Intrafibrillar mineralization vs. bone fragility

描述（申请人提供）：作为一种天然复合材料，骨脆性是由不同层次的多种因素造成的。临床上，骨脆性骨折与超微结构改变直接相关。这种超微结构的变化可能会显着影响骨纳米力学，并随后导致骨脆性骨折的增加。在骨形成过程中，胶原纤维网络首先由成骨细胞铺设。然后，矿化开始于胶原纤维的差距区域，并逐渐扩展到纤维内和纤维外空间。从生物力学的角度来看，原纤维内矿化可能在胶原纤维的硬化中发挥关键作用，并作为矿物和胶原相之间的联锁机制。先前的证据表明，原纤维内矿化的丧失与刚度和强度的显著降低有关 和骨生成障碍患者的骨脆性增加。为了探讨其潜在机制，本研究将研究纤维内矿化对骨纳米力学的影响及其对骨脆性的影响。一般的假设是，骨脆性与原纤维内矿化的程度直接相关。为了验证这一假设，提出了两个具体目标：目标1是使用先进的同步加速器X射线散射技术确定野生型、轻度和重度oim小鼠骨样本中原纤维内矿化程度的变化。工作假设是，在oim小鼠模型中，纤维内矿化的程度随着成骨障碍的严重程度而降低。目的二是利用oim小鼠模型研究骨纤维内矿化对骨纳米力学的影响及其对整体组织脆性的影响。将使用目标2中的oim小鼠模型检验两个假设。一种是矿物相中的预应变随着原纤维内矿化程度的降低而降低，从而导致骨的拉伸强度降低，另一种是矿物相分担的载荷随着原纤维内矿化程度的降低而增加，从而导致小鼠模型中骨的弹性模量、强度和韧性降低。这项研究将是第一次努力解决这个非常重要的，而相当具有挑战性的问题，使用一种新的纳米力学方法。完成本研究后，我们希望阐明纤维内矿化在骨纳米力学中的作用及其对大块组织脆性的影响。这一认识将为研究导致纤维内矿化丧失的潜在病理机制（如成骨不完全）提供纳米力学基础。此外，本研究中提出的同步辐射X射线散射和纳米力学方法将为未来开发与异常纤维内矿化相关的骨疾病的有效治疗提供有用的评估工具。

DESCRIPTION (provided by applicant): As a natural composite material, bone fragility is due to multiple factors at different hierarchical levels. Clinically, bone fragility fractures are associated directly with ultrastructural changes. Such ultrastructural changes could significantly affect bone nanomechanics and subsequently lead to increases in bone fragility fractures. During bone formation, collagen fibril network is first laid down by osteoblasts. Then, mineralization is initiated at the gap region of collagen fibrils and gradually extended into both intrafibrillar and extrafibrillar spaces. From biomechanics perspectives, intrafibrillar mineralization may play a pivotal role in stiffening the collagen fibrils and serving as an interlocking mechanism between the mineral and collagen phases. Previous evidence that loss of intrafibrillar mineralization is associated with significant decreases in stiffness and strength and increases in bone fragility in osteogenesis imperfecta patients shows. To explore the underlying mechanism, the effect of intrafibrillar mineralization on bone nanomechanics and its impact to bone fragility will be investigated in this study. The general hypothesis is that bone fragility is directly related to the degree of intrafibrillar mineralization. To test the hypothesi, two specific aims are proposed: Aim 1 is to determine changes in the degree of intrafibrillar mineralization in bone samples from wild type, mild, and severe oim mice using advanced synchrotron X-ray scattering techniques. The working hypothesis for is that the degree of intrafibrillar mineralization decreases with the severity of osteogenesis imperfecta in oim mouse models. Aim 2 is to determine the effect of intrafibrillar mineralization on the nanomechanics of bone and its impact to the bulk tissue fragility using the oim mouse models. Two hypotheses will be tested using the oim mouse models in Aim 2. One is that the pre-strain in the mineral phase decreases with diminishing degree of intrafibrillar mineralization, thus leading to a reduced tensile strength of bone, and the other is that The load sharing by the mineral phase increases as the degree of intrafibrillar mineralization diminishes, thus leading to the reduction in the elastic modulus, strength, and toughness of bone in oim mouse models. This study will be the first effort to tackle this very important while considerably challenging issue using a novel nanomechanics approaches. Upon completion of this study, we expect to elucidate the role of intrafibrillar mineralization in bone nanomechanics and its impact to the bulk tissue fragility. Ths understanding will give rise to a nanomechanics basis for studies on the underlying pathological mechanisms (e.g. osteogenesis imperfect) that cause the loss of intrafibrillar mineralization. In addition, the synchrotron X-ray scattering and nanomechanics methodologies proposed in this study will offer a useful evaluation tool for future development of effective therapeutic treatment on bone disorders associated with abnormal intrafibrillar mineralization.