Functional Significance of Cortical Bone Microstructure

目的：杰出的骨骼生物学家哈罗德·弗罗斯特指出：“骨骼本身记录了它的遗传、生长、发育、使用和滥用。”因此，骨骼的动态而持久的性质为我们了解现存和灭绝的生物体的生活史提供了一个窗口。尽管有这种潜力，我们对骨骼微结构的重要性只有一个初步的了解，尤其是皮质骨--致密的骨骼外壳。事实上，我们刚刚开始在三维(3D)中描述这种复杂的组织--这是一项由高分辨率成像推动的创新。为了解决这一知识鸿沟，我的研究计划的首要目标是破译皮质骨微结构中编码的信息。不同类型的载荷是否反映在不同的微观结构模式中？这些适应是在生长过程中通过一种被称为“建模”的过程中“内置”的系统进化的吗？它们是在生物体的个体发育过程中通过一个被称为“重塑”的周转过程而产生的吗？这些过程是如何相互作用的？通过回答这些问题，我的研究计划将为骨骼的适应过程提供新的线索，从而能够从骨骼中更详细和更有力地解释生命历史。 方法：我的团队一直处于应用高分辨率3D微计算机断层扫描(Micro-CT)成像的前沿，以获得对皮质骨微结构的新见解。在目前的提案中，这项工作得到了延伸和扩大。将进行两个研究流派： 流1：3D技术的扩展应用，以执行体外比较研究。一个具体的例子将是研究与飞行相关的适应--一种与鸟类独特的基于建模的微结构模式相联系的运动模式。推动这项工作的假设是，鸟类和哺乳动物导致飞行的趋同进化导致了相似的皮质骨骼特征。这项研究将是第一次对鸟类和飞行哺乳动物(蝙蝠)进行这种比较。 流2：皮质骨重塑的3D分析扩展到活体纵向成像领域。2013年，我的团队建立了对大鼠皮质骨孔率的活体成像的原则证明。这是利用加拿大的国家同步加速器设施--加拿大光源(CLS)实现的。在这一创新的基础上，我们将率先对改建事件进行纵向跟踪。这将提供一种直接的方法来测试与骨转换的空间调节相关的假说。我们的第一个目标将是研究负荷、微损伤和重塑事件的诱发/进展之间的假设关系。具体地说，我们将测试这些假说，即重塑事件与骨骼内的机械条件一致，并且它们被主动地“引导”向微损伤。这一用于研究重塑空间调控的新型体内平台的进一步开发和应用将是一个重大的进步，为该领域提供了独特的经验数据，到目前为止，该领域主要是理论上的。 意义：骨骼以3D形式存在，并随着时间的推移进行重塑--它是一个四维(4D)组织。因此，二维分析在充分描述这种组织的特征方面是有限的。通过先进的成像，目前提出的研究计划将对皮质骨的系统发育和个体发育适应产生新的见解。这对于我们理解现在和过去物种的骨微结构都具有重要意义。因此，产生的数据将在骨生物学及其从材料工程到古生物学的各个分支学科中有广泛的应用。

OBJECTIVE: The preeminent bone biologist Harold Frost noted that “the skeleton inscribes within itself a record of its genetics, growth, development, use and abuse.” The dynamic yet enduring nature of bone thus provides a window on the life history of organisms both extant and extinct. Despite this potential we have only a rudimentary understanding of the significance of bone microstructure and this is particularly so for cortical bone – the dense outer shell of bones. Indeed, we have just begun to characterize this complex tissue in three dimensions (3D) – an innovation facilitated by high resolution imaging. To address this knowledge gap the overarching goal of my research program is to decipher the information encoded within the microstructure of cortical bone. Are different types of loading reflected in different microstructural patterns? Are these adaptations phylogenetic, 'built-in' during growth through a process known as 'modeling'? Do they arise during the ontogeny of an organism through a process of turnover known as 'remodeling'? How do these processes interact? By answering such questions my research program will shed new light on the adaptive processes of bone and thereby enable more detailed and robust interpretations of life history from the skeleton. APPROACH: My team has been at the forefront of the application of high resolution 3D micro-Computed Tomography (micro-CT) imaging to obtain new insights into cortical bone microstructure. In the current proposal this work is extended and expanded. Two Research Streams will be pursued: STREAM 1: An expanded application of 3D techniques to execute ex vivo comparative studies. A specific example will be the examination of adaptations associated with flight – a mode of locomotion which has been linked to unique modeling-based microstructural patterns in birds. The hypothesis driving this work is that the convergent evolution leading to flight in birds and mammals has resulted in similar cortical bone features. This study will be the first such comparison of birds and flying mammals (bats). STREAM 2: The extension of 3D analysis of cortical bone remodeling into the realm of in vivo longitudinal imaging. In 2013 my group established proof-of-principle for in vivo imaging of cortical bone porosity in the rat. This was achieved utilizing Canada’s national synchrotron facility – the Canadian Light Source (CLS). Building upon this innovation, we will pioneer longitudinal tracking of remodeling events. This will provide a direct means of testing hypotheses related to the spatial regulation of bone turnover. Our first objective will be to examine the postulated relations between loading, microdamage and the induction/progression of remodeling events. Specifically, we will test the hypotheses that remodeling events are aligned by mechanical conditions within the bone and that they are actively ‘steered’ towards microdamage. The further development and application of this novel in vivo platform for the study of the spatial regulation of remodeling will represent a significant advance, providing unique empirical data to a field which has, to date, been largely theoretical. SIGNIFICANCE: Bone exists in 3D and remodels over time – it is a four dimensional (4D) tissue. Two-dimensional analysis is thus limited in its ability to fully characterize this tissue. Through advanced imaging the currently proposed research program will generate new insights into the phylogenetic and ontogenetic adaptation of cortical bone. This is significant for our understanding of bone microstructure in both present and past species. The data generated will thus have wide ranging applications in bone biology and its various sub-disciplines spanning from materials engineering to palaeontology.