Spatio-temporal regulation of cortical bone remodeling

骨是一种动态组织，具有重塑、更新和适应其内部微结构的能力。这一进化过程可以追溯到志留纪（4.44亿年前），并使包括人类在内的大型长寿陆生动物得以出现。通过破骨细胞吸收和成骨细胞形成的紧密耦合，骨重塑修复损伤并优化骨的结构和材料特性。这种适应需要这些不同类型的细胞精确的时空协调，形成被称为基本多细胞单位（BMUs）的短暂伙伴关系，以取代被称为次级骨元的离散骨包。骨重塑对骨骼健康的长期维持至关重要。相反，BMU调节的中断是骨质疏松症等慢性疾病的根源，破坏了植入物的稳定性，阻碍了组织移植物/工程支架的整合，甚至由于低重力下骨骼的损失而阻碍了外星探索/殖民。尽管经过几个世纪的研究，由于缺乏原位（3D）和体内（4D 3D随时间）数据，我们对BMUs在空间和时间上的调节的理解仍然是初级的。事实上，包括生物学、数学、工程和材料科学在内的许多STEM领域目前都在努力更好地理解骨重塑，但都受到缺乏经验数据的挑战。因此，这个领域的大部分仍然是理论性的，越来越多的人希望通过计算机建模来弥补知识上的差距。为了直接解决这些限制，Cooper博士的研究小组一直处于先进成像（常规和同步加速器）应用的前沿，以研究衰老、适应和疾病对骨骼外（皮质）壳微结构的影响。目前的提案特别旨在进一步利用加拿大光源同步加速器（主题1）进一步完善一个基于兔子的动态四维追踪单个BMUs的新平台，然后首次部署这种创新方法来直接测试长期存在的监管假设（主题2）。需要解决的关键问题包括：1)BMUs的分布是随机的，还是主动针对伤害等刺激？2)载荷引起的组织应变等生物力学因素是否会动态影响骨髓的大小、方向和进展？回答这些和相关的问题将促进我们对骨微结构中编码的进化和发育信息的理解，反过来，从材料工程到古生物学，对骨生物学产生广泛的影响。最终，所产生的基本见解将有助于改进生物医学策略（行为，制药，外科等）的发展，以减轻骨病的深刻的人类和经济成本，骨病折磨着数百万人，并在全球范围内花费数十亿美元。

Bone is a dynamic tissue with the capacity to remodel to renew and adapt its internal microarchitecture. The evolution of this process reaches back to the Silurian (444 million years ago) and enabled the rise of large long-lived terrestrial animals, including humans. Through closely coupled osteoclastic resorption and osteoblastic formation, remodeling repairs damage and optimizes the structural and material properties of bone. This adaptation requires precise spatio-temporal coordination of these disparate cell types into transient partnerships known as Basic Multicellular Units (BMUs) which replace discrete packets of bone called secondary osteons. Remodeling carried out by BMUs is critical for the long-term maintenance of healthy bone. Conversely, disruption of BMU regulation lies at the root of chronic diseases like osteoporosis, undermines stability of implants, hinders integration of tissue grafts/engineered scaffolds, and even impedes extraterrestrial exploration/colonization due to the loss of bone in low gravity. Despite centuries of study, our understanding of the regulation of BMUs in space and time remains rudimentary due to a lack of in situ (3D) and in vivo (4D 3D over time) data. Indeed, many STEM fields including biology, mathematics, engineering and material science currently strive for a better understanding of bone remodeling and all are challenged by the lack of empirical data. As a consequence, much of this field remains theoretical and increasing looks to in silico computational modeling to bridge gaps in knowledge. To directly address these limitations, Dr. Cooper's research group has been at the forefront of the application of advanced imaging (conventional and synchrotron) to study the impacts of aging, adaptation and disease on the microarchitecture of the outer (cortical) shell of bone. The current proposal specifically aims to further hone a novel rabbit-based platform for the dynamic 4D tracking of individual BMUs using the Canadian Light Source synchrotron (Theme 1) and then to deploy this innovative approach to directly test long-standing regulatory hypotheses for the first time (Theme 2). Key questions that will be addressed include: 1) Are BMUs random in their distribution or are they actively targeted towards stimuli such as damage? 2) Are the size, direction and progression of BMUs dynamically impacted by biomechanical factors such as tissue strain induced by loading? Answering these and related questions will advance our understanding of the evolutionary and developmental information encoded within bone microarchitecture and, in turn, yield wide ranging impacts in bone biology spanning from materials engineering to palaeontology. Ultimately, the fundamental insights generated will help inform the development of improved biomedical strategies (behavioral, pharmaceutical, surgical, etc.) to mitigate the profound human and economic costs of bone diseases which afflict millions and cost billions worldwide.