Zhou Wenxian, Cheng Hui, Fan Chenghu, Zhou Xin, Chen Wenyu, Xie Chenglong, Hu Yuezheng, Chen Yue, Wang Xiaobing, Wu Jinyu
Institute of Genomic Medicine, Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Medical University, 325000, Wenzhou, Zhejiang, China.
Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, Zhejiang, China.
J Autoimmun. 2025 Feb;151:103359. doi: 10.1016/j.jaut.2025.103359. Epub 2025 Jan 11.
The aim of this study was to explore the functional role of LAMP3-mediated epithelial-mesenchymal transition (EMT) in fibroblast-like synoviocytes (FLSs) in rheumatoid arthritis (RA) patients and to evaluate its potential as a therapeutic target.
Changes in EMT and LAMP3 were investigated in the synovial tissue and FLSs of RA patients. In vitro experiments were performed using the EMT inhibitor C19, siRNA, and lentivirus to examine the impact of EMT and LAMP3 on RA-FLSs and the underlying mechanisms involved. Finally, C19 was administered to mice with collagen-induced arthritis (CIA) to validate the therapeutic efficacy of C19 in treating arthritis.
Compared with patients with osteoarthritis (OA), RA patients exhibited increased EMT and increased expression of LAMP3 in the synovium. The results from the in vitro experiments demonstrated that inhibiting EMT effectively reduced the excessive proliferation, anti-senescent properties, migration, and invasive behavior of RA-FLSs, as well as the secretion of MMP1, MMP3, and MMP13. Additionally, regulating the expression of LAMP3 not only affected the EMT pathway but also impacted the excessive proliferation and invasive behavior of RA-FLSs. In the CIA model, administration of the EMT inhibitor C19 significantly alleviated the progression of arthritis.
These findings demonstrate the inhibitory impact of EMT on arthritis and suggest that inhibiting EMT or LAMP3 may be a promising novel therapeutic approach for treating RA.
本研究旨在探讨溶酶体相关膜蛋白3（LAMP3）介导的上皮-间质转化（EMT）在类风湿关节炎（RA）患者成纤维样滑膜细胞（FLS）中的功能作用，并评估其作为治疗靶点的潜力。
研究了RA患者滑膜组织和FLS中EMT及LAMP3的变化。使用EMT抑制剂C19、小干扰RNA（siRNA）和慢病毒进行体外实验，以研究EMT和LAMP3对RA-FLS的影响及其潜在机制。最后，将C19给予胶原诱导性关节炎（CIA）小鼠，以验证C19治疗关节炎的疗效。
与骨关节炎（OA）患者相比，RA患者滑膜中的EMT增加，LAMP3表达升高。体外实验结果表明，抑制EMT可有效降低RA-FLS的过度增殖、抗衰老特性、迁移和侵袭行为，以及基质金属蛋白酶1（MMP1）、基质金属蛋白酶3（MMP3）和基质金属蛋白酶13（MMP13）的分泌。此外，调节LAMP3的表达不仅影响EMT途径，还影响RA-FLS的过度增殖和侵袭行为。在CIA模型中，给予EMT抑制剂C19可显著减轻关节炎的进展。
这些发现证明了EMT对关节炎具有抑制作用，并表明抑制EMT或LAMP3可能是治疗RA的一种有前景的新型治疗方法。
