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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

基本信息

批准号：
10448298
负责人：
Claire Acevedo
金额：
$ 13.64万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448298
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 Persons Population Research Research Design Resistance Ribose Risk Risk Factors Roentgen Rays Role Sampling Slide Socioeconomic Factors 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 diagnostic tool 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

项目摘要

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。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The influence of AGEs and enzymatic cross-links on the mechanical properties of collagen fibrils

DOI：
10.1016/j.jmbbm.2023.105870
发表时间：
2023-05-06
期刊：
JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS
影响因子：
3.9
作者：
Kamml, Julia;Ke, Chun-Yu;Kammer, David S.
通讯作者：
Kammer, David S.

Effect of non-enzymatic glycation on collagen nanoscale mechanisms in diabetic and age-related bone fragility.

DOI：
10.32604/biocell.2023.028014
发表时间：
2023-06-21
期刊：
Biocell : official journal of the Sociedades Latinoamericanas de Microscopia Electronica ... et. al
影响因子：
0
作者：
Rosenberg JL;Woolley W;Elnunu I;Kamml J;Kammer DS;Acevedo C
通讯作者：
Acevedo C

Mineral and cross-linking in collagen fibrils: The mechanical behavior of bone tissue at the nano-scale