FGFR1经Dvl2/Wnt信号调节纤毛介导的骨细胞功能在疲劳骨折中的作用机制研究

应力性骨折即疲劳骨折是常见的运动系统损伤。目前对其发生病理过程有初步认识，已知骨细胞对力学信号感知与反应在其中发挥重要作用，但详细机制不清。在前期研究中发现，骨细胞中的FGFR1可能参与其力学感知及功能活性的调节，且缺失FGFR1的骨细胞存在细胞重要感受器-纤毛的异常。我们提出FGFR1可能经JNK1调节Dvl2/Wnt信号及纤毛长度与功能，进而影响骨细胞的功能与活性，参与应力性骨折的发生与修复。本课题拟利用骨细胞中增强/敲除FGFR1小鼠，建立力学加载模型，通过骨骼表型分析及细胞培养结合JNK1、Dvl2相关干预措施，深入研究FGFR1经调控纤毛及骨细胞功能在应力性骨折发生、发展中的作用与机制。本研究可望明确FGFR1参与骨细胞功能维持及应力性骨折发生与修复的新机制，为探索应力性骨折的防治措施，以及为纤毛疾病的机制及治疗策略研究提供借鉴。

Stress fracture, also known as fatigue fracture, is one of the most common injuries of skeleton system. To date, there is relatively less understanding of its pathological process，especially the underlying mechanism. The sensing and response of osteocytes to mechanical stimuli play an important role in the pathogenesis of stress fracture, but the detailed mechanism is largely unknown. In recent study, we found that the FGFR1 signaling in osteocytes may be involved in the regulation of its functional state and mechanical perception, and the osteocytes lacking FGFR1 have abnormalities of cilia, a complex signaling center and sensor. We thus propose that FGFR1 may regulate the function of osteocytes via JNK1 mediated regulation of Dvl2/Wnt signaling, and participate in the pathogenesis and repair of stress fractures. To reveal the detailed cellular and molecular mechanisms, we will combine mice with genetically modified FGFR1 in osteocytes with cell culture and JNK1 and Dvl2 related intervention reagents in vitro to study the roles and mechanisms of FGFR1 in the regulation of stress fractures through primary cilia. This study is expected to clarify the novel mechanism of FGFR1 signaling involved in the maintenance of osteocytes and the pathogenesis of stress fracture, providing an experimental basis for exploring the prevention and treatment of stress fracture, and studying the mechanism and treatment strategies of other ciliopathies.