IGF2BP3-mediated m⁶A modification of RASGRF1 promoting joint injury in rheumatoid arthritis

Abstract

With the deepening of epigenetic research, studies have shown that N⁶-methyladenosine (m⁶A) is closely related to the development of rheumatoid arthritis (RA), but the mechanism is still unclear. In the study, we collected synovial tissues from normal controls and patients with osteoarthritis (OA) or RA. The levels of m⁶A and inflammation were analyzed by immunofluorescence staining and western blotting. The roles of IGF2BP3 in cell proliferation and inflammatory activation were explored using transfection and RNA immunoprecipitation assays. IGF2BP3^−/− mice were generated and used to establish an arthritis mouse model by transferring serum from adult arthritis K/BxN mice. We found m⁶A levels were markedly increased in RA patients and mouse models, and the expression of IGF2BP3 was upregulated in individuals with RA and related to the levels of inflammatory markers. IGF2BP3 played an important part in RA-fibroblast-like synoviocytes (FLS) by promoting cell proliferation, migration, invasion, inflammatory cytokine release and inhibiting autophagy. In addition, IGF2BP3 inhibited autophagy to reduce ROS production, thereby decreasing the inflammatory activation of macrophages. More importantly, RASGRF1-mediated mTORC1 activation played a crucial role in the ability of IGF2BP3 to promote cell proliferation and inflammatory activation. In an arthritis model of IGF2BP3^−/− mice, IGF2BP3 knockout inhibited RA-FLS proliferation and inflammatory infiltration, and further ameliorated RA joint injury. Our study revealed an important role for IGF2BP3 in RA progression. The targeted inhibition of IGF2BP3 reduced cell proliferation and inflammatory activation and limited RA development, providing a potential strategy for RA therapy.

Keywords

Medical and Health Sciences / Clinical Sciences

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Funding

The National Natural Science Foundation of China (U22A20374,52373273) and National High Level Hospital Clinical Research Funding of China-Japan Friendship Hospital (Grant number: 2024-NHLHCRF-JBGS-WZ-02).

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