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Targeting the IL-6–Yap–Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis
OBJECTIVE: We aimed to understand the role of the transcriptional co-factor Yes-associated protein (Yap) in the molecular pathway underpinning the pathogenic transformation of synovial fibroblasts (SF) in rheumatoid arthritis (RA) to become invasive and cause joint destruction. METHODS: Synovium fro...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8762018/ https://www.ncbi.nlm.nih.gov/pubmed/34844926 http://dx.doi.org/10.1136/annrheumdis-2021-220875 |
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author | Symons, Rebecca A Colella, Fabio Collins, Fraser L Rafipay, Alexandra J Kania, Karolina McClure, Jessica J White, Nathan Cunningham, Iain Ashraf, Sadaf Hay, Elizabeth Mackenzie, Kevin S Howard, Kenneth A Riemen, Anna H K Manzo, Antonio Clark, Susan M Roelofs, Anke J De Bari, Cosimo |
author_facet | Symons, Rebecca A Colella, Fabio Collins, Fraser L Rafipay, Alexandra J Kania, Karolina McClure, Jessica J White, Nathan Cunningham, Iain Ashraf, Sadaf Hay, Elizabeth Mackenzie, Kevin S Howard, Kenneth A Riemen, Anna H K Manzo, Antonio Clark, Susan M Roelofs, Anke J De Bari, Cosimo |
author_sort | Symons, Rebecca A |
collection | PubMed |
description | OBJECTIVE: We aimed to understand the role of the transcriptional co-factor Yes-associated protein (Yap) in the molecular pathway underpinning the pathogenic transformation of synovial fibroblasts (SF) in rheumatoid arthritis (RA) to become invasive and cause joint destruction. METHODS: Synovium from patients with RA and mice with antigen-induced arthritis (AIA) was analysed by immunostaining and qRT-PCR. SF were targeted using Pdgfrα-CreER and Gdf5-Cre mice, crossed with fluorescent reporters for cell tracing and Yap-flox mice for conditional Yap ablation. Fibroblast phenotypes were analysed by flow cytometry, and arthritis severity was assessed by histology. Yap activation was detected using Yap–Tead reporter cells and Yap–Snail interaction by proximity ligation assay. SF invasiveness was analysed using matrigel-coated transwells. RESULTS: Yap, its binding partner Snail and downstream target connective tissue growth factor were upregulated in hyperplastic human RA and in mouse AIA synovium, with Yap detected in SF but not macrophages. Lineage tracing showed polyclonal expansion of Pdgfrα-expressing SF during AIA, with predominant expansion of the Gdf5-lineage SF subpopulation descending from the embryonic joint interzone. Gdf5-lineage SF showed increased expression of Yap and adopted an erosive phenotype (podoplanin+Thy-1 cell surface antigen−), invading cartilage and bone. Conditional ablation of Yap in Gdf5-lineage cells or Pdgfrα-expressing fibroblasts ameliorated AIA. Interleukin (IL)-6, but not tumour necrosis factor alpha (TNF-α) or IL-1β, Jak-dependently activated Yap and induced Yap–Snail interaction. SF invasiveness induced by IL-6 stimulation or Snail overexpression was prevented by Yap knockdown, showing a critical role for Yap in SF transformation in RA. CONCLUSIONS: Our findings uncover the IL-6–Yap–Snail signalling axis in pathogenic SF in inflammatory arthritis. |
format | Online Article Text |
id | pubmed-8762018 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-87620182022-01-26 Targeting the IL-6–Yap–Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis Symons, Rebecca A Colella, Fabio Collins, Fraser L Rafipay, Alexandra J Kania, Karolina McClure, Jessica J White, Nathan Cunningham, Iain Ashraf, Sadaf Hay, Elizabeth Mackenzie, Kevin S Howard, Kenneth A Riemen, Anna H K Manzo, Antonio Clark, Susan M Roelofs, Anke J De Bari, Cosimo Ann Rheum Dis Inflammatory Arthritis OBJECTIVE: We aimed to understand the role of the transcriptional co-factor Yes-associated protein (Yap) in the molecular pathway underpinning the pathogenic transformation of synovial fibroblasts (SF) in rheumatoid arthritis (RA) to become invasive and cause joint destruction. METHODS: Synovium from patients with RA and mice with antigen-induced arthritis (AIA) was analysed by immunostaining and qRT-PCR. SF were targeted using Pdgfrα-CreER and Gdf5-Cre mice, crossed with fluorescent reporters for cell tracing and Yap-flox mice for conditional Yap ablation. Fibroblast phenotypes were analysed by flow cytometry, and arthritis severity was assessed by histology. Yap activation was detected using Yap–Tead reporter cells and Yap–Snail interaction by proximity ligation assay. SF invasiveness was analysed using matrigel-coated transwells. RESULTS: Yap, its binding partner Snail and downstream target connective tissue growth factor were upregulated in hyperplastic human RA and in mouse AIA synovium, with Yap detected in SF but not macrophages. Lineage tracing showed polyclonal expansion of Pdgfrα-expressing SF during AIA, with predominant expansion of the Gdf5-lineage SF subpopulation descending from the embryonic joint interzone. Gdf5-lineage SF showed increased expression of Yap and adopted an erosive phenotype (podoplanin+Thy-1 cell surface antigen−), invading cartilage and bone. Conditional ablation of Yap in Gdf5-lineage cells or Pdgfrα-expressing fibroblasts ameliorated AIA. Interleukin (IL)-6, but not tumour necrosis factor alpha (TNF-α) or IL-1β, Jak-dependently activated Yap and induced Yap–Snail interaction. SF invasiveness induced by IL-6 stimulation or Snail overexpression was prevented by Yap knockdown, showing a critical role for Yap in SF transformation in RA. CONCLUSIONS: Our findings uncover the IL-6–Yap–Snail signalling axis in pathogenic SF in inflammatory arthritis. BMJ Publishing Group 2022-02 2021-11-29 /pmc/articles/PMC8762018/ /pubmed/34844926 http://dx.doi.org/10.1136/annrheumdis-2021-220875 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Inflammatory Arthritis Symons, Rebecca A Colella, Fabio Collins, Fraser L Rafipay, Alexandra J Kania, Karolina McClure, Jessica J White, Nathan Cunningham, Iain Ashraf, Sadaf Hay, Elizabeth Mackenzie, Kevin S Howard, Kenneth A Riemen, Anna H K Manzo, Antonio Clark, Susan M Roelofs, Anke J De Bari, Cosimo Targeting the IL-6–Yap–Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis |
title | Targeting the IL-6–Yap–Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis |
title_full | Targeting the IL-6–Yap–Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis |
title_fullStr | Targeting the IL-6–Yap–Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis |
title_full_unstemmed | Targeting the IL-6–Yap–Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis |
title_short | Targeting the IL-6–Yap–Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis |
title_sort | targeting the il-6–yap–snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis |
topic | Inflammatory Arthritis |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8762018/ https://www.ncbi.nlm.nih.gov/pubmed/34844926 http://dx.doi.org/10.1136/annrheumdis-2021-220875 |
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