hsa_circ_0001508/miR-381-3p/HDAC4作用轴双向调控ADSCs成软骨分化的机制研究

组织工程软骨种子细胞成软骨分化后稳定性较差且早期易退变，与细胞调控密切相关。ncRNAs与miRNAs组成的ceRNA调控环在间充质干细胞成软骨分化及退变中发挥重要作用，circRNAs因结构稳定且具组织特异性而备受瞩目。申请人在两个国自然基金资助下证实miR-381在ADSCs成软骨分化中特异性高表达，可同时促进成软骨分化及软骨退变，即具备双向调控能力，可用表观遗传及ceRNA调控网络协同作用来解释。经预实验及信息学分析发现hsa_circ_0001508可作为ceRNA竞争结合miR-381-3p而拮抗其对HDAC4的调控，致软骨早期退变，进一步预实验亦证实这一可能性。本研究拟从细胞-组织-整体层面阐明hsa_circ_0001508/miR-381-3p/HDAC4作用轴，进而干预该轴使ADSCs成软骨分化早期更好地分化，中晚期退变得以抑制，为解决组织工程软骨早期退变难题提供新思路。

To date, we have not been able to differentiate the mesenchymal stem cells in chondrocytes to form a bioengineered cartilage without early degeneration. Non-coding RNAs (ncRNAs), acting as a ceRNA, have been established to participate in the crucial processes of MSCs chondrogenesis and cartilage degeneration. Circular RNAs (circRNAs), one of the most widespread ncRNAs in eukaryotes, form a covalently closed continuous loop, are presumably more stable than most linear RNAs. Supported by two National Natural Science Foudation of China, we have demonstrated that miR-381 can alter chondrogenesis of ADSCs as well as cartilage degeneration at the same time. One possible mechanism is the epigenetic interactions of circRNA-miRNA-mRNA as a ceRNA network. Our analysis has led to one chondrocyte-related circRNAs (hsa_circ_0001508), which may competitively combine to miR-381-3p and suppress its regulation to HDAC4, causing the early degeneration of chondrocytes. Our preliminary data also confirmed this possibility. In this study, we will provide novel insight for better understanding of ceRNA-mediated gene regulation of hsa_circ_0001508/miR-381-3p/HDAC4 signal axis in chondrogenesis and early chondrocyte degeneration. With the understanding of this specific ceRNA network, we will facilitate the regulation of ADSCs differentiation and degeneration and provide possible new insight for the reconstruction of cartilage tissue engineering.