Kindlin-2调节骨骼发育和稳态平衡的作用及其机制研究

项目名称： Kindlin-2调节骨骼发育和稳态平衡的作用及其机制研究

项目编号： No.81472049

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 肖国芝

作者单位： 南方科技大学

项目金额： 90万元

中文摘要： 骨骼发育及其稳态平衡的维持是一个复杂的过程，必须进行精确的调控才能维持机体的正常功能。我们最近发现，在肢体间充质干细胞中特异敲除细胞粘附调节分子Kindlin-2的表达，可造成小鼠软骨内成骨和膜内成骨过程受损，导致严重骨骼畸形如短肢和颅顶骨完全缺失。删除Kindlin-2的表达显著降低Sox9在软骨细胞的表达和软骨细胞的密度, 破坏软骨柱的形成, 从而延迟初级骨化中心的形成。在软骨细胞特异删除Kindlin-2表达则损伤软骨细胞功能和软骨形成，导致小鼠进行性侏儒症和脊椎后凸畸形。这些结果证明了Kindlin-2对骨骼发育具有重要的调节作用。本课题将应用分子和细胞生物学手段及新型小鼠模型，继续深入系统地研究Kindlin-2分子调节骨骼发育和骨骼稳态平衡的作用及机制。本课题将进一步探索Kindlin-2缺失在促进骨关节炎的发生和发展中的可能作用，为骨关节炎的治疗提供新的靶点。

中文关键词： 骨骼发育；稳态平衡；骨关节炎

英文摘要： Skeletal development and homeostasis are complex processes that must be precisely controlled. We have recently found that deletion of Kindlin-2 expression in limb mesenchymal progenitor cells in mice results in multiple striking skeletal abnormalities including severe limb shortening and complete loss of skull vault due to impairment of both endochondral and intramembranous bone formation. Kindlin-2 ablation in mesenchymal progenitor cells dramatically reduces Sox9 expression and the density of chondrocytes and completely disrupts the chondrocyte column formation in the growth plates， which results in a large delay of the formation of primary ossification center in long bones and digits. Furthermore, ablation of Kindlin-2 expression in chondrocytes leads to progressive dwarfism and kyphosis in mice associated with defective chondrocyte function and chondrogenesis. These results, for the first time to our knowledge, demonstrate that Kindlin-2 plays a critical role in the regulation of skeletal development. In this study, we will continue this extremely exciting project by using a combination of sophisticated molecular and cellular approaches along with multiple novel mouse models and determine the role and mechanism whereby Kindlin-2 controls skeletal development and homeostasis. In addition, we will explore possible involvement of loss of Kindlin-2 in the development and progression of osteoarthritis using our animal models. Results from this study will help on identifying new therapeutic targets for the treatment of patients with osteoarthritis.

英文关键词： skeletal development;hemeostasis;osteoarthritis