Role and Therapeutic Potential for Targeting Fibroblast Growth Factor 10/<scp>FGFR1</scp> in Relapsed Rheumatoid Arthritis

Xiaohui Meng(Nanjing University of Chinese Medicine), Zechuan Chen(Shanghai Institute of Applied Physics), Teng Li(Shanghai Institute of Applied Physics), Zhixing Nie(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Haihui Han(Shanghai University of Traditional Chinese Medicine), Sheng Zhong(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Zhinan Yin(Jinan University), Songtao Sun(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Jun Xie(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Jun Shen(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Xirui Xu(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Chenxin Gao(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Lei Ran(Shanghai University of Traditional Chinese Medicine), Bo Xu(Shanghai University of Traditional Chinese Medicine), Zheng Xiang(Shanghai University of Traditional Chinese Medicine), Jianye Wang(Shanghai University of Traditional Chinese Medicine), Pengfei Sun(Shanghai University of Traditional Chinese Medicine), Pengfei Xin(Shanghai University of Traditional Chinese Medicine), A Xinyu(Shanghai University of Traditional Chinese Medicine), Chengbo Zhang(Shanghai University of Traditional Chinese Medicine), Guowei Qiu(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Huali Gao(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Yanqin Bian(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Minglan Xu(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Boran Cao(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Fang Li(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Lin Zheng(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine), Xiaoming Zhang(Shanghai Institute of Applied Physics), Lianbo Xiao(Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine)
Arthritis & Rheumatology
August 19, 2023
10.1002/art.42674
Cited by 36Open Access
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Abstract

OBJECTIVE: Fibroblast-like synoviocytes (FLSs) contribute to inflammation and joint damage in rheumatoid arthritis (RA). However, the regulatory mechanisms of FLSs in relapse and remission of 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 patients with relapse RA 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 quantitative real-time PCR (qPCR) and multiplex immunohistochemistry (mIHC). We further targeted the critical signals in vitro and in vivo using the collagen-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 FLSs from patients with relapse RA for which mIHC confirmed the increased expression of FGF10. Although the type I interferon pathway was also activated in the lining FLSs, in vitro stimulation experiment suggested that it was independent of the FGF10 pathway. FGF10 knockdown by small interfering RNA in FLSs significantly reduced the expression of receptor activator of NF-κB ligand. Moreover, recombinant FGF10 protein enhanced bone erosion in the primary human-derived pannus cell culture, whereas the FGF receptor (FGFR) 1 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.

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