FTO-mediated RNA m6A methylation regulates synovial aggression and inflammation in rheumatoid arthritis

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1870; no. 7; p. 167341
• Main Authors: Li, Ruiru, Kuang, Yu, Niu, Yuanyuan, Zhang, Shuoyang, Chen, Simin, Su, Fan, Wang, Jingnan, Lin, Shuibin, Liu, Di, Shen, Chuyu, Liang, Liuqin, Zheng, Song Guo, Jie, Ligang, Xiao, Youjun, Xu, Hanshi
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.10.2024
• Subjects: ADAMTS15; Fibroblast-like synoviocytes; FTO; Invasion; m6A modification; Migration; Rheumatoid arthritis; FTO; ADAMTS15; m6A modification; Rheumatoid arthritis; Migration; Fibroblast-like synoviocytes; Invasion
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167341

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. [Display omitted] •Increased FTO promotes the migration, invasion and inflammatory response of RA FLS.•FTO controls RA FLS functions by enhancing ADAMTS15 mRNA stability in an m6A-IGF2BP1dependent manner.•The FTO-mediated m6A modification plays an important role in regulating synovial inflammation and joint damage in RA.