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： 随着 2 型糖尿病 (T2D) 的进展，骨折和随后的高发病率的风险会增加， 骨矿物质密度（BMD）的临床评估对于诊断这种风险并不是特别有效。 此外，降低 T2D 患者骨折风险需要了解骨骼的变化 从而影响抗断裂能力。为了解决这些未满足的需求，拟议项目的目标是 i) 确定 T2D 骨折风险增加的主要原因，ii) 识别 T2D 骨折风险增加的分子变化 可显着影响抗骨折能力的骨基质，以及 iii) 确定基质敏感工具的能力 评估年龄匹配的非糖尿病患者和糖尿病患者之间骨质量的显着差异。在 目标1，来自非糖尿病和T2D捐献者的尸体骨骼的年龄和性别匹配将被全面匹配 进行分析以确定与 T2D 相关的主要抗骨折能力下降是否是骨韧性降低， 与全骨强度较低相比，抗疲劳性较低和/或断裂韧性​​较低 物质层面。此外，矩阵特征能够解释这些疾病中与 T2D 相关的差异。 骨的机械特性将根据体积 BMD 和微观结构进行评估（通过评估） 微计算机断层扫描）以及矿化程度和骨密度（评估 背散射电子成像）。基质特征将包括 I 型胶原蛋白的二级结构 由拉曼光谱 (RS)、结合水和孔隙水的酰胺 I 波段的亚峰比确定 通过质子核磁共振 (NMR) 弛豫测定法确定的体积分数，以及对 由循环和冲击参考点 (RPI) 确定的微压痕特性。在目标 2 中，重点 将研究新的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。具体来说，重点将放在翻译后修饰（PTM）上 胶原蛋白 I 和非胶原骨基质蛋白作为影响之间氢键的机制 水和基质。与糖尿病有关，这些 PTM 将包括非酶促糖基化末端 产物（AGE）以及酶促羟基化、糖基化和羧化。在目标 3 中，对基质敏感， 临床技术将确定非糖尿病患者的骨质量是否存在显着差异 以及已确诊的 T2D 患者。通过匹配各组之间的年龄和 BMD 衍生的 T 分数，我们将 确定骨材料强度指数是否影响 RPI、结合水和孔隙水浓度 NMR 信号 (T2) 和 Amide I 亚峰的超短时间回波磁共振成像 (UTE-MRI) 空间偏移、经皮 RS 的比率全部在胫骨中轴处获得，将有可能增加 骨折风险的临床评估。本提案目标的完成将为使用 糖尿病骨病临床诊断中的基质敏感工具，并有可能识别其中的特定目标 降低糖尿病患者骨折风险的骨基质。