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

描述(由申请人提供)：随着年龄的增长和糖尿病的发作，骨折的风险会增加，这种增加不能完全用骨密度(BMD)的变化来解释。因此，临床抗折性评估还应包括胶原蛋白的定量特征。此外，要降低老年人和糖尿病患者的骨折风险，需要完全了解降低骨折抵抗力的骨骼变化的生物物理基础。针对这些需求，该提案旨在确定结合在骨基质上的水和核磁共振(核磁共振)确定的驻留在骨孔中的水在多大程度上解释了骨骼在衰老和疾病方面对骨折的抵抗力。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骼抵抗骨折的能力，而不仅仅是骨骼强度。目标1将确定核磁共振可测量的属性--包括那些可由临床MRI量化的属性--是否导致与年龄相关的减少 在人的皮质骨和松质骨的屈服后韧性、疲劳寿命、裂纹萌生韧性和裂纹扩展韧性，并与其他解释因素有关。目的2将通过一系列影响基质-水相互作用和骨骼断裂特性的操作实验来检验结合水的潜在决定因素。AIMS 1和AIMS 2的样本将从不同年龄(23岁至100岁)的捐赠者的身体股骨中提取。然后，利用临床前的大鼠疾病模型，Aim 3将确定核磁共振特性是否可以解释1)2型糖尿病对骨骼骨折抗力的有害影响，2)双磷酸盐治疗对卵巢切除导致的骨折抗力下降的保护作用。此外，还将确定核磁共振属性是否能解释整个骨骼的强度和脆性与骨骼结构的关系。为了探索在每个目标下核磁共振和断裂性能变化的生物物理基础，将测量骨的一些特征。微型计算机断层扫描将量化体积骨密度和结构和架构；高效液相色谱将定量成熟交联物的浓度和胶原含量以及变性胶原的比例；热重分析将定量胶原、矿物和水的部分；拉曼光谱将定量矿物结构；显微镜(光学和电子)将定量骨性架构和胶原原纤维取向。统计模型将确定核磁共振衍生特性对骨骼断裂特性的相对贡献。这将解决用核磁共振测量基质结合水和孔隙度与改善骨骼健康的相关性。长期目标是确定影响骨折抵抗的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。

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.