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Int J Biol Sci 2024; 20(5):1617-1633. doi:10.7150/ijbs.90677 This issue Cite

Research Paper

The FTO-CMPK2 Pathway in Fibroblast-like Synoviocytes Modulates Rheumatoid Arthritis Synovial Inflammation and Cartilage Homeostasis via mtDNA Regulation

Li Jin^1,2,#, Qiyue Chen^2,#, Ke Hu^1,2, Dandan Fan¹, Heping Zhang², Jiaxin Deng¹, Weizhong Qi^2,3,✉, Qinghong Yu^1,✉

1. Rheumatology and Clinical Immunology, ZhuJiang Hospital, Southern Medical University, 510280, Guangzhou, China.
2. Translational Medicine Research Center, ZhuJiang Hospital, Southern Medical University, 510280, Guangzhou, China.
3. Clinical Research Center, ZhuJiang Hospital, Southern Medical University, 510280, Guangzhou, China.
^#Li Jin and Qiyue Chen contributed equally to this work.

✉ Corresponding authors: Weizhong Qi, Clinical Research Center, ZhuJiang Hospital, Southern Medical University, 510280, Guangzhou, China. Email: qiwzedu.cn. Qinghong Yu, Rheumatology and Clinical Immunology, ZhuJiang Hospital, Southern Medical University, 510280, Guangzhou, China. Email: yuqinghongedu.cn. More

Abstract

In rheumatoid arthritis (RA), a debilitating autoimmune disorder marked by chronic synovial inflammation and progressive cartilage degradation, fibroblast-like synoviocytes (FLS) are key pathogenic players. Current treatments targeting these cells are limited. Our study focused on the Fat Mass and Obesity-associated protein (FTO), known for its roles in cell proliferation and inflammatory response modulation, and its involvement in RA. We specifically examined the inflammatory regulatory roles of FTO and CMPK2, a mitochondrial DNA synthesis protein, in FLS. Utilizing a combination of in vitro and in vivo methods, including FTO inhibition and gene knockdown, we aimed to understand FTO's influence on RA progression and chondrocyte functionality. Our findings showed that increased FTO expression in RA synovial cells enhanced their proliferation and migration and decreased senescence and apoptosis. Inhibiting FTO significantly slowed the disease progression in our models. Our research also highlighted that the FTO-CMPK2 pathway plays a crucial role in regulating synovial inflammation through the mtDNA-mediated cGAS/STING pathway, affecting chondrocyte homeostasis. This study indicates that targeting the FTO-CMPK2 axis could be a promising new therapeutic strategy for managing RA.

Keywords: rheumatoid arthritis, FTO, CMPK2, synovitis, Mitochondrial DNA

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