m6A甲基化驱动circ_0003578为核心的RNA调控网络在维持软骨稳态中的作用机制研究

解决阻遏软骨退变和维持软骨稳态这一关键问题，核心是如何利用细胞调控。我们芯片和实验初步发现circ_0003578在人间充质干细胞（MSCs）成软骨分化和软骨退变中起作用，调控miR-455-3p在促进软骨分化和延缓软骨退变的效应。我们也发现在人软骨退变中m6A相关酶中甲基转移酶WTAP特异性高表达，且实验和信息学显示WTAP与circ_0003578密切相关，而进一步预实验证实WTAP促进circ_0003578作用的发挥，可能通过WTAP驱动circ_0003578对miR-455-3p的协同调控，从而维持软骨内环境稳定。本研究拟通过体内外实验从细胞-组织-整体层次阐明circ_0003578和miR-455-3p组成的RNA网络协同m6A甲基化阻抑MSCs向成软骨细胞分化中早期退变、促进分化的规律，维持软骨稳态，从而促进解决关节软骨和组织工程软骨的退变这一难题，利于研究应用转化。

The key of solving the important problem of preventing cartilage degeneration and maintaining cartilage homeostasis is determined by the utilization of cell regulation. Our microarray and experiment results showed that circ_0003578 played a crucial role in chondrogenic differentiation and cartilage degeneration of human mesenchymal stem cells (MSCs), and regulated the effect of miR-455-3p in promoting chondrogenic differentiation and delaying cartilage degeneration. We also found that WTAP, a RNA N6-methyladenosine related methyltransferase, was highly expressed in human degenerated chondrocytes. Moreover, the experiment and bioinformatic analysis showed that WTAP was correlated with circ_0003578. Our further experiments confirmed that WTAP can improve the effect of circ_0003578. These results indicated that WTAP may drive circ_0003578 to coordinate miR-455-3p regulation, maintaining the stability of cartilage biological environment. The aim of this study was to elucidate the mechanism of RNA network composed of circ_0003578 and miR-455-3p，in combination with m6A methylation, to inhibit the early degeneration and promote differentiation in MSCs chondrogenic differentiation, and to maintain the cartilage homeostasis through the experiments in vivo and in vitro. So as to solve the problem of degeneration in articular cartilage and tissue engineered cartilage, which can be beneficial to research transform to application.