滑膜成纤维细胞ER o糖基化驱动软骨降解

IF 15.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Le Son Tran, Joanne Chia, Xavier Le Guezennec, Keit Min Tham, Anh Tuan Nguyen, Virginie Sandrin, Way Cherng Chen, Tan Tong Leng, Sreedharan Sechachalam, Khai Pang Leong, Frederic A. Bard
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引用次数: 0

摘要

关节炎滑膜成纤维细胞(SFs)如何激活软骨ECM降解尚不清楚。GALNT酶在高尔基体中启动o糖基化;当转移到内质网时,它们的活性刺激ECM降解。在这里,我们发现在人类类风湿和骨关节炎滑膜sf中,galnt被重新定位到ER。在类风湿性关节炎小鼠模型中,galnt的重新定位发生在关节炎症状出现前不久,并随着动物的恢复而减弱。一种ER GALNTs抑制剂在体外阻止软骨ECM降解,这种嵌合蛋白在sf中的表达导致软骨的保护。galnt的内质网靶点之一是钙连蛋白,它被输出到关节炎SFs的细胞表面。钙连蛋白通过降低ECM二硫键参与基质降解。抗钙连蛋白抗体阻断ECM降解,保护动物免受RA。综上所述,内质网o糖基化是关节炎SFs的关键开关,糖基化表面Calnexin可能是一个治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

ER O-glycosylation in synovial fibroblasts drives cartilage degradation

ER O-glycosylation in synovial fibroblasts drives cartilage degradation

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.

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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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