CircNPHP4通过miR-556-5p靶向NLRP3炎症小体调控终板软骨退变在腰椎Modic改变中的作用及机制研究

腰椎Modic改变与腰痛密切相关，但其病理机制尚未完全明确。研究提示终板软骨退变与Modic改变密切相关。申请人前期研究发现，NLRP3炎症小体介导的终板软骨退变是引起Modic改变的关键因素；高通量测序和实验表明退变的终板软骨内高表达circNPHP4，且可与miR-556-5p互作，调控NLRP3的表达和活化。因此申请人提出假设：circNPHP4通过内源竞争RNA(ceRNA)机制抑制miR-556-5p与NLRP3结合，活化NLRP3炎症小体，进而促进终板软骨退变，最终引发Modic改变。本项目拟从临床组织、细胞、及动物水平，揭示NLRP3炎症小体介导的终板软骨退变在Modic改变中的作用；阐明circNPHP4/miR-556-5p对NLRP3的ceRNA调控机制。本项目将从circRNA这个新视角探讨NLRP3介导的终板软骨退变在Modic改变中的机制，为腰痛的诊疗提供新思路。

Modic changes are thought to be an important pathogenesis of back pain，while its pathogenesis is unclear. Our previous data have suggested that cartilaginous endplate degeneration was the key contributor to Modic changes accompanied with abnormal elevated activation of NLRP3 inflammasome, as well in oxidative stress-induced chondrocyte in vitro where NLRP3 activation was highly associated with elevated inflammation. RNA sequencing and bioinformatics analysis revealed that the upregulated expression level of circNPHP4 in cartilaginous endplate with Modic changes, and associated with NLRP3 inflammasome activation. Luciferase reporter assay suggested that circNPHP4 and miR-556-5p might be involved in the regulation of NLRP3 expression. Emerging evidence shows that there is an interactive relationship between miRNAs and circRNAs, referred to as ceRNA (competing endogenous RNA) mechanism. Therefore, we hypothesize that upregulated circNPHP4 could inhibit miR-556-5p through ceRNA mechanism, and further promotes NLRP3 expression and activation. Furthermore, the upregulated and activated NLRP3 inflammasome accelerates the degeneration of cartilaginous endplate and promotes the presence of Modic changes. The present project aims to clarify the molecular mechanism of circNPHP4/miR-556-5p in regulating NLRP3 expression through clinical tissue investigation, cell experiments, and animal examination, so as to provide new insights for treatment of Modic changes related back pain.