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生，骨折的风险增加，这种增加不能仅仅用骨密度（BMD）的变化来解释。因此，临床评估抗骨折性也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降低骨折抵抗力的生物物理基础。为了满足这些需求，该提案旨在确定与骨基质结合的水和驻留在骨孔隙中的水的程度，正如核磁共振（NMR）所确定的那样，解释骨骼在衰老和疾病方面的抗骨折性。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骼抵抗骨折的能力，而不仅仅是骨骼强度。目的1将确定核磁共振可测量的属性-包括临床核磁共振可量化的属性-是否有助于与年龄相关的减少

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.