Comparing the Roles of Bone Cells and Marrow Cells in the Adaptive Response of Bone to Loading

健康的骨骼对于保持积极的生活方式至关重要。骨骼在受到锻炼或日常活动的定期负荷时会变得更强壮。相反，在长时间不活动或所施加的力低于正常值时，例如在太空飞行或长时间卧床休息期间，它们会变得更加脆弱。利用这种现象的潜在机制可能会提供新的方法来对抗由于衰老和疾病引起的骨质流失。 骨适应的过程由嵌入骨内的细胞和骨髓中的细胞的协调活动控制，但每个细胞家族独立发挥作用的潜力尚不清楚。在这个项目中，小的骨样本将在一个培养箱中保持活力，并施加机械载荷以刺激新骨生长。将检测并比较骨内和骨髓中细胞的反应，以确定最有效地单独或组合靶向它们以维持骨强度的潜在方法。在这项研究中获得的见解有可能为未来研究预防骨质流失的新型药物治疗提供信息。此外，该研究将通过与当地高中建立的关系产生教育影响，以鼓励更广泛地参与科学和工程，并与高威的爱尔兰大学继续开展国际合作。骨适应依赖于成骨细胞、破骨细胞和骨细胞的协调活动。骨细胞作为骨变形的主要传感器，并向邻近细胞发出信号以影响骨形成和吸收。然而，骨髓中的许多细胞也是机械敏感的，并且可能有助于骨的适应性反应。 本研究将采用应用于小梁外植体的离体机械刺激来研究其在骨髓和骨细胞中的作用。低强度机械刺激（LMMS）将用于在骨髓中诱导剪切应力，而骨的小加速度和质量实际上不会导致骨变形。计算模型将用于量化骨髓剪切应力，这将在空间上与骨形成相关。LMMS对β-连环蛋白信号传导的影响将在WNT信号传导的激动剂和拮抗剂的存在下定量，以鉴定在骨髓细胞内起作用的机械生物学机制。

A healthy skeleton is essential to maintaining an active lifestyle. Bones grow stronger when subjected to regular loading from exercise or daily activities. Conversely, they become more fragile during prolong inactivity or when the applied forces are below normal, such as during space flight or prolonged bed rest. Exploiting the underlying mechanisms of this phenomenon may provide new methods to combat bone loss due to aging and disease. The process of bone adaptation is controlled by the coordinated activity of cells embedded inside the bone and with cells in the bone marrow, but the potential for each family of cells to act independently is not known. In this project, small samples of bone will be kept alive in an incubator with mechanical loading applied to stimulate new bone growth. The response of cells within the bone and in the bone marrow will be detected and compared in order to identify potential ways to most effectively target them individually or in combination to maintain bone strength. The insights gained in this research have the potential to inform future investigations into novel pharmacological treatments to prevent bone loss. Furthermore, the research will have an educational impact through an established relationship with a local high school to encourage a broader participation in science and engineering and a continued international collaboration with the University of Ireland, Galway. Bone adaptation relies on the coordinated activity of osteoblasts, osteoclasts, and osteocytes. Osteocytes act as the primary sensors of bone deformation and signal neighboring cells to affect bone formation and resorption. However, many cells resident in the bone marrow are also mechanosensitive, and could contribute to the adaptive response of bone. This study will employ ex vivo mechanical stimulation applied to trabecular explants to study its effects in both bone marrow and osteocytes. Low magnitude mechanical stimulation (LMMS) will be used to induce shear stress in bone marrow while the small acceleration and mass of the bone result in effectively no bone deformation. Computational models will be used to quantify the marrow shear stress, which will be spatially correlated to bone formation. The effects of LMMS on beta-catenin signaling will be quantified in the presence of both agonists and antagonists to WNT signaling to identify the mechanobiological mechanisms that act within the marrow cells.