Role and Therapeutic Potential for Targeting Fibroblast Growth Factor 10/FGFR1 in Relapsed Rheumatoid Arthritis
Xiaohui Meng, Zechuan Chen, Teng Li, Zhixing Nie, Haihui Han, Sheng Zhong, Zhinan Yin, Songtao Sun, Jun Xie, Jun Shen, Xirui Xu, Chenxin Gao, Lei Ran, Bo Xu, Zheng Xiang, Jianye Wang, Pengfei Sun, Pengfei Xin, Xinyu A, Chengbo Zhang, Guowei Qiu, Huali Gao, Yanqin Bian, Minglan Xu, Boran Cao, Fang Li, Lin Zheng, Xiaoming Zhang, Lianbo Xiao - Immunology
- Rheumatology
- Immunology and Allergy
Objectives
Fibroblast‐like synoviocytes (FLS) contribute to inflammation and joint damage in rheumatoid arthritis (RA). However, the regulatory mechanisms of FLS in relapse and remission RA remain unknown. Identifying FLS heterogeneity and their underlying pathogenic roles may lead to discovering novel disease‐modifying antirheumatic drugs.
Methods
Combining single‐cell RNA‐sequencing (scRNA‐seq) and spatial transcriptomics, we sequenced six matched synovial tissue samples from three relapse RA patients and three patients in remission. We analyzed the differences in the transcriptomes of the FLS subsets between the relapse and remitted phases. We validated several key signaling pathways using qPCR and multiplex immunohistochemistry (HC). We further targeted the critical signals in vitro and in vivo using collage‐induced arthritis (CIA) model in rats.
Results
Lining and sublining FLS subsets were identified using scRNA‐seq. Differential analyses indicated that the fibroblast growth factor (FGF) pathway was highly activated in the lining FLS from relapse RA patients where mIHC confirmed the increased expression of FGF10. While the type I interferon pathway was also activated in the lining FLS, in vitro stimulation experiment suggested that it was independent of the FGF10 pathway. FGF10 knockdown by siRNA in FLS significantly reduced the expression of RANKL. Moreover, recombinant FGF10 protein enhanced bone erosion in the primary human‐derived pannus cell culture, whereas the FGFR1 inhibitor attenuated this process. Finally, administering an FGFR1 inhibitor displayed a therapeutic effect in a CIA rat model.
Conclusion
The FGF pathway is a critical signaling pathway in relapse RA. Targeted tissue‐specific inhibition of FGF10/FGFR1 may provide new opportunities to treat patients with relapse RA.