Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes disability worldwide. Exosomes released by fibroblast-like synoviocytes in RA (RA-FLSs-Exos) play a role in the development of RA, and circular RNAs (circRNAs) are important for RA progression. This study aimed to investigate the molecular mechanisms underlying the effects of RA-FLSs-Exos in RA and identify the potential pathway responsible for these effects. We initially conducted microarray analysis to identify dysregulated circRNAs in exosomes associated with RA. We then co-cultured isolated RA-FLSs-Exos with chondrocytes to examine their role in RA. In vivo experiments were performed using collagen-induced arthritis mouse models, and circFTO knockdown was achieved through intra-articular injection of AAV5 vectors. Our findings revealed increased expression of circFTO in both RA-FLSs-Exos and synovial tissues from patients with RA. Exosomal circFTO hindered chondrocyte proliferation, migration, and anabolism while promoting apoptosis and catabolism. Mechanistically, we discovered that circFTO facilitates the formation of methyltransferases complex to suppress SRY-related high-mobility group box 9 (SOX9) expression with assistance from YTH domain family 2 (YTHDF2) through an m6A-dependent mechanism. Furthermore, inhibition of circFTO improved symptoms of RA in vivo. Taken together, our study demonstrates that exosomal circFTO derived from FLSs contributes to the progression of RA by targeting SOX9. These findings highlight a promising target for treating RA.

中文翻译：

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成纤维样滑膜细胞衍生的外泌体 circFTO 通过增强软骨细胞中 SOX9 的 N6-甲基腺苷修饰而恶化类风湿性关节炎

类风湿性关节炎（RA）是一种慢性炎症性疾病，在全世界范围内导致残疾。RA 中成纤维细胞样滑膜细胞释放的外泌体 (RA-FLSs-Exos) 在 RA 的发展中发挥作用，而环状 RNA (circRNA) 对于 RA 的进展很重要。本研究旨在研究 RA-FLSs-Exos 在 RA 中作用的分子机制，并确定导致这些作用的潜在途径。我们最初进行了微阵列分析，以识别与 RA 相关的外泌体中失调的 circRNA。然后，我们将分离的 RA-FLS-Exos 与软骨细胞共培养，以检查它们在 RA 中的作用。使用胶原诱导的关节炎小鼠模型进行体内实验，通过关节内注射 AAV5 载体实现 circFTO 敲低。我们的研究结果显示 circFTO 在 RA-FLSs-Exos 和 RA 患者滑膜组织中表达增加。外泌体 circFTO 阻碍软骨细胞增殖、迁移和合成代谢，同时促进细胞凋亡和分解代谢。从机制上讲，我们发现 circFTO 通过 m6A 依赖性机制，在 YTH 结构域家族 2 (YTHDF2) 的帮助下，促进甲基转移酶复合物的形成，从而抑制 SRY 相关的高迁移率族盒 9 (SOX9) 表达。此外，抑制 circFTO 可以改善体内 RA 的症状。综上所述，我们的研究表明，源自 FLS 的外泌体 circFTO 通过靶向 SOX9 促进 RA 的进展。这些发现凸显了治疗 RA 的一个有希望的目标。