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增加， 骨密度(BMD)的临床评估在诊断这种风险方面并不是特别有效。 此外，降低T2D患者的骨折风险需要了解骨骼的变化 这会影响抗裂性。针对这些未得到满足的需求，拟议的项目旨在：i)确定 T2D增加骨折风险的主要生物力学原因，II)确定骨折的分子变化 可显著影响抗折性的骨基质，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在骨质量方面的显著差异。在……里面 目标1，来自非糖尿病和T2D捐赠者的身体骨将全面匹配年龄和性别 分析以确定与T2D相关的断裂阻力的主要降低是否是较低的骨骼韧性， 较低的抗疲劳性和/或较低的断裂韧性，而不是整个骨骼和 材质级别。此外，矩阵特征能够解释这些与T2D相关的差异 骨的力学性能将根据体积骨密度和微观结构进行评估(通过 微型计算机断层扫描)以及矿化程度和骨密度(经评估 背散射电子成像)。基质特征将包括I型胶原的二级结构AS 由来自拉曼光谱(RS)的酰胺I带、结合水和孔隙水的亚峰比率确定 用质子核磁共振(核磁共振)弛豫法测定的体积分数和对 微压痕性能由循环和冲击参考点(RPI)共同决定。在《目标2》中，焦点 将对新的分子机制在糖尿病潜在的基质结合变化中的作用进行研究 水和胶原蛋白结构。具体地说，重点将放在翻译后修改(PTM)上 I型胶原和非胶原骨基质蛋白影响氢键的机制 水和基质。与糖尿病有关，这些PTM将包括非酶晚期糖基化末端 产物(AGEs)以及酶促羟化、糖基化和羧化。在目标3中，对矩阵敏感， 临床技术将确定非糖尿病患者的骨骼质量是否有显著差异 以及已有T2D的患者。通过匹配两组之间的年龄和BMD得出的T-值，我们将 从冲击RPI、结合和孔隙水浓度确定骨材料强度指数 核磁共振信号的超短回波时间磁共振成像(UTE-MRI)(T2)和酰胺I亚峰 空间偏移的比率，经皮RS，全部在胫骨中段获得，将潜在地增加价值 骨折风险的临床评估。这项提案目标的完成将为使用 在糖尿病骨疾病的临床诊断中的基质敏感工具，并潜在地识别特定的靶点 降低糖尿病患者骨折风险的骨基质。