Targeting the IL-6-Yap-Snail signalling axis in synovial fibroblasts ameliorates inflammatory arthritis

Rebecca A. Symons, Fabio Colella, Fraser L. Collins, Alexandra J. Rafipay, Karolina Kania, Jessica J. McClure, Nathan White, Iain Cunningham, Sadaf Ashraf, Elizabeth Hay, Kevin S. Mackenzie, Kenneth A. Howard, Anna H. K. Riemen, Antonio Manzo, Susan M. Clark, Anke J. Roelofs, Cosimo De Bari*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)
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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 Pdgfr alpha-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 Pdgfr alpha-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 Pdgfr alpha-expressing fibroblasts ameliorated AIA. Interleukin (IL)-6, but not tumour necrosis factor alpha (TNF-alpha) or IL-1 beta, 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.

Original languageEnglish
Pages (from-to)214-224
Number of pages11
JournalAnnals of the Rheumatic Diseases
Issue number2
Early online date29 Nov 2021
Publication statusPublished - Feb 2022

Bibliographical note

The authors thank staff at the University of Aberdeen’s Animal Facility, Microscopy and Histology Facility, qPCR Facility, and the Iain Fraser Cytometry Centre for their expert support. The authors also thank the NHS Grampian Biorepository for facilitating the collection of human tissue samples.
Additionally, thanks is given to Denis Evseenko for critical review of the manuscript.
This work was supported by funding from the Medical Research Council (grants MR/L020211/1, MR/L022893/1), Versus Arthritis (formerly Arthritis Research UK, grants 20775, 19429, 21156, 20050, 19667, 20865, 21800), Tenovus Scotland (grant G13/14), and European Union’s Horizon 2020 research
and innovation programme under Marie Sklodowska Curie (Grant 642414).


  • arthritis
  • experimental
  • rheumatoid
  • fibroblasts
  • inflammation
  • SIZE
  • Humans
  • Signal Transduction/physiology
  • Fibroblasts/metabolism
  • Synovial Membrane/metabolism
  • Cells, Cultured
  • Snail Family Transcription Factors/metabolism
  • YAP-Signaling Proteins/metabolism
  • Arthritis, Experimental/pathology
  • Animals
  • Interleukin-6/metabolism
  • Mice
  • Arthritis, Rheumatoid/metabolism


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