| Autor: |
Xu Cao, Song Wu, Xinxing Wang, Junjie Huang, Wenxiu Zhang, Chi Liang |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
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| Zdroj: |
Molecular Medicine, Vol 29, Iss 1, Pp 1-13 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
1528-3658 |
| DOI: |
10.1186/s10020-023-00633-6 |
| Popis: |
Abstract Background Chronic inflammation, mainly derived from fibroblast-like synoviocytes (FLSs), plays a central role in the pathomechanism of osteoarthritis (OA). Recently, epithelial-mesenchymal transition (EMT) signaling was found to be activated in OA-derived FLSs with a pro-inflammatory phenotype. However, the role of EMT signaling in regulating FLS function and OA-related inflammation remains unknown. Methods The synovium of OA patients were evaluated for EMT and inflammation markers. The FLSs with activated EMT signaling were co-cultured with chondrocytes (chond). Gene expression of OA synovial samples were analyzed. The role of receptor tyrosine kinase C-kit was investigated in OA-FLSs and an OA rat model. The downstream pathways driven by C-kit were explored in OA-FLSs. Results EMT marker N-cadherin (N-CDH) was upregulated in 40.0% of the OA samples. These N-CDH + OA samples showed higher expression of pro-inflammatory factors. In co-culture, FLSs derived from N-CDH + OA samples induced a typical degenerative phenotype of chonds and stimulated their production of matrix degrading enzymes. C-kit was significantly upregulated and spatially co-localized with N-CDH in N-CDH + OA samples. In OA-FLSs, C-kit activated intracellular EMT signaling and induced destructive features of OA-FLSs. In OA rat model, C-kit largely promoted synovial inflammation and cartilage destruction, whereas knocking-down C-kit significantly restored the health of OA joints. Using GSK3β S9A mutant, we demonstrated that C-kit drives EMT signaling in OA-FLS by promoting phosphorylation of GSK3β and nuclear retention of the EMT transcription factor Snail. Conclusion C-kit drives EMT signaling in OA-FLSs and promotes a destructive FLS phenotype, leading to synovial inflammation and cartilage destruction. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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