环状RNA circ-foxo3通过FOXO3调控软骨细胞自噬在骨关节炎发病中作用机理的研究

Osteoarthritis (OA)is characterized by degeneration of articular cartilage, its pathogenesis is still unclear and there is no effective therapeutic approaches. Our previous study has shown that stimulating autophagy can inhibit chondrocytes apoptosis. But the regulating mechanism of autophagy in chondrocytes is still not clear. Some studies have shown that transcription factor FOXO3 participated in the regulation of autophagy. Circular RNA circ-foxo3 which was derived from FOXO3 has close relationship with apoptosis. But the effects of FOXO3 and circ-foxo3 in the pathogenesis of OA is not clear. Our results showed that the expression of FOXO3 and circ-foxo3 decreased in the articular cartilage of OA patients, while inhibition of FOXO3 can induce chondrocytes apoptosis. These results suggested that circ-foxo3 and FOXO3 play important roles in the pathogenesis of OA. Based on our study and others, we hypothesized that circ-foxo3 might play a role in the pathogenesis of OA, it may induce FOXO3 expression and further regulate autophagy in chondrocytes. In the present study, the effect of circ-foxo3, FOXO3 and autophagy on the articular cartilage degeneration was investigated in vitro, in vivo, and further illuminate the specific molecular mechanism. New theoretical basis is expected to provide for seeking new therapeutic targets of OA.

骨关节炎是一种以关节软骨退变为主要表现的常见老年疾病，其发病机理仍不清楚，也缺乏有效的防治措施。我们前期研究表明自噬水平升高能够抑制软骨细胞凋亡，对软骨细胞具有保护作用，但软骨细胞自噬的确切调控机制仍不清楚。文献报道转录因子FOXO3参与细胞内自噬调节，来源于FOXO3的环状RNA circ-foxo3也与细胞凋亡调控密切相关，但对两者在骨关节炎发病中的作用缺乏了解。我们预实验发现骨关节炎病人软骨中，circ-foxo3和FOXO3的表达均降低，抑制FOXO3表达后软骨细胞凋亡增加，提示circ-foxo3和FOXO3在骨关节炎发病中可能具有一定的作用。因此本课题假设circ-foxo3通过调控FOXO3基因，参与自噬调控进而影响软骨细胞的功能，从临床标本、体外和动物实验对软骨细胞自噬的这一可能调节过程进行研究，明确其在骨关节炎发病中的作用机理，为骨关节炎的防治提供理论基础。

骨关节炎（osteoarthritis,OA）作为一种以关节软骨退变为主要表现的常见老年疾病，其发病机理仍不清楚。本研究是在前期研究软骨细胞自噬水平适当升高后可抑制细胞的凋亡的基础上，通过探究环状RNA circ-foxo3与转录因子FOXO3对软骨细胞自噬与凋亡水平的调节。此前研究报道转录因子FOXO3参与细胞内自噬调节，来源于FOXO3的环状RNA circ-foxo3也与细胞凋亡调控密切相关，但对两者在骨关节炎发病中的作用缺乏了解。. 我们研究表明在小鼠OA关节软骨中环状RNA circ-foxo3与非OA组相比，其表达显著降低，同时软骨细胞自噬表达水平降低，凋亡比率显著增加，细胞外基质合成分解代谢严重失衡。相反，通过慢病毒转染等措施促进软骨细胞内circ-foxo3表达，可显著抑制OA的进展，表现出一定的OA治疗效果，这表明circ-foxo3在OA的发病发展中发挥重要用作。. 接下来，我们进一步探究发现，环状RNA circ-foxo3主要通过作用其亲本FOXO3基因来发挥调控作用，上调软骨细胞自噬表达水平、抑制细胞凋亡，同时发挥促进细胞外基质二型胶原、糖胺聚糖的合成、抑制其降解的作用。. 本研究进一步探究了OA的发病机制，不仅存在巨大学术价值，而且可能为未来发展OA治疗的新技术、新靶点提供有力的理论支持。