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

比较骨细胞和骨髓细胞在骨对负载的适应性反应中的作用

• 批准号: 1435467
• 负责人: Glen Niebur
• 金额: $ 37万
• 依托单位: University of Notre Dame
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1435467&HistoricalAwards=false
• 关键词: Comparing; Roles; Bone; Cells; Marrow

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.

健康的骨骼对保持积极的生活方式至关重要。骨骼在经常锻炼或日常活动的负荷下会变得更强壮。相反，在长时间不活动或当施加的力低于正常水平时，例如在太空飞行或长时间卧床休息期间，它们变得更加脆弱。利用这一现象的潜在机制可能为对抗衰老和疾病导致的骨质流失提供新的方法。骨适应过程是由嵌入骨内的细胞和骨髓细胞的协调活动控制的，但每种细胞家族独立作用的潜力尚不清楚。在这个项目中，小的骨骼样本将被保存在一个培养箱中，并施加机械负荷来刺激新骨骼的生长。将检测和比较骨内细胞和骨髓细胞的反应，以便确定最有效地单独或联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药物治疗提供信息。此外，通过与当地一所高中建立关系，鼓励更广泛地参与科学和工程，并与爱尔兰大学戈尔韦分校继续开展国际合作，该研究将对教育产生影响。骨适应依赖于成骨细胞、破骨细胞和骨细胞的协调活动。骨细胞是骨变形的主要传感器，并向邻近细胞发出信号，影响骨的形成和吸收。然而，许多驻留在骨髓中的细胞也具有机械敏感性，并可能有助于骨骼的适应性反应。本研究将采用体外机械刺激对骨小梁外植体进行体外机械刺激，研究其在骨髓和骨细胞中的作用。低强度的机械刺激（LMMS）将用于诱导骨髓中的剪切应力，而骨的小加速度和质量导致骨有效地不变形。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。在WNT信号的激动剂和拮抗剂存在的情况下，LMMS对β -连环蛋白信号的影响将被量化，以确定在骨髓细胞内起作用的机械生物学机制。