Cargando…

Receptor tyrosine kinase C-kit promotes a destructive phenotype of FLS in osteoarthritis via intracellular EMT signaling

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. Ho...

Descripción completa

Detalles Bibliográficos
Autores principales: Cao, Xu, Wu, Song, Wang, Xinxing, Huang, Junjie, Zhang, Wenxiu, Liang, Chi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10037859/
https://www.ncbi.nlm.nih.gov/pubmed/36959556
http://dx.doi.org/10.1186/s10020-023-00633-6
_version_ 1784911964611280896
author Cao, Xu
Wu, Song
Wang, Xinxing
Huang, Junjie
Zhang, Wenxiu
Liang, Chi
author_facet Cao, Xu
Wu, Song
Wang, Xinxing
Huang, Junjie
Zhang, Wenxiu
Liang, Chi
author_sort Cao, Xu
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-023-00633-6.
format Online
Article
Text
id pubmed-10037859
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-100378592023-03-25 Receptor tyrosine kinase C-kit promotes a destructive phenotype of FLS in osteoarthritis via intracellular EMT signaling Cao, Xu Wu, Song Wang, Xinxing Huang, Junjie Zhang, Wenxiu Liang, Chi Mol Med Research Article 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-023-00633-6. BioMed Central 2023-03-23 /pmc/articles/PMC10037859/ /pubmed/36959556 http://dx.doi.org/10.1186/s10020-023-00633-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Cao, Xu
Wu, Song
Wang, Xinxing
Huang, Junjie
Zhang, Wenxiu
Liang, Chi
Receptor tyrosine kinase C-kit promotes a destructive phenotype of FLS in osteoarthritis via intracellular EMT signaling
title Receptor tyrosine kinase C-kit promotes a destructive phenotype of FLS in osteoarthritis via intracellular EMT signaling
title_full Receptor tyrosine kinase C-kit promotes a destructive phenotype of FLS in osteoarthritis via intracellular EMT signaling
title_fullStr Receptor tyrosine kinase C-kit promotes a destructive phenotype of FLS in osteoarthritis via intracellular EMT signaling
title_full_unstemmed Receptor tyrosine kinase C-kit promotes a destructive phenotype of FLS in osteoarthritis via intracellular EMT signaling
title_short Receptor tyrosine kinase C-kit promotes a destructive phenotype of FLS in osteoarthritis via intracellular EMT signaling
title_sort receptor tyrosine kinase c-kit promotes a destructive phenotype of fls in osteoarthritis via intracellular emt signaling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10037859/
https://www.ncbi.nlm.nih.gov/pubmed/36959556
http://dx.doi.org/10.1186/s10020-023-00633-6
work_keys_str_mv AT caoxu receptortyrosinekinaseckitpromotesadestructivephenotypeofflsinosteoarthritisviaintracellularemtsignaling
AT wusong receptortyrosinekinaseckitpromotesadestructivephenotypeofflsinosteoarthritisviaintracellularemtsignaling
AT wangxinxing receptortyrosinekinaseckitpromotesadestructivephenotypeofflsinosteoarthritisviaintracellularemtsignaling
AT huangjunjie receptortyrosinekinaseckitpromotesadestructivephenotypeofflsinosteoarthritisviaintracellularemtsignaling
AT zhangwenxiu receptortyrosinekinaseckitpromotesadestructivephenotypeofflsinosteoarthritisviaintracellularemtsignaling
AT liangchi receptortyrosinekinaseckitpromotesadestructivephenotypeofflsinosteoarthritisviaintracellularemtsignaling