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.

项目总结