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

量化胶原交联对骨脆性增加的贡献

• 批准号: 10303860
• 负责人: Claire Acevedo
• 金额: $ 18.73万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303860
• 关键词: Adult; Advanced Glycosylation End Products; Affect; American; Behavior; Biological Assay; Biomechanics; Blood Glucose; Bone structure; Cattle; Cells; Collagen; Collagen Fibril; Complex; Complication; Computer Models; Consumption; Data; Diabetes Mellitus; Disease; Elements; Femur; Fibrillar Collagen; Fracture; Goals; Grain; Health Expenditures; High Prevalence; Hyperglycemia; Impairment; In Situ; In Vitro; Lead; Length; Minerals; Modeling; Molecular; Nature; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; North America; Numeric Rating Scale; Obesity; Osteon; Pathogenesis; Pathway interactions; Patients; Population; Research; Research Design; Resistance; Ribose; Risk; Risk Factors; Roentgen Rays; Role; Sampling; Slide; Socioeconomic Factors; Structure; Synchrotrons; Techniques; Testing; Type 2 diabetic; Visual Acuity; Work; bone; bone fragility; bone mass; bone quality; cortical bone; crosslink; density; diabetic; diabetic patient; diabetic rat; experimental study; fracture risk; fragility fracture; imaging properties; mechanical behavior; mechanical properties; microCT; molecular dynamics; molecular mechanics; molecular scale; multi-scale modeling; multidisciplinary; nanoscale; non-diabetic; novel; novel diagnostics; novel strategies; prevent; simulation; sugar; therapeutic target; three dimensional structure; tool

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.

项目总结 在过去的几十年里，食糖消费的急剧上升、缺乏活动和社会经济因素导致了 导致肥胖和2型糖尿病人口迅速增加。成年糖尿病患者骨折风险增加一倍 与骨量相似的非糖尿病成年人相比。如果越来越明显的是高血糖会影响 骨质量与脆性骨折的关系、骨折风险增加的发病机制 T2D还没有被很好地理解。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显著降低而不是改变。 在骨骼结构上。这被认为与已知的特定非酶交联链的增加有关。 作为高级糖基化终末产物(AGEs)，防止胶原蛋白分子相互滑动。 然而，AGEs交联物对全骨抗折性的独立影响尚不清楚。 该项目的总体目标是表征胶原纳米尺度的行为，以确定 AGE-胶原交联物对T2D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。 我们将使用矿化胶原纤维的真实分子尺度的数值模型和有限元模型。 目的：探讨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 然后用来测试每个长度尺度上不同年龄浓度的骨骼的行为(通过 核糖化)来验证我们的数值模型并量化作为整个骨骼的函数的胶原变形 变形。这一新的多尺度模型将通过以下方式建立对机制的新的量化理解 在糖尿病人群中，皮质骨胶原水平的变化会增加骨折的风险， 最终确定一条预防和治疗糖尿病患者骨折的新途径。