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）：随着衰老和糖尿病的发作，骨断裂的风险有所增加，这种增加不能完全通过骨矿物质密度（BMD）的变化来解释。因此，抗断裂性抗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断裂风险需要完全了解降低骨折耐药性的骨骼变化的生物物理基础。在满足这些需求时，该提案旨在确定与骨基质和居住在骨孔中的水结合的程度，由核磁共振（NMR）确定，解释了Bone在衰老和疾病方面对断裂的抗性。 NMR是临床磁共振成像（MRI）的基础，并且提出的机械测试表征了骨骼抵抗断裂的能力，而不仅仅是骨骼强度。 AIM 1将确定NMR测量属性（包括临床MRI可量化的属性）是否有助于与年龄相关的降低 在后产物的韧性，疲劳，裂纹启动韧性以及人类皮质和小梁骨的裂纹生长韧性，并与其他解释性因素有关。 AIM 2将通过一系列会影响基质 - 水相互作用和骨骼的断裂特性来检查结合水的潜在决定因素。目标1和2的标本将从尸体股骨（23至100岁）中获取。然后，使用临床前的大鼠疾病模型，AIM 3将确定NMR性质是否可以解释1）2型糖尿病对骨骨折耐药性的有害作用和2）双膦酸盐治疗对卵巢切除术对卵巢术诱导的抗骨折耐药性降低的保护作用。另外，将确定NMR属性是否可以解释与骨骼结构有关的全骨强度和脆性。为了探索每个目标中NMR和断裂特性变化的生物物理基础，将测量许多骨骼特征。微计算机断层扫描将量化体积BMD以及结构和建筑；高性能液相色谱法将量化成熟的交联和胶原蛋白含量的浓度以及变性胶原蛋白的一部分；热重量分析将量化胶原蛋白，矿物质和水分；拉曼光谱法将量化矿物结构；显微镜（光和电子）将量化骨结构和胶原原纤维方向。统计模型将确定NMR衍生特性对骨骼断裂特性的关系贡献。这将解决NMR测量矩阵结合水和孔隙率的相关性，以改善骨骼健康。长期目标是确定影响断裂抗性重要决定因素的因素，并发展基于MRI的骨折风险的准确，基于MRI的诊断评估。