FGFR3在终板/椎间盘稳态维持中作用及机制研究

椎间盘退行性变发生率非常高，严重危害国民健康，其病理基础是椎间盘变性。由于对其确切病生机制缺乏深入研究，除手术外，目前尚无有效的靶向治疗方法。近年来发现椎间盘软骨终板退变在椎间盘退变发生中起关键作用，但对其退变的分子机制了解不多。我们前期发现调节骨骼发育和关节软骨稳态的重要分子FGFR3在软骨终板表达，且FGFR3功能增强或敲除突变小鼠的终板矿化延迟或提前，提示FGFR3在终板,乃至椎间盘退变中发挥重要作用。本项目将用在终板软骨可诱导增强、敲除FGFR3功能的小鼠模型，及椎间盘、终板软骨细胞、髓核(共)培养系统等来研究FGFR3及其下游信号对终板软骨细胞活性、功能状态、软骨基质代谢等的直接作用，及由此对终板及椎间盘稳态维持的影响，以明确FGFR3信号在椎间盘终板乃至整个椎间盘退变中的作用与机制，为寻找经调节FGFs/FGFR3信号延缓椎间盘退变策略提供实验依据。

Disc degeneration disease (DDD) is currently very popular, which severely harms the health of people. The pathological base of DDD is the degeneration of intervertebral disk. Because of the lacking of fully understanding of its pathogeneses,there is no effective targeted therapies for DDD, except surgury. Recent studies suggest that the degeneration of endplates play key role in the pathogeneis of disk degeneration, but the molecular pathways are not fully elucidated. Our recent data indicate that there is expression of FGFR3, a key molecule regulating skeleton development and aticular cartilage homeostasis, in endplates, and the endplates of mice with gain-of-function mutation or deficiency of FGFR3 exhibit delayed or accelerated mineralization, suggesting that FGFR3 may play important role in the maintainance of homeostasis of endplates, and therefore disk. In this project，by utilizing mouse models with inducible deletion or activation of FGFR3 specifically in endplate cartilage and cultured or co-cultured endplate chondrocytes and nucleus pulposus cells, we will explore the role and its mechanisms of FGFR3 and its downstream pathways in the degeneration of endplates and disks, which will provide the experimental bases for developing therapeutic approaches for DDD through modulating FGFs/FGFR3 signaling pathways.