Abstract：
Fibroblast-like synoviocytes (FLS) plays an important role in synovial inflammation and joint damage in rheumatoid arthritis (RA). As the most abundant mRNA modification, N6-methyladenosine (m6A) is involved in the development of various diseases; however, its role in RA remains to be defined. In this study, we reported the elevated expression of the m6A demethylase fat mass and obesity-associated protein (FTO) in FLS and synovium from RA patients. Functionally, FTO knockdown or treatment with FB23-2, an inhibitor of the mRNA m6A demethylase FTO, inhibited the migration, invasion and inflammatory response of RA FLS, however, FTO-overexpressed RA FLS exhibited increased migration, invasion and inflammatory response. We further demonstrated that FTO promoted ADAMTS15 mRNA stability in an m6A-IGF2BP1 dependent manner. Notably, the severity of arthritis was significantly reduced in CIA mice with FB23-2 administration or CIA rats with intra-articular injection of FTO shRNA. Our results illustrate the contribution of FTO-mediated m6A modification to joint damage and inflammation in RA and suggest that FTO might be a potential therapeutic target in RA.
摘要：
成纤维样滑膜细胞(FLS)在类风湿关节炎(RA)滑膜炎症和关节损伤中起重要作用。作为最丰富的mRNA修饰，N6-甲基腺苷（m6A）参与各种疾病的发展;然而，其在RA中的作用尚待定义。在这项研究中,我们报道了RA患者FLS和滑膜中m6A脱甲基酶脂肪量和肥胖相关蛋白(FTO)的表达升高.功能上,FTO敲低或用FB23-2处理，FB23-2是m6A去甲基酶FTOmRNA的抑制剂，抑制了迁移，RAFLS的侵袭和炎症反应，然而,FTO过表达的RAFLS表现出增加的迁移，侵袭和炎症反应。我们进一步证明FTO以m6A-IGF2BP1依赖性方式促进ADAMTS15mRNA稳定性。值得注意的是,在给予FB23-2的CIA小鼠或关节内注射FTOshRNA的CIA大鼠中，关节炎的严重程度显着降低。我们的结果说明了FTO介导的m6A修饰对RA的关节损伤和炎症的贡献，并表明FTO可能是RA的潜在治疗靶标。
