Tran Le Son, Chia Joanne, Le Guezennec Xavier, Tham Keit Min, Nguyen Anh Tuan, Sandrin Virginie, Chen Way Cherng, Leng Tan Tong, Sechachalam Sreedharan, Leong Khai Pang, Bard Frederic A
Institute of Molecular and Cell Biology, Singapore, Singapore.
Albatroz Therapeutics Pte Ltd, Singapore, Singapore.
Nat Commun. 2025 Mar 14;16(1):2535. doi: 10.1038/s41467-025-57401-9.
How arthritic synovial fibroblasts (SFs) activate cartilage ECM degradation remains unclear. GALNT enzymes initiate O-glycosylation in the Golgi; when relocated to the ER, their activity stimulates ECM degradation. Here, we show that in human rheumatoid and osteoarthritic synovial SFs, GALNTs are relocated to the ER. In an RA mouse model, GALNTs relocation occurs shortly before arthritis symptoms and abates as the animal recovers. An ER GALNTs inhibitor prevents cartilage ECM degradation in vitro and expression of this chimeric protein in SFs results in the protection of cartilage. One of the ER targets of GALNTs is the resident protein Calnexin, which is exported to the cell surface of arthritic SFs. Calnexin participates in matrix degradation by reducing ECM disulfide bonds. Anti-Calnexin antibodies block ECM degradation and protect animals from RA. In sum, ER O-glycosylation is a key switch in arthritic SFs and glycosylated surface Calnexin could be a therapeutic target.
目前尚不清楚关节炎滑膜成纤维细胞（SFs）如何激活软骨细胞外基质（ECM）降解。GALNT酶在高尔基体中启动O-糖基化；当它们重新定位于内质网（ER）时，其活性会刺激ECM降解。在此，我们表明在人类类风湿性关节炎和骨关节炎滑膜SFs中，GALNTs会重新定位于内质网。在类风湿性关节炎（RA）小鼠模型中，GALNTs重新定位发生在关节炎症状出现前不久，并在动物恢复时减轻。内质网GALNTs抑制剂可在体外阻止软骨ECM降解，并且在SFs中表达这种嵌合蛋白可保护软骨。GALNTs在内质网的靶标之一是驻留蛋白钙联结蛋白，它会输出到关节炎SFs的细胞表面。钙联结蛋白通过减少ECM二硫键参与基质降解。抗钙联结蛋白抗体可阻断ECM降解并保护动物免受类风湿性关节炎的侵害。总之，内质网O-糖基化是关节炎SFs中的关键开关，糖基化的表面钙联结蛋白可能是一个治疗靶点。
