Department of Orthopaedics, Third Xiangya Hospital, Central South University, Changsha, 410013, China.
Department of Orthopaedics, Third Xiangya Hospital, Central South University, Changsha, 410013, China.
Int Immunopharmacol. 2024 Nov 15;141:112987. doi: 10.1016/j.intimp.2024.112987. Epub 2024 Aug 24.
Rheumatoid arthritis (RA) is an enduring autoimmune inflammatory condition distinguished by continual joint inflammation, hyperplasia of the synovium, erosion of bone, and deterioration of cartilage.Fibroblast-like synoviocytes (FLSs) exhibiting "tumor-like" traits are central to this mechanism.ADP-ribosylation factor-like 4c (ARL4C) functions as a Ras-like small GTP-binding protein, significantly impacting tumor migration, invasion, and proliferation.However, it remains uncertain if ARL4C participates in the stimulation of RA FLSs exhibiting "tumor-like" features, thereby fostering the advancement of RA. In our investigation, we unveiled, for the inaugural instance, via the amalgamated scrutiny of single-cell RNA sequencing (scRNA-seq) and Bulk RNA sequencing (Bulk-seq) datasets, that activated fibroblast-like synoviocytes (FLSs) showcase high expression of ARL4C, and the ARL4C protein expression in FLSs derived from RA patients significantly surpasses that observed in individuals with osteoarthritis (OA) and traumatic injury (trauma).Silencing of the ARL4C gene markedly impeded the proliferation of RA FLSs by hindered the transition of cells from the G0/G1 phase to the S phase, and intensified cell apoptosis and diminished the migratory and invasive capabilities. Co-culture of ARL4C gene-silenced RA FLSs with monocytes/macrophages significantly inhibited the polarization of monocytes/macrophages toward M1 and the repolarization of M2 to M1.Furthermore, intra-articular injection of shARL4C significantly alleviated synovial inflammation and cartilage erosion in collagen-induced arthritis (CIA) rats. In conclusion, our discoveries propose that ARL4C assumes a central role in the synovial inflammation, cartilage degradation, and bone erosion associated with RA by triggering the PI3K/AKT and MAPK signaling pathways within RA FLSs.ARL4C holds promise as a prospective target for the development of pharmaceutical agents targeting FLSs, with the aim of addressing RA.
类风湿关节炎（RA）是一种持续的自身免疫性炎症性疾病，其特征为持续的关节炎症、滑膜增生、骨质侵蚀和软骨退化。表现出“肿瘤样”特征的成纤维样滑膜细胞（FLS）是这种机制的核心。ADP-核糖基化因子样 4c（ARL4C）作为一种 Ras 样小 GTP 结合蛋白发挥作用，显著影响肿瘤的迁移、侵袭和增殖。然而，尚不清楚 ARL4C 是否参与刺激表现出“肿瘤样”特征的 RA FLS，从而促进 RA 的进展。在我们的研究中，我们首次通过单细胞 RNA 测序（scRNA-seq）和 Bulk RNA 测序（Bulk-seq）数据集的联合分析发现，激活的成纤维样滑膜细胞（FLS）表现出高表达 ARL4C，并且源自 RA 患者的 FLS 中的 ARL4C 蛋白表达明显高于骨关节炎（OA）和创伤性损伤（创伤）患者。沉默 ARL4C 基因显著抑制了 RA FLS 的增殖，阻碍了细胞从 G0/G1 期向 S 期的转变，并增强了细胞凋亡，降低了迁移和侵袭能力。与单核细胞/巨噬细胞共培养 ARL4C 基因沉默的 RA FLS 显著抑制了单核细胞/巨噬细胞向 M1 的极化和 M2 向 M1 的再极化。此外，关节内注射 shARL4C 显著减轻胶原诱导关节炎（CIA）大鼠的滑膜炎症和软骨侵蚀。总之，我们的发现表明，ARL4C 通过触发 RA FLS 中的 PI3K/AKT 和 MAPK 信号通路，在 RA 相关的滑膜炎症、软骨降解和骨侵蚀中发挥核心作用。ARL4C 有望成为针对 FLS 的药物开发的有前途的靶点，以解决 RA 问题。
