miR-9通过SIRT1/NF-κB通路调控骨关节炎软骨细胞凋亡的机制研究

Osteoarthritis (OA) is the most common chronic progressive osteoarticular disease. MicroRNAs, one of the small molecular RNA family, which can play an important role in the post-transcriptional gene regulation by inhibiting target gene and regulate several physiological and pathophysiological processes.In our prophase research, we have found that chondrocyte apoptosis play the key role in the pathogenesis of osteoarthritis and SIRT1/NF-κB pathyway regulate chondrocyte apoptosis.MiR-9 was significantly decreased in osteoarthritis and bioinformatics analysis showed that SIRT1 is the predicted target gene of miR-9. This suggested miR-9 may play a role in regulation of chondrocyte apoptosis through SIRT1/NF-κB signal pathyway. This study is planned to build high expression/loss of expression of miR-9 in chondrocyte in vitro and in vivo models of osteoarthritis. Observe the effect of changing the expression of miR-9 on chondrocyte apoptosis. And research the signal transduction mechanism of regulation of chondrocyte apoptosis by miR-9 through SIRT1 downstream signaling pathway.This study investigate the role of of miR-9 in chondrocyte apoptosis of osteoarthritis and signal transduction mechanism at cell, molecular and whole levels. which has important significance to clarify the role of miR-9 in the pathogenesis of osteoarthritis. And provide new ideas and targets for the treatment of osteoarthritis.

骨关节炎是一种常见的慢性退行性骨关节疾病。近年发现的microRNAs广泛参与调控细胞分化、增殖、凋亡等生理及病理生理过程。我们前期研究表明软骨细胞凋亡在骨关节炎的发病机制中居于核心地位，SIRT1/NF-κB通路在软骨细胞凋亡中发挥重要作用。miR-9在骨关节炎中显著下降，生物信息学方法分析表明SIRT1为miR-9的预测靶基因，推测miR-9可能通过SIRT1/NF-κB通路调控骨关节炎软骨细胞凋亡。本项目拟在整体和离体骨关节炎模型上，构建miR-9高/低表达的软骨细胞和miR-9基因沉默及高表达的小鼠骨关节炎模型，观察miR-9表达变化对软骨细胞凋亡的影响，并研究其调控SIRT1及下游信号通路参与软骨细胞凋亡的机制，从分子、细胞和整体水平探寻miR-9对骨关节炎软骨细胞凋亡的影响及机制。本项目对于阐明miR-9在骨关节炎发病中的作用具有重要意义，并为骨关节炎治疗提供新的思路和靶点。

骨关节炎是一种常见的慢性退行性骨关节疾病。软骨细胞凋亡在骨关节炎的发病机制中居于核心地位。近年发现的microRNAs广泛参与调控细胞 分化、增殖、凋亡等生理及病理生理过程。本研究显示：miR-9-5p在骨关节炎中表达下降， miR-9-5p可抑制OA软骨细胞增值水平并抑制其凋亡水平。用生物信息学方法分析表明miRNA-9-5p调控的靶基因包含SIRT1、NF-κB等基因，我们在体内、体外实验中验证了miR-9-5p通过调控SIRT1可促进OA软骨细胞的凋亡，表明了miR-9-5p通过抑制SIRT1来抑制OA软骨细胞的增殖并促进其凋亡。进一步研究显示巨噬细胞极化与OA进展呈正相关。miR-9-5p可以通过降解SIRT1表达来调节AMPK和NF-κB信号通路来调节巨噬细胞极化。本研究首次观察了miR-9-5p表达与软骨细胞凋亡及凋亡相关蛋白的关系，确定miR-9-5p调控软骨细胞凋亡的靶基因及信号转导机制，并从整体水平上观察miR-9-5p对骨关节炎的影响。同时，我们将miR-9-5p/SIRT1调控机制在关节炎的滑膜组织中也做了验证，发现该信号轴在滑膜组织中的巨噬细胞极化也具有明显的调控作用。本研究从分子、细胞、整体水平探讨miR-9-5p对骨关节炎的影响及相关机制，对于阐明miR-9-5p在骨关节炎发病中的作用具有重要的理论意义。

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