ER O-glycosylation in synovial fibroblasts drives cartilage degradation
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, GALN...
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| Language: | English |
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57401-9 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Le Son Tran |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-013b1bb1e459422a8c54c0e8e5f2f2ee |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-013b1bb1e459422a8c54c0e8e5f2f2ee2025-08-20T02:20:05ZengNature PortfolioNature Communications2041-17232025-03-0116111410.1038/s41467-025-57401-9ER O-glycosylation in synovial fibroblasts drives cartilage degradationLe Son Tran0Joanne Chia1Xavier Le Guezennec2Keit Min Tham3Anh Tuan Nguyen4Virginie Sandrin5Way Cherng Chen6Tan Tong Leng7Sreedharan Sechachalam8Khai Pang Leong9Frederic A. Bard10Institute of Molecular and Cell BiologyInstitute of Molecular and Cell BiologyInstitute of Molecular and Cell BiologyInstitute of Molecular and Cell BiologyInstitute of Molecular and Cell BiologyRoche Pharma Research & Early Development, Innovation Center BaselSingapore Bioimaging ConsortiumDepartment of Orthopaedic Surgery, Tan Tock Seng HospitalDepartment of Hand and Reconstructive Microsurgery, Tan Tock Seng HospitalDepartment of Rheumatology, Allergy & Immunology, Tan Tock Seng HospitalInstitute of Molecular and Cell BiologyAbstract 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.https://doi.org/10.1038/s41467-025-57401-9 |
| spellingShingle | 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 ER O-glycosylation in synovial fibroblasts drives cartilage degradation Nature Communications |
| title | ER O-glycosylation in synovial fibroblasts drives cartilage degradation |
| title_full | ER O-glycosylation in synovial fibroblasts drives cartilage degradation |
| title_fullStr | ER O-glycosylation in synovial fibroblasts drives cartilage degradation |
| title_full_unstemmed | ER O-glycosylation in synovial fibroblasts drives cartilage degradation |
| title_short | ER O-glycosylation in synovial fibroblasts drives cartilage degradation |
| title_sort | er o glycosylation in synovial fibroblasts drives cartilage degradation |
| url | https://doi.org/10.1038/s41467-025-57401-9 |
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