Collaborative Research: Determining the Impacts of Lacunar-Canalicular Remodeling on Bone Fracture Toughness

该奖项将支持研究骨骼在衰老过程中的脆弱性，这是一个尚未解决的主要问题。超过40%的60岁以上的女性和25%的60岁以上的男性会经历脆性骨折。这项研究的目的是提高我们对骨韧性起源的理解，并测试骨韧性的丧失是否可以用骨细胞的健康来解释。骨细胞是嵌入骨中的应变感应细胞。这些细胞通过一个膨胀的多孔网络相互连接。骨细胞可以移除和替换（即重塑）围绕这一扩张网络的骨组织。因此，骨细胞在维持骨质量，特别是韧性方面可能具有重要但被忽视的作用。由于骨细胞健康在衰老和疾病中下降，了解打断骨细胞健康是否会降低骨韧性是很重要的。本项目将促进对骨细胞如何、在何处、为何重塑骨以及骨细胞重塑对骨韧性的影响的理解。调查人员将招募和培训代表性不足的研究生和本科生完成这项工作。这项工作还将涉及代表性不足的本科生和高中生，并将让K-12学生和教师参与骨骼生物力学和材料科学的推广活动。本项目采用几种新方法研究骨细胞腔隙-小管重构对骨质量和骨折韧性的影响。首先，将使用有限元建模、组织学和组织形态学来评估骨细胞重塑骨组织的比例，并评估骨细胞骨重塑是否与骨组织应变有关。其次，俄歇电子能谱将用于生成骨细胞腔隙附近的骨矿物质和基质成分的亚微米分辨率图。接触共振原子力显微镜图将提供骨能量耗散的评估，这决定了骨断裂韧性，在亚微米尺度上的变化。第三，高脂肪饮食将被用作研究腔隙-小管重构如何影响骨折韧性的新平台。这些模型利用脂肪对骨细胞健康的有害影响来调节腔隙-小管重塑活动。该项目的关键成果是：(1)重塑骨细胞的数量和位置，以及确定腔隙-小管重塑是否与骨组织应变有关，(2)在重塑和非重塑骨细胞附近的生理相关分辨率下的骨成分和力学性能，以及(3)确定腔隙-小管重塑是否对骨折韧性有益。该项目由生物力学和力学生物学项目以及促进竞争研究的既定项目（EPSCoR）共同资助。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This award will support research to study bone fragility in aging, a major unsolved problem. Over 40 percent of women and 25 percent of men over 60 will experience a fragility fracture. The purpose of this research is to improve our understanding of the origins of bone toughness and to test if the loss of bone toughness is explained by the health of bone cells called osteocytes. Osteocytes are strain-sensing cells embedded in bone. These cells are interconnected by an expansive porous network. Osteocytes can remove and replace (that is, remodel) bone tissue surrounding this expansive network. Therefore, osteocytes may have an important but overlooked role in maintaining bone quality, specifically toughness. Because osteocyte health declines in aging and disease, it is important to understand whether interrupting osteocyte health decreases bone toughness. This project will advance the understanding of how, where, and why the osteocyte remodels bone and the impacts of osteocyte bone remodeling on bone toughness. The investigators will recruit and train underrepresented graduate and undergraduate students in the completion of the work. This work will also involve underrepresented undergraduate and high school students in the research and will engage K-12 students and teachers in bone biomechanics and materials science outreach activities. This project partners several novel approaches to investigate the impacts of osteocyte lacunar-canalicular remodeling on bone quality and fracture toughness. First, finite element modeling, histology, and histomorphometry will be used to assess the fraction of osteocytes that are remodeling bone tissue and evaluate whether osteocyte bone remodeling is related to bone tissue strain. Second, Auger electron spectroscopy will be used to produce submicron-resolution maps of bone mineral and matrix composition near osteocyte lacunae. Contact resonance atomic force microscopy maps will deliver an assessment of how bone energy dissipation, which determines bone fracture toughness, varies at the submicrometer-scale. Third, a high dietary fat diet will be used as a novel platform to study how lacunar-canicular remodeling affects bone fracture toughness. These models exploit the detrimental effect of fat on osteocyte health to modulate lacunar-canicular remodeling activities. The key outcomes of the project are (1) the number and location of remodeling osteocytes and determination of whether lacunar-canicular remodeling is related to bone tissue strain, (2) bone composition and mechanical properties at a physiologically-relevant resolution near remodeling and non-remodeling osteocytes, and (3) determination of whether lacunar-canicular remodeling beneficially impacts bone fracture toughness. This project is jointly funded by the Biomechanics and Mechanobiology program and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.