RhoA/ROCK通路在应力诱导后纵韧带细胞骨向分化中的作用及机制研究

Ossification of the posterior longitudinal ligament (OPLL) is one of the most common spinal diseases， which is closely related to mechanical stress stimulation and the activation of osteogenic signal pathways. However, the transduction mechanism between mechanical and osteogenic signal is still not clear. RhoA is an important cytoskeletal-function related protein，which can be activated by mechanical stress-mediated cytoskeletal remodeling. Meanwhile，RhoA/ROCK is an important upstream regulation signal of osteogenesis pathways including MAPK and PI3K pathway. In our previous studies, we observed that RhoA-related microRNAs and SNPs are differentially distributed in population with OPLL. Also, RhoA as well as its effector, ROCK, are significantly over-expressed in OPLL patients. We therefore hypothesized that in the process of OPLL, RhoA / ROCK plays a connecting role as responding to upstream mechanics signals and regulating downstream osteogenic signals. In this study，we intend to investigate the response mechanism of RhoA / ROCK to mechanical signals expression and its correlation with osteogenic activity in posterior longitudinal ligament cell model loaded with cyclic stretch stress. Positive/negative interventions will be implemented at different key sites to clarify the specific pathways in regulating osteogenesis of posterior longitudinal ligament cells, hoping to provide experimental evidence for the understanding and targeted therapy of cervical OPLL.

后纵韧带骨化（OPLL）是一种常见颈椎疾患，其发病与机械应力刺激密切相关，但力学信号与成骨信号通路之间的具体转导机制尚不明确。RhoA及其效应分子ROCK是重要的细胞骨架功能蛋白，具有应力敏感性；同时也是重要成骨相关信号的上游调节通路。我们前期发现：OPLL人群中，存在RhoA相关miRNAs与SNPs的差异分布；RhoA和ROCK表达亦显著增高；抑制RhoA表达后，可明显降低后纵韧带细胞成骨作用。因此推测，RhoA/ROCK是韧带细胞骨向分化的重要信号转导环节，具有应答上游力学信号并调控下游成骨信号的作用。本课题拟以加载周期性牵张应力的后纵韧带细胞模型，研究RhoA/ROCK对力学信号的应答机制；并通过在各关键位点实施正/反向干预，探讨其调控细胞骨向分化的具体信号途径。为进一步阐明颈椎OPLL的发生机制及临床靶向治疗提供理论基础。

后纵韧带骨化（OPLL）是一种常见颈椎疾患，给患者家庭及社会造成了沉重负担。目前针对OPLL的治疗主要为对症治疗，效果欠佳。目前研究认为其发病与机械应力刺激密切相关，但具体机制尚不明确。RhoA及其效应分子ROCK是重要的细胞骨架功能蛋白，具有应力敏感性；同时也是重要成骨相关信号的上游调节通路。我们发现：OPLL人群中，存在RhoA相关miRNAs与SNPs的差异分布，RhoA和ROCK表达亦显著增高。因此推测，RhoA/ROCK是韧带细胞骨向分化的重要信号转导环节，具有应答上游力学信号并调控下游成骨信号的作用。本课题使用加载周期性牵张应力的后纵韧带细胞模型，研究RhoA/ROCK对力学信号的应答机制；并通过在各关键位点实施干预，探讨其调控细胞骨向分化的具体信号途径。为进一步阐明颈椎OPLL的发生机制及临床靶向治疗提供理论基础。