Non-collagenous proteins vs. bone fragility

非胶原蛋白与骨脆性

基本信息

批准号：
8891369
负责人：
Xiaodu Wang
金额：
$ 20.05万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2017-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Bone fragility fracture is a major health care concern for our rapidly aging society due to its elevated risk of long-term disability and even premature death and is always associated with ultrastructural changes in bone. In the hierarchy of bone, lamellae, as the basic building unit of human bone, are a sheet-like biocomposite consisting of mineralized collagen fibrils, an extrafibrillar matrix comprised of mineral crystals and non-collagenous proteins (NCPs), and water filling the interstitial spaces. Although the mechanical behavior of mineralized collagen fibrils have been extensively studied, the contribution of the extrafibrillar matrix to the mechanical behavior of bone is still poorly understood. Previous evidence shows that NCPs may not only regulate bone metabolisms but also play a significant role in the ultrastructural integrity of bone. In this study, we propose a mechanistic model of the extrafibrillar matrix in bone that the mineral crystals in the matrix are bounded through a thin organic interface of NCPs. The overall hypothesis is that non-collagenous proteins (NCPs) play a critical role in bone nanomechanics by facilitating the interfacial sliding between the HA polycrystals in the extrafibrillar matrix of bone. To test the hypothesis, both numerical simulations and experimental verifications will be implemented to address the two specific aims. Aim 1: To determine the effect of the organic interface between HA polycrystals on the mechanical behavior of the extrafibrillar matrix in bone using a finite element approach with a novel interface zone model: In Aim 1, a novel interface zone model will be used in the finite element simulation of the extrafibrillar, in which hydroxyapatite (HA) polycrystals are bounded through an organic interface, which is comprised of NCPs and water molecules and allows for sliding and separation between the mineral crystals. It is anticipated that the plastic deformation is realized through the sliding between HA crystals along the organic interface. In addition, the effect of crystal size and shape and orientation distribution on the mechanical behavior of the extrafibrillar matrix will be scrutinized in this study. Aim 2 To experimentally verify the novel mechanistic model using an in vitro experimental model: In Aim 2, we hypothesize that the organic interface between the mineral crystals in the extrafibrillar matrix will be compromised if the structure of proteoglycans is altered by removing polysaccharides, which are the major components of proteoglycans that help anchor the GAGs onto the core proteins. The interruption of PGs will result in a defected interface zone between the mineral crystals, thus leading to weakening of the lamellae. To test the hypothesis, we propose to use a novel nanoscratch test technique [81] to measure the in situ mechanical properties of individual lamellae with and without impairment of proteoglycans. The novel mechanistic model proposed in this study, if proved, will open a new avenue for studying the structural role of NCPs in bone fragility. The potential impact of such understanding is multifaceted. First, it will significantly improve the multiscale modeling of bone tissues. Second, this concept can be extended to elucidate the involvement of NCPs in age- and disease related bone fragility fractures. Finally, NCPs may be used as biomarkers in clinical settings to assess the risk of bone fragility fractures.

描述（由申请人提供）：骨脆性骨折是我们快速老龄化社会的一个主要医疗保健问题，因为它导致长期残疾甚至过早死亡的风险较高，并且总是与骨的超微结构变化相关。在骨的层次结构中，片层作为人体骨骼的基本构建单元，是一种片状生物复合材料，由矿化胶原纤维、由矿物晶体和非胶原蛋白 (NCP) 组成的纤维外基质以及填充间质的水组成。空间。尽管矿化胶原纤维的机械行为已被广泛研究，但纤维外基质对骨机械行为的贡献仍然知之甚少。先前的证据表明，NCPs不仅可以调节骨代谢，而且在骨超微结构完整性中发挥重要作用。在这项研究中，我们提出了一个机制模型骨中的纤维外基质，基质中的矿物晶体通过 NCP 的薄有机界面结合。总体假设是，非胶原蛋白 (NCP) 通过促进骨纤维外基质中 HA 多晶之间的界面滑动，在骨纳米力学中发挥着关键作用。为了检验这一假设，将实施数值模拟和实验验证来解决这两个具体目标。目标 1：使用有限元方法和新型界面区域模型确定 HA 多晶之间的有机界面对骨中纤维外基质机械行为的影响：在目标 1 中，将在原纤维的有限元模拟，其中羟基磷灰石 (HA) 多晶通过有机界面结合，该有机界面由 NCP 和水分子组成，允许矿物之间的滑动和分离晶体。预计塑性变形是通过HA晶体之间沿着有机界面的滑动来实现的。此外，本研究还将仔细研究晶体尺寸、形状和取向分布对原纤维外基质机械行为的影响。目标 2 使用体外实验模型对新的机制模型进行实验验证：在目标 2 中，我们假设如果通过去除多糖来改变蛋白聚糖的结构，则原纤维外基质中矿物晶体之间的有机界面将受到损害，多糖是蛋白聚糖的主要成分，有助于将 GAG 锚定到核心蛋白上。 PGs 的中断将导致矿物晶体之间的界面区域出现缺陷，从而导致片层的弱化。为了检验这一假设，我们建议使用一种新颖的纳米划痕测试技术[81]来测量有或没有蛋白聚糖损伤的单个薄片的原位机械性能。本研究提出的新机制模型如果得到证实，将为研究 NCP 在骨脆性中的结构作用开辟一条新途径。这种理解的潜在影响是多方面的。首先，它将显着改善骨组织的多尺度建模。其次，这一概念可以扩展到阐明 NCP 与年龄和疾病相关的脆性骨折的参与。最后，NCP 可用作临床环境中的生物标志物，以评估骨脆性骨折的风险。