The Roles of Collagen and Water in the Fracture Resistance of Bone

胶原蛋白和水在骨抗骨折性中的作用

• 批准号: 8532824
• 负责人: Jeffry Stephen Nyman
• 金额: $ 32.86万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532824
• 关键词: Address; Adult; Advanced Glycosylation End Products; Affect; Age; Age of Onset; Age-Years; Aging; Architecture; Binding; Biomechanics; Bone Density; Bone Matrix; Bone Tissue; Characteristics; Chemicals; Clinical; Clinical assessments; Collagen; Collagen Fibril; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Disease model; Elderly; Electrons; Epitopes; Estrogens; Exhibits; Fatigue; Female; Femur; Formalin; Fracture; Glycoproteins; Goals; Growth; High Pressure Liquid Chromatography; Human; Hydration status; Individual; Length; Life; Magnetic Resonance Imaging; Measurable; Measurement; Measures; Mechanics; Metaphysis; Methods; Microscopic; Mineral Waters; Minerals; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Magnetic Resonance; Osteon; Osteopenia; Osteoporosis; Outcome Measure; Ovariectomy; Porosity; Property; Proteins; Protons; Raman Spectrum Analysis; Rattus; Relative (related person); Relative Risks; Relaxation; Reporting; Research; Resistance; Resistance development; Risk; Roentgen Rays; Role; Series; Signal Transduction; Solid; Solubility; Specimen; Statistical Models; Structure; Techniques; Testing; Tissues; Water; Withdrawal; Work; X-Ray Computed Tomography; Zoledronic Acid; age related; base; bisphosphonate; bone; bone health; bone mass; bone strength; clinical Diagnosis; crosslink; density; diabetic; diabetic rat; imaging modality; improved; inhibitor/antagonist; light microscopy; male; new therapeutic target; non-diabetic; pre-clinical; prevent; protective effect; public health relevance; research study; sample fixation; sham surgery; substantia spongiosa; treatment effect

DESCRIPTION (provided by applicant): There is an increase in the risk of bone fracture with aging and the onset of diabetes, and this increase cannot be solely explained by changes in bone mineral density (BMD). As such, clinical assessment of fracture resistance should also include quantitative characteristics of collagen. Moreover, lowering fracture risk for the elderly and those individuals with diabetes requires a complete understanding of the biophysical basis for the changes in bone that decrease fracture resistance. Addressing these needs, the proposal aims to determine the extent to which water that is bound to the bone matrix and water residing in bone pores, as determined by Nuclear Magnetic Resonance (NMR), explain bone's resistance to fracture with respect to aging and disease. NMR underlies clinical Magnetic Resonance Imaging (MRI), and the proposed mechanical tests characterize the ability of bone to resist fracture, not just bone strength. Aim 1 will determine whether NMR-measurable attributes - including those quantifiable by clinical MRI - contribute to the age-related decreases in the post-yield toughness, fatigue life, crack initiation toughness, and crack growth toughness of human cortical and trabecular bone, and do so in relation to other explanatory factors. Aim 2 will examine potential determinants of bound water through series of manipulations experiments that will affect matrix-water interactions and the fracture properties of bone. Specimens for Aims 1 and 2 will be extracted from cadaveric femurs that are acquired from donors of varying age (23 to 100 years of age). Then, using pre-clinical, rat models of disease, Aim 3 will determine whether NMR properties can explain 1) the deleterious effect of type-2 diabetes on the fracture resistance of bone and 2) the protective effect of bisphosphonate treatment on ovariectomy-induced decrease in fracture resistance. In addition, it will be determined if the NMR attributes can explain whole bone strength and brittleness in relation to bone structure. To explore the biophysical basis for the changes in the NMR and fracture properties in each aim, a number of characteristics of bone will be measured. Micro-Computed Tomography will quantify volumetric BMD and structure and architecture; high performance liquid chromatography will quantify the concentration of mature crosslinks and collagen content as well as fraction of denatured collagen; thermal gravimetric analysis will quantify the collagen, mineral, and water fractions; Raman spectroscopy will quantify mineral structure; microscopy (light and electron) will quantify osteonal architecture and collagen fibril orientation. Statistical models will determine the relatie contribution of the NMR-derived properties to the fracture properties of bone. This will address the relevance of measuring matrix-bound water and porosity by NMR to improving bone health. The long-term goal is to identify the factors affecting the important determinants of fracture resistance and developing accurate, MRI-based diagnostic assessments of fracture risk.

描述（由申请人提供）：随着年龄的增长和糖尿病的发病，骨折的风险增加，这种增加不能仅仅用骨矿物质密度（BMD）的变化来解释。因此，抗断裂性的临床评估还应包括胶原蛋白的定量特征。此外，降低老年人和糖尿病患者的骨折风险需要完全了解骨骼变化的生物物理基础，这些变化降低了骨折抵抗力。为了满足这些需求，该提案旨在确定结合到骨基质的水和驻留在骨孔中的水的程度，如通过核磁共振（NMR）所确定的，解释骨对老化和疾病的抗断裂性。核磁共振是临床磁共振成像（MRI）的基础，拟议的力学测试表征了骨抵抗骨折的能力，而不仅仅是骨强度。目标1将确定NMR可测量属性（包括可通过临床MRI量化的属性）是否有助于年龄相关性降低 在屈服后韧性，疲劳寿命，裂纹萌生韧性，和裂纹增长韧性的人皮质骨和骨小梁，并这样做与其他解释因素。目的2将通过一系列影响基质-水相互作用和骨断裂特性的操作实验来研究结合水的潜在决定因素。目标1和2的样本将从不同年龄（23 - 100岁）供体的尸体股骨中提取。然后，使用临床前大鼠疾病模型，目标3将确定NMR特性是否可以解释1）2型糖尿病对骨抗骨折性的有害影响和2）双膦酸盐治疗对卵巢切除术诱导的抗骨折性降低的保护作用。此外，将确定NMR属性是否可以解释与骨结构相关的全骨强度和脆性。为了探索每个目标中NMR和骨折特性变化的生物物理基础，将测量骨的许多特征。微型计算机断层扫描将量化体积BMD和结构和架构;高效液相色谱将量化成熟交联的浓度和胶原蛋白含量以及变性胶原蛋白的分数;热重分析将量化胶原蛋白、矿物质和水的分数;拉曼光谱将量化矿物质结构;显微镜（光和电子）将量化骨组织结构和胶原原纤维取向。统计模型将确定核磁共振衍生的特性对骨断裂特性的相对贡献。这将解决通过NMR测量基质结合水和孔隙率与改善骨骼健康的相关性。长期目标是确定影响骨折抵抗力重要决定因素的因素，并开发准确的基于MRI的骨折风险诊断评估。