Geng Qishun, Jiao Yi, Diao Wenya, Xu Jiahe, Wang Zhaoran, Wang Xing, Wang Zihan, Zhao Lu, Yang Lei, Wang Yilin, Deng Tingting, Wang Bailiang, Xiao Cheng
China-Japan Friendship Clinical Medical College, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, China.
Bone Res. 2025 May 12;13(1):51. doi: 10.1038/s41413-025-00434-z.
With the deepening of epigenetic research, studies have shown that N-methyladenosine (mA) 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 mA 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 mA 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.
随着表观遗传学研究的深入，研究表明N-甲基腺苷（mA）与类风湿关节炎（RA）的发展密切相关，但其机制仍不清楚。在本研究中，我们收集了正常对照以及骨关节炎（OA）或RA患者的滑膜组织。通过免疫荧光染色和蛋白质印迹分析了mA水平和炎症情况。使用转染和RNA免疫沉淀试验探讨了IGF2BP3在细胞增殖和炎症激活中的作用。构建了IGF2BP3基因敲除小鼠，并通过输注成年关节炎K/BxN小鼠的血清建立关节炎小鼠模型。我们发现RA患者和小鼠模型中的mA水平显著升高，IGF2BP3的表达在RA患者中上调，且与炎症标志物水平相关。IGF2BP3通过促进细胞增殖、迁移、侵袭、炎性细胞因子释放及抑制自噬，在RA-成纤维样滑膜细胞（FLS）中发挥重要作用。此外，IGF2BP3抑制自噬以减少ROS产生，从而降低巨噬细胞的炎症激活。更重要的是，RASGRF1介导的mTORC1激活在IGF2BP3促进细胞增殖和炎症激活的能力中起关键作用。在IGF2BP3基因敲除小鼠的关节炎模型中，IGF2BP3基因敲除抑制了RA-FLS增殖和炎症浸润，并进一步改善了RA关节损伤。我们的研究揭示了IGF2BP3在RA进展中的重要作用。靶向抑制IGF2BP3可减少细胞增殖和炎症激活，并限制RA的发展，为RA治疗提供了一种潜在策略。
