Quantifying the contribution of collagen cross-linking to increased bone fragility

项目摘要 在过去的几十年里，糖消费量的急剧上升，缺乏活动和社会经济因素导致了 肥胖和2型糖尿病人群的迅速增加。成人糖尿病患者骨折风险增加一倍 与骨量相似的非糖尿病成人相比。如果越来越清楚高血糖影响 骨质量和参与脆性骨折，骨折风险增加的发病机制和机制， T2D还没有得到很好的理解。我们最近在糖尿病大鼠模型中的发现表明，2型糖尿病大鼠的脆性行为 糖尿病骨主要是由于胶原蛋白变形能力的大量减少，而不是改变 在骨骼结构中。这被认为与已知的特定非酶交联的增加有关 作为晚期糖基化终产物（AGEs），防止胶原蛋白分子相互滑动。 然而，AGEs交联对全骨抗骨折性的独立影响尚不清楚。 该项目的总体目标是表征胶原蛋白的纳米级行为，以确定 AGE胶原交联对T2D患者全骨力学行为和骨脆性的影响。我们建议 通过将多尺度数值模拟与专门的实验相结合来确定这些机制。 将使用矿化胶原纤维的现实分子尺度数值模型和有限元模型 确定AGEs浓度对全骨阻力的影响。同步加速器和原子力显微镜实验将 然后用于测试具有不同AGEs浓度的每个长度尺度下的骨的行为（通过 核糖基化），以验证我们的数值模型，并量化胶原变形作为全骨的函数， 变形这个新的多尺度模型将建立一个新的定量理解的机制， 其在皮质骨的胶原水平上的变化增加了糖尿病人群中骨折的风险， 最终确定一种预防和治疗糖尿病患者骨折的新途径。

PROJECT SUMMARY Over the last decades, the drastic rise in sugar consumption, lack of activity and socio-economic factors has led to a rapid increase in obese and type 2 diabetic populations. Diabetic adults have double the risk of fracture compared with non-diabetic adults with a similar bone mass. If it is becoming clear that high blood glucose affects bone quality and is involved in fragility fracture, the pathogenesis and mechanisms of increased fracture risk in T2D are not well understood. Our recent findings in a diabetic rat model indicate that brittle behavior in type 2 diabetic bone was primarilty due to a substantial reduction in collagen capacity of deformation rather than change in bone structure. This is thought to be associated with the increase of specific non-enzymatic cross-links known as Advanced Glycation End products (AGEs), preventing the collagen molecules to slide onto each other. However, the independent influence of AGEs cross-links on the whole-bone resistance to fracture is unknown. The overall objective of this project is to characterize the collagen nanoscale behavior to establish the role of AGE collagen crosslinks on the whole-bone mechanical behavior and bone fragility in T2D. We propose to identify these mechanisms by combining multiscale numerical modeling with dedicated experimentation. Realistic molecular-scale numerical models of mineralized collagen fibrils and finite element models will be used to establish the effect of AGEs concentration on whole-bone resistance. Synchrotron and AFM experiments will then be used to test bone’s behavior at each length scale with different AGEs concentration (achieved via ribosylation) to validate our numerical models and quantify collagen deformation as a function of whole-bone deformation. This new multiscale model will establish a new quantitative understanding of the mechanisms by which changes at the collagen level of cortical bone increase bone fracture risk in the diabetic population, ultimately identifying a novel pathway to prevent and treat fracture in diabetic patients.