Age-Related Effect of Bone Remodeling on Bone Toughness

描述（由申请人提供）：先前的研究已经证明，老化骨的脆性增加与骨中胶原蛋白的完整性显著相关。然而，对潜在的机制知之甚少。本研究的目的是阐明如何在胶原网络中诱导与年龄相关的变化，以及这些变化是否导致骨质量的恶化。在这项拟议的研究中，我们试图研究与年龄相关的骨重建对胶原蛋白的完整性及其与组织韧性降低的相关性的影响。已知新形成的次级骨单位是通过骨重建过程形成的。因此，通过研究次级骨单位的变化，可以检查骨重建对胶原完整性和骨质量的年龄依赖性影响。我们的假设是，胶原蛋白分子的年龄依赖性变化是通过骨重建过程诱导的;这种变化直接导致老年骨韧性下降。为此，将致力于实现以下具体目标：目标1。检查继发性骨单位材料特性的年龄相关变化-假设：继发性骨单位的材料特性随年龄增长而变化。将使用微机械加工装置从60具人类尸体股骨的次级骨单位和间质骨区域制备三点弯曲测试样本。试样将在微机械测试装置中进行测试。将研究骨重建对继发性骨单位和间质骨组织机械完整性的年龄相关影响。目标2.研究继发性骨单位中胶原分子的年龄相关变化-假设：继发性骨单位中胶原分子的完整性随年龄变化。将重复使用目标1中进行机械测试的样本，以确定次级骨单位和间质骨区域中的胶原完整性。将使用高效液相色谱技术测定胶原蛋白变性和交联浓度。然后，将研究骨重建对骨中胶原完整性的年龄相关影响。此外，胶原完整性和继发性骨单位的力学行为的相关性也将被探讨。目标3：探讨胶原蛋白的增龄性变化与骨韧性下降的相关性-假设：胶原蛋白的增龄性变化直接导致老年骨韧性下降。胶原蛋白网络和骨的整体机械特性将与其他组成和结构特性一起确定为年龄的函数。结合目的1和2的结果，将研究胶原在与年龄相关的骨韧性降低中的作用。这项研究将为年龄相关的骨质量恶化的潜在机制提供见解，并将促进未来预防和治疗年龄和疾病相关骨折的研究。

DESCRIPTION (provided by applicant): Previous studies have demonstrated that the increased fragility of aged bone correlates significantly with the integrity of collagen in bone. However, the underlying mechanism is poorly understood. The objective of this study is to elucidate how age-related changes are induced in the collagen network and whether such changes lead to the deterioration in bone quality. In this proposed study, we attempt to investigate the age-related effect of bone remodeling on the integrity of collagen and its correlation with the reduced toughness of the tissue. It has been known that newly formed secondary osteons are formed through bone remodeling process. Thus, by studying changes in the secondary osteons, one can examine the age-dependent effect of bone remodeling on the collagen integrity and the quality of bone. Our hypothesis of the present proposal is that age-dependent changes in collagen molecules are induced through bone remodeling process; and such changes directly contribute to the decreased toughness of aged bone. To this end, the following Specific Aims will be addressed: Aim 1. To examine age-related changes in material properties of the secondary osteons- Hypothesis: Material properties of secondary osteons change with increasing age. Three-point bending test specimens will be prepared from the secondary osteons and interstitial bone regions of sixty human cadaveric femurs using a micromachining device. The specimens will be tested in a micro mechanical testing device. The age-related effect of bone remodeling on the mechanical integrity of secondary osteons and interstitial bone tissues will be investigated. Aim 2. To examine age-related changes in collagen molecules within the secondary osteons-Hvpothesis: The integrity of collagen molecules in secondary osteons changes with age. The specimens mechanically tested in Aim 1 will be reused to determine the collagen integrity in the secondary osteons and interstitial bone regions. Collagen denaturation and crosslinks concentrations will be determined using high performance liquid chromatography techniques. Then, the age-related effect of bone remodeling on the integrity of collagen in bone will be investigated. In addition, the correlation of collagen integrity and mechanical behavior of secondary osteons will be explored. Aim 3. To explore the correlation of age-related changes in collagen with the decreased toughness of bone-Hypothesis: Age-related changes in collagen directly contribute to the decreased toughness of aged bone. Bulk mechanical properties of the collagen network and bone will be determined as a function of age in conjunction with other compositional and structural properties. Combining the results of Aims 1 and 2, the role of collagen in the age-related decrease in bone toughness will be investigated. This study will provide insights in the underlying mechanism of age-related deterioration in bone quality and will facilitate future studies in the prevention and treatment of age and disease-related bone fractures.