淫羊藿苷-力学耦合作用对抗骨疲劳损伤的机理研究

More medical researchers are focus on revealing the mechanism of bone fatigue damage and investigating the effective action against bone fatigue damage in recent years. To solve the above problems, it not only needs elaborate the generation and development of bone tissue micro-crack under the mechanical loading, but get the whole picture of the mechanobiology response of cells. The present project was aimed to establish the cell model and animal model of bone fatigue damage to study the cellular and molecular biological mechanisms, including the caspase signaling pathway-mediated osteocyte apoptosis, ERK and NF-кB signaling pathways-mediated osteoblast promoting bone formation, and NF-кB signaling pathway-mediated osteoclast promoting bone resorption. The development of bone tissue micro-crack and mechanical property, and the changes of related factors on osteocyte apoptosis, osteoblast promoting bone formation, osteoclast promoting bone resorption were investigated in animal model of bone fatigue damage, which was verifying with the study results of cellular and molecular mechanism. Moreover, the coupling effect of drug (icariin) and mechanical loading was used to treat with bone fatigue damage and the mechanobiology mechanisms were elaborated simutaneously. The present study will play an important role in revealing the bone damage and repair under fatigue loading, which also provide the theoretical and technical support on clinical prevention and treatment for bone fatigue damage.

揭示骨疲劳损伤的机制，发现对抗骨疲劳损伤的有效措施是目前医学研究的热点。要解决这些问题，不仅需要阐明力学载荷下骨组织微裂纹的产生与发展，还需更全面了解细胞的力学生物学响应。本课题拟建立骨疲劳损伤的细胞模型和动物模型，通过Caspase信号途径介导的骨细胞凋亡，ERK通路和NF-кB通路影响成骨细胞骨形成，及NF-кB信号通路调节破骨细胞骨吸收，来研究疲劳骨损伤的细胞分子生物学机制；并通过疲劳骨损伤的动物模型，从骨组织微裂纹发展，力学性能宏观变化，及骨组织中骨细胞凋亡、成骨细胞骨形成和破骨细胞骨吸收功能等相关因子的分子水平变化，与体外细胞分子机制研究进行验证。通过药物（淫羊藿苷）-力学耦合干预来对抗骨疲劳损伤，阐述其对抗疲劳骨损伤的力学生物学机理。本研究对揭示疲劳载荷下的骨损伤与修复重建机理有重要意义，也为临床上预防和治疗疲劳骨损伤提供理论和技术支持。

探索骨损伤过程中的力学生物学效应,寻找骨疲劳损伤的有效对抗措施,是预防和治疗骨疲劳损伤的关键问题。针对目前的单一治疗，本项目将力学刺激和药物（淫羊藿苷）进行耦合用于骨疲劳损伤的治疗，并探究其可能的分子生物学机制。体外研究结果表明，力学刺激和淫羊藿苷耦合作用能够通过调节Caspase-3及Bcl-2相关信号通路抑制骨细胞的凋亡，通过上调Wnt信号影响成骨细胞的分化，通过调节NF-κB信号通路抑制破骨细胞的骨吸收。体内研究表明，力学刺激与淫羊藿苷耦合作用不仅能够改善骨疲劳损伤大鼠骨显微裂纹数目、尺寸以及骨细胞陷窝数目，还能够改善尺骨的宏观力学性能以及微观结构的变化。同时力学刺激与淫羊藿苷耦合作用能够调节Caspase-3和Bcl-2信号通路来抑制骨细胞的凋亡，还能够调节破骨细胞骨吸收相关TRAP、RANKL以及骨形成相关ALP、OCN、BMP-2等表达来减少骨疲劳损伤。通过体内外实验阐明力学刺激与淫羊藿苷耦合作用调节骨疲劳损伤的分子机制，明确耦合作用的最佳治疗条件，可用于骨疲劳损伤的预防和治疗。