Abstract
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.
Funder
National Natural Science Foundation of China
Science and Technology Innovation Leading Plan of High-Tech Industry in Hunan Province
Medical Research Development Fund Project
Youth Fund Project of Natural Science Foundation of Hunan Province
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine