The Role of Tissue Matrix in the Fracture Resistance of Diabetic Bone

组织基质在糖尿病骨抗骨折中的作用

• 批准号: 9317431
• 负责人: Jeffry Stephen Nyman
• 金额: $ 17.38万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-18 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317431
• 关键词: Address; Advanced Glycosylation End Products; Affect; Age; Amides; Architecture; Binding; Binding Proteins; Biochemical; Biomechanics; Bone Density; Bone Matrix; Bone Tissue; Cadaver; Carbonates; Characteristics; Clinical; Collagen; Collagen Type I; Defect; Diabetes Mellitus; Diabetic mouse; Diagnostic; Diagnostic Procedure; Dual-Energy X-Ray Absorptiometry; Elderly; Enzymes; Femur; Fracture; Goals; Human; Hydrogen Bonding; Hydroxylation; Hydroxylysine; Hydroxyproline; Individual; Knowledge; Linear Models; Mass Spectrum Analysis; Measurement; Measures; Mechanics; Mediating; Minerals; Modification; Modulus; Molecular; Mus; N(6)-carboxymethyllysine; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Osteocalcin; Pathogenicity; Population; Porosity; Post-Translational Modification Alteration; Post-Translational Protein Processing; Predictive Value; Property; Raman Spectrum Analysis; Research; Resistance; Risk; Role; Sampling; Series; Shapes; Site; Stress; Structure; Techniques; Technology; Testing; Tissues; Water; Work; X-Ray Computed Tomography; analytical tool; base; bone; bone fragility; bone quality; bone strength; carboxylation; clinical diagnostics; clinically relevant; clinically translatable; cortical bone; crosslink; crystallinity; density; diabetic; diabetic patient; fracture risk; glycosylation; improved; liquid chromatography mass spectrometry; mechanical properties; mouse model; new therapeutic target; non-diabetic; novel; novel diagnostics; novel strategies; pentosidine; pre-clinical; prevent; tool

Project Summary The increasing risk of bone fracture with the progression of diabetes is not solely due to reduced bone mineral density (BMD). Since BMD is seemingly normal or even elevated among those with type 2 diabetes, lowering fracture risk among type 2 diabetics requires an understanding of what aspects within the bone tissue matrix contribute to the increase in fracture risk. In addressing this clinically relevant problem, we propose i) to identify pathogenic changes in the bone tissue matrix that contribute to bone fragility as diabetes progresses and ii) to determine how well clinically translatable diagnostic tools (sensitive to the matrix and the mineral of the bone) reflect the diabetes-related changes in fracture resistance. We hypothesize that i) a decrease in the bound water within the bone matrix contributes significantly to the increased fragility of the diabetic bone, ii) a decrease in the matrix bound water is due to diabetes-induced changes in post-translational modifications (PTMs) within bone matrix, and iii) tools capable of measuring bound water in the bone, secondary structure of collagen, and tissue indentation resistance can be used to assess fracture resistance in diabetes. In Aim 1, we will identify molecular differences in PTMs of collagen and osteocalcin between non- diabetic and diabetic bone in mice (model of type 2 diabetes) and in humans (cadaveric tissue from non-insulin dependent diabetics and non-diabetics). Specifically, using liquid chromatography and mass spectrometry, the relative abundance of modifications at individual sites will be quantified for enzyme-mediated hydroxylation and glycosylation of collagen I and carboxylation of osteocalcin and for non-enzymatic PTMs such as carboxymethyllysine and pentosidine, which have been associated with fracture risk. These PTMs potentially affect hydrogen bonding with water and/or the secondary structural organization of collagen. In Aim 2, we will determine whether 1H nuclear magnetic resonance (NMR), Raman spectroscopy (RS), and reference point indentation (RPI) can assess characteristics that differentiate non-diabetic from diabetic bone in mice and in humans. These techniques are chosen for their sensitivity to bound water within bone tissue matrix (NMR), to matrix maturity ratio (RS), and to mechanical consequence of diabetic changes to the matrix and possibly cortical porosity, respectively. Along with areal BMD, micro-computed tomography will be used to quantify volumetric bone and tissue mineral density as well as micro-structure of cortical bone. Mechanical testing will be used to quantify differences in several material properties of bone contributing to the diabetes-related difference in fracture resistance. With correlation analysis and general linear models, we will determine how well RS-, RPI- or NMR-derived values predict the type 2 diabetes-related decrease in the fracture resistance of bone. Moreover, we will determine whether PTMs can explain the possible changes in bound water and matrix maturity ratio in diabetes, thereby providing a potential underlying mechanism.

项目摘要 随着糖尿病的进展，骨折的风险增加并不仅仅是因为骨质减少。 矿物质密度(BMD)。由于2型糖尿病患者的骨密度似乎正常，甚至升高， 降低2型糖尿病患者的骨折风险需要了解骨组织中的哪些方面 基质导致骨折风险的增加。为了解决这个与临床相关的问题，我们建议： 确定糖尿病进展过程中导致骨脆性的骨组织基质的病原性变化 和ii)确定临床可翻译的诊断工具(对基质和矿物的敏感性 骨骼)反映了糖尿病相关的骨折抗力的变化。我们假设：i)减少了 骨基质中的结合水显著增加了糖尿病骨骼的脆性，ii)a 基质结合水的减少是由于糖尿病引起的翻译后修饰的变化 骨基质中的(PTMS)，以及iii)能够测量骨中结合水的工具，二级结构 胶原蛋白和组织压痕阻力可用于评估糖尿病患者的骨折耐受性。 在目标1中，我们将确定胶原和骨钙素的PTM的分子差异 小鼠(2型糖尿病模型)和人类(非胰岛素身体组织)的糖尿病和糖尿病骨 依赖糖尿病患者和非糖尿病患者)。具体地说，使用液相色谱和质谱仪， 对于酶介导的羟化作用，将量化各个部位的相对丰富的修饰和 I型胶原的糖基化和骨钙素的羧化以及非酶PTMS，如 羧甲基赖氨酸和戊西丁，它们与骨折风险有关。这些PTM可能 影响与水的氢键和/或胶原的二级结构组织。 在目标2中，我们将确定1H核磁共振(NMR)、拉曼光谱(RS)、 参考点缩进(RPI)可以评估区分非糖尿病患者和糖尿病患者的特征 老鼠和人类的骨骼。选择这些技术是因为它们对骨骼内的结合水敏感。 组织基质(核磁共振)、基质成熟度比(RS)，以及糖尿病对 分别是基质和可能的皮质孔隙度。随着面骨密度的增加，微型计算机断层扫描将被 用于定量测量体积骨和组织的矿物质密度以及皮质骨的微观结构。 力学测试将被用来量化骨的几种材料特性的差异，这对 糖尿病相关的骨折抵抗力差异。通过相关分析和一般线性模型，我们将 确定RS-、RPI-或核磁共振衍生值预测2型糖尿病相关的 骨的抗折性。此外，我们还将确定技术指标是否能解释 结合水和基质成熟度在糖尿病中的比率，从而提供了一个潜在的潜在机制。