Li Meiling, Nam Min-Kyung, Kim Jung Gon, Kang Juyeon, Park Se-Hyeon, Lee Su-Hyun, Kim Chaerin, Song David, Jin Jingchun, Yoo Seung-Ah, Bucala Richard, Kim Wan-Uk
Department of Biomedicine & Health Sciences, Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea; Department of Rheumatology and Immunology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Biomedicine & Health Sciences, Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Mol Ther. 2025 Aug 11. doi: 10.1016/j.ymthe.2025.08.016.
The destructive potential of rheumatoid arthritis (RA) lies in the aggressive behavior of fibroblast-like synoviocytes (FLSs), which actively contribute to the erosion of cartilage and bone and may persist even in the face of apparent clinical remission. Therapeutic approaches targeting RA-FLSs have been developed to treat RA; however, there are no clinically approved drugs available at present. Here, single-cell RNA sequencing of RA-FLSs identified a distinct macrophage migration inhibitory factor (MIF) subset with mitochondrial and endoplasmic reticulum dysfunction. MIF conditions led to increased survival, proliferation, and migration of FLSs, along with the upregulation of CD44 and the CD44v6 isoform expression. We next explored whether a stable, recombinant form of galectin-9 (sGal-9), which acts as a CD44 blockade, regulates the MIF-induced aggressive phenotype of RA-FLSs. We found that sGal-9 remarkably reduced the increased proliferation, migration, and invasion of RA-FLSs by inhibiting the MIF-CD44 pathway. Moreover, both local and systemic administration of sGal-9 substantially inhibited excessive cartilage and bone destruction by RA-FLSs in a xenotransplantation arthritis model and alleviated the severity of collagen-induced arthritis in mice, comparable to Enbrel and tofacitinib. Conclusively, these data suggest that sGal-9 is effective at repressing destructive phenotypes of RA-FLSs as a novel anti-MIF agent.
类风湿性关节炎（RA）的破坏潜力在于成纤维细胞样滑膜细胞（FLS）的侵袭性行为，这些细胞积极促成软骨和骨的侵蚀，甚至在明显的临床缓解期也可能持续存在。针对RA-FLSs的治疗方法已被开发用于治疗RA；然而，目前尚无临床批准的药物。在此，对RA-FLSs进行单细胞RNA测序，鉴定出一个具有线粒体和内质网功能障碍的独特巨噬细胞迁移抑制因子（MIF）亚群。MIF条件导致FLS的存活、增殖和迁移增加，同时CD44和CD44v6异构体表达上调。接下来，我们探讨作为CD44阻滞剂的稳定重组形式的半乳糖凝集素-9（sGal-9）是否调节MIF诱导的RA-FLSs侵袭性表型。我们发现，sGal-9通过抑制MIF-CD44途径显著降低了RA-FLSs增加的增殖、迁移和侵袭。此外，在异种移植性关节炎模型中，局部和全身给予sGal-9均能显著抑制RA-FLSs对软骨和骨的过度破坏，并减轻小鼠胶原诱导性关节炎的严重程度，与恩利和托法替布相当。总之，这些数据表明，sGal-9作为一种新型抗MIF药物，在抑制RA-FLSs的破坏表型方面是有效的。
