ER O-glycosylation in synovial fibroblasts drives cartilage degradation

Le Son Tran, Joanne Chia, Xavier Guezennec, Keit Min Tham, Anh Tuan Nguyen, Virginie Sandrin, Way Cherng Chen, Tan Tong Leng, Sreedharan Sechachalam, Khai Pang Leong and Frederic A. Bard ()
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Le Son Tran: Institute of Molecular and Cell Biology
Joanne Chia: Institute of Molecular and Cell Biology
Xavier Guezennec: Institute of Molecular and Cell Biology
Keit Min Tham: Institute of Molecular and Cell Biology
Anh Tuan Nguyen: Institute of Molecular and Cell Biology
Virginie Sandrin: Roche Pharma Research & Early Development, Innovation Center Basel
Way Cherng Chen: Singapore Bioimaging Consortium
Tan Tong Leng: Tan Tock Seng Hospital
Sreedharan Sechachalam: Tan Tock Seng Hospital
Khai Pang Leong: Tan Tock Seng Hospital
Frederic A. Bard: Institute of Molecular and Cell Biology

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57401-9

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