lncRNA作为ceRNA参与miR-140-5p调控骨关节炎相关基因修饰和表达的作用机制

Downregulation of miR-140-5p in articular chondrocytes induced imbalance of anabolism and catabolism is the central mechanism for osteoarthritis. The molecular mechanism of how chondrocytes downregulate miR-140-5p expression is unclear. Our previous studies had found that while osteoarthritis chondrocytes downregulated miR-140-5p expression, many lncRNAs and miR-140-5p target genes (such as ADAMTS5, MMP-13, SOX4, etc) increase their expression. Among all of the lncRNAs, four kinds of lncRNA such as TRNS1, TRNAW4, LOC729466 , RNY3 contain miR-140-5p binding site. Combined with the recently proposed and confirmed competing endogenous RNA (ceRNA) hypothesis, we suppose the following hypothesis: four kinds of lncRNA may competitively bind to miR-140-5p, results in reduced expression level or decreased activity of miR-140-5p, and then increase its target genes expression, evoke onset and progression of osteoarthritis. Thus, on the basis of pre-experiment, the research group will verify the above corollary, reveal the ceRNA regulatory mechanisms of osteoarthritis, to provide a new perspective on the pathogenesis of osteoarthritis and help us further integrate the role of ncRNA in the pathogenesis of osteoarthritis, and provide new clinical interventions ideas and targets.

已知关节软骨细胞miR-140-5p表达下调诱导的软骨合成和分解代谢失衡是骨关节炎发病的中心机制，但其表达下调的分子机制尚不清楚。前期研究发现，骨关节炎软骨细胞miR-140-5p下调的同时，多种lncRNAs及ADAMTS5、MMP-13、SOX4等miR-140-5p靶基因表达上调，其中四种lncRNAs包括TRNS1、TRNAW4、LOC729466、RNY3具有miR-140-5p结合位点，结合近期提出的竞争性内源RNA（ceRNA）假说，我们提出以下假设：四种lncRNAs可能作为ceRNA竞争性结合 miR-140-5p，导致其表达下降或活性降低，相应miR-140-5p靶基因表达上调，诱发骨关节炎起病和进展。所以，在预实验基础上，课题组将验证以上假设，揭示骨关节炎发病的ceRNA调控机制，为探究骨关节炎发病机制提供新视角，同时为临床干预提供新的思路和靶点。