Although multiple factors could influence the quality of bone and increase the bone fragility in diabetes, there is accumulating evidence for the association between osteoporosis and vascular calcification, which is an independent predictor of cardiovascular disease morbidity and mortality. Advanced glycation end products (AGEs) are formed by a non-enzymatic reaction between aldehydes of reducing sugars and the amino groups of proteins, lipids and nucleic acids that could contribute to the aging of macromolecules. The formation and accumulation of AGEs have been known to progress at an accelerated rate under diabetes. There is a growing body of evidence that AGEs and their receptor (RAGE) system elicit oxidative stress generation and subsequently evoke inflammatory responses in vascular wall cells, osteoblasts and osteoclasts, thereby being involved in both vascular calcification and osteoporosis in diabetes. Further, cross-linking in the organic bone matrix by AGEs could adversely affect the fracture resistance of bone. Therefore, in this paper, I review the pathophysiological role of the AGEs-RAGE-oxidative stress system in decreased BMD and increased bone fragility in diabetes. I also discuss here the potential therapeutic interventions of the AGEs-RAGE axis for preventing osteoporosis in diabetes.
最近的荟萃分析显示，1 型和 2 型糖尿病患者的骨折风险均增加。骨矿物质密度（BMD）的降低不一定能解释这种关联，因为 2 型糖尿病患者的 BMD 升高而不是降低，而 1 型糖尿病患者的 BMD 则一直较低。尽管有多种因素可能影响骨骼质量并增加糖尿病患者的骨骼脆弱性，但越来越多的证据表明骨质疏松症与血管钙化之间存在关联，血管钙化是心血管疾病发病率和死亡率的独立预测因素。晚期糖基化终产物（AGEs）是由还原糖的醛基与蛋白质、脂质和核酸的氨基之间的非酶反应形成的，这可能导致大分子的衰老。在糖尿病中，AGEs 的形成和积累速度已知会加快。越来越多的证据表明，AGEs 及其受体（RAGE）系统会引发氧化应激的产生，并随后在血管壁细胞、成骨细胞和破骨细胞中引发炎症反应，从而参与糖尿病中的血管钙化和骨质疏松症。此外，AGEs 在有机骨基质中的交联可能会对骨骼的抗断裂能力产生不利影响。因此，在本文中，我回顾了 AGEs-RAGE-氧化应激系统在糖尿病中降低 BMD 和增加骨骼脆弱性的病理生理作用。我还讨论了 AGEs-RAGE 轴在预防糖尿病性骨质疏松症方面的潜在治疗干预措施。
