Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Shanghai Guanghua Hospital of Integrative Medicine, Shanghai, China.
Arthritis Rheumatol. 2024 Jan;76(1):32-47. doi: 10.1002/art.42674. Epub 2023 Nov 28.
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.
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.
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.
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.
成纤维样滑膜细胞（FLS）在类风湿关节炎（RA）的炎症和关节损伤中起作用。然而，FLS 在 RA 缓解和复发中的调节机制尚不清楚。确定 FLS 的异质性及其潜在的致病作用可能会发现新的疾病修饰抗风湿药物。
我们结合单细胞 RNA 测序（scRNA-seq）和空间转录组学，对来自 3 例 RA 复发患者和 3 例缓解患者的 6 对匹配滑膜组织样本进行测序。我们分析了复发和缓解阶段 FLS 亚群之间转录组的差异。我们使用定量实时 PCR（qPCR）和多重免疫组化（mIHC）验证了几个关键信号通路。我们还在大鼠胶原诱导性关节炎（CIA）模型中体外和体内靶向关键信号。
使用 scRNA-seq 鉴定了衬里和亚衬里 FLS 亚群。差异分析表明，在 RA 复发患者的衬里 FLS 中，成纤维细胞生长因子（FGF）途径高度激活，mIHC 证实 FGF10 的表达增加。尽管 I 型干扰素途径也在衬里 FLS 中被激活，但体外刺激实验表明它与 FGF10 途径无关。用小干扰 RNA 敲低 FLS 中的 FGF10 显著降低了核因子-κB 配体受体激活剂的表达。此外，重组 FGF10 蛋白增强了原代人来源的滑膜细胞培养物中的骨侵蚀，而 FGFR1 抑制剂减弱了这一过程。最后，在 CIA 大鼠模型中给予 FGFR1 抑制剂显示出治疗效果。
FGF 途径是 RA 复发的关键信号通路。针对 FGF10/FGFR1 的组织特异性抑制可能为治疗 RA 复发患者提供新的机会。
