Diabetes-Related Changes Affecting Bone Quality

影响骨质量的糖尿病相关变化

• 批准号: 10155432
• 负责人: Jeffry Stephen Nyman
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155432
• 关键词: Address; Advanced Glycosylation End Products; Affect; Age; Amides; Architecture; Biomechanics; Bone Density; Bone Matrix; Bone structure; Cadaver; Characteristics; Clinical; Clinical assessments; Collagen; Defect; Diabetes Mellitus; Diagnosis; Diagnostic; Diagnostic Procedure; Discipline; Dual-Energy X-Ray Absorptiometry; Electrons; Equilibrium; Event; FDA approved; Fatigue; Female; Femur; Foundations; Fracture; Gender; Glycosylated hemoglobin A; Goals; Hip Fractures; Hip region structure; Hydrogen Bonding; Hydroxylation; Image; Individual; Magnetic Resonance Imaging; Mass Spectrum Analysis; Measurement; Measures; Modification; Molecular; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Osteoporosis; Pathogenicity; Patient risk; Patients; Periodicity; Pharmaceutical Preparations; Post-Translational Protein Processing; Prevalence; Prevention; Property; Proteins; Protons; Quality of life; Raman Spectrum Analysis; Research; Research Personnel; Resistance; Resolution; Risk; Sampling; Signal Transduction; Structure; Techniques; Technology; Time; Tissues; Veterans; Water; Woman; bone; bone quality; bone toughness; carboxylation; clinical Diagnosis; clinical diagnostics; cortical bone; density; diabetic; diabetic bone disease; fracture risk; glycosylation; improved; indexing; male; mechanical properties; men; microCT; mineralization; minimally invasive; mortality; non-diabetic; novel; novel diagnostics; novel strategies; recruit; risk prediction; sex; therapeutic target; tibia; tool

Project Summary/Abstract: The risk of bone fracture and subsequent high morbidity increases with the progression of type 2 diabetes (T2D), and the clinical assessment of bone mineral density (BMD) is not particularly effective in diagnosing this risk. Moreover, lowering fracture risk among patients with T2D requires an understanding of the changes in the bone that affect fracture resistance. Addressing these unmet needs, the proposed project aims i) to determine the primary biomechanical reason for the increase in fracture risk with T2D, ii) to identify molecular changes in the bone matrix that can significantly affect fracture resistance, and iii) to ascertain the ability of matrix-sensitive tools to assess significant differences in bone quality between age-matched non-diabetics and diabetic individuals. In Aim 1, cadaveric bone from non-diabetic and T2D donors matching for age and gender will be comprehensively analyzed to determine whether the primary T2D-related decrease in fracture resistance is lower bone toughness, lower fatigue resistance, and/or lower fracture toughness as opposed to lower strength at the whole-bone- and material-level. Moreover, the ability of matrix characteristics to explain T2D-related differences in these mechanical properties of bone will be assessed in relation to volumetric BMD and micro-structure (assessed by micro-computed tomography) as well as the degree of mineralization and osteonal density (assessed backscattered electron imaging). Matrix characteristics will include secondary structure of collagen I as determined by sub-peak ratios of the Amide I band from Raman spectroscopy (RS), bound and pore water volume fractions as determined by proton nuclear magnetic resonance (NMR) relaxometry, and resistance to microindentation properties as determined by both cyclic and impact reference point (RPI). In Aim 2, the focus will be on the contribution of novel molecular mechanisms to the underlying diabetic changes in matrix-bound water and collagen structure. Specifically, emphasis will be placed on post-translational modifications (PTMs) of collagen I and non-collagenous bone matrix proteins as a mechanism that affects hydrogen bonding between water and the matrix. Implicated in diabetes, these PTMs will include non-enzymatic advanced glycation end products (AGEs) as well as enzymatic hydroxylation, glycosylation, and carboxylation. In Aim 3, matrix-sensitive, clinical techniques will determine whether bone quality is significantly different between patients without diabetes and patients with established T2D. By matching age and BMD-derived T-scores between the groups, we will ascertain whether bone material strength index from impact RPI, bound and pore water concentrations from ultra-short time-to-echo magnetic resonance imaging (UTE-MRI) of NMR signals (T2), and Amide I sub-peak ratios from spatially offset, transcutaneous RS, all acquired at the tibia mid-shaft, will potentially add value to the clinical assessment of fracture risk. The completion of the Aims of this proposal will lay the foundation for use of matrix-sensitive tools in clinical diagnostics of diabetic bone disease and potentially identify specific targets within the bone matrix for lowering fracture risk among diabetics.

项目摘要/摘要： 骨断裂和随后高发病率的风险随着2型糖尿病（T2D）的进展而增加 骨矿物质密度（BMD）的临床评估在诊断这种风险方面并不特别有效。 此外，降低T2D患者的断裂风险需要了解骨骼的变化 这会影响断裂抗性。解决这些未满足的需求，拟议的项目的目的是i）确定 T2D骨折风险增加的主要生物力学原因，ii）确定分子变化 可以显着影响断裂抗性的骨基质，iii）确定基质敏感工具的能力 评估年龄匹配的非糖尿病和糖尿病患者之间骨质质量的显着差异。在 AIM 1，非糖尿病和T2D供体的尸体骨骼与年龄和性别相匹配 被分析以确定骨折耐药性的主要T2D相关降低是否是较低的骨骼韧性， 较低的疲劳性耐药性和/或较低的断裂韧性，而不是在整个骨和较低的强度 材料级。此外，矩阵特征解释了与T2D相关的差异的能力 骨骼的机械性能将根据体积BMD和微结构进行评估（通过 微型层析成像）以及矿化和骨密度的程度（评估 反向散射电子成像）。矩阵特征将包括胶原蛋白I的二级结构 由拉曼光谱（RS），结合和孔隙水的酰胺I条带的亚峰值比确定 由质子核磁共振（NMR）松弛测定法确定的体积分数，对 由循环和影响参考点（RPI）确定的微观指示特性。在AIM 2中，重点 将基于新型分子机制对基质结合的潜在糖尿病变化的贡献 水和胶原蛋白结构。具体而言，将重点放在翻译后修饰（PTMS）上 胶原I和非胶原骨基质蛋白作为影响氢键的机制 水和矩阵。与糖尿病有关，这些PTM将包括非酶晚期糖基末端 产物（年龄）以及酶促羟基化，糖基化和羧化。在AIM 3中，矩阵敏感， 临床技术将确定没有糖尿病患者之间的骨骼质量是否显着差异 和已建立的T2D的患者。通过匹配年龄和组之间的BMD衍生的T得分，我们将 确定骨骼材料强度指数是否来自撞击RPI，结合和孔隙水的浓度。 NMR信号（T2）和Amide I子峰 从空间偏移的比率，毛线中的毛线rs（均在胫骨中轴中获得）可能会增加价值 断裂风险的临床评估。该提案目标的完成将为使用 糖尿病骨病的临床诊断中的基质敏感工具，并可能识别在内部的特定靶标 用于降低糖尿病患者断裂风险的骨基质。