scholarly journals The arthritis severity locusCia5dis a novel genetic regulator of the invasive properties of synovial fibroblasts

2008 ◽  
Vol 58 (8) ◽  
pp. 2296-2306 ◽  
Author(s):  
Teresina Laragione ◽  
Max Brenner ◽  
Adriana Mello ◽  
Marc Symons ◽  
Pércio S. Gulko
Keyword(s):  
Synovial Fibroblasts ◽  
Arthritis Severity ◽  
Genetic Regulator

The Role of Synovial Fibroblasts in Mediating Joint Destruction in Rheumatoid Arthritis

2005 ◽  
Vol 11 (5) ◽  
pp. 563-568 ◽  
Author(s):  
Ingmar Meinecke ◽  
Edita Rutkauskaite ◽  
Steffen Gay ◽  
Thomas Pap
Keyword(s):  
Rheumatoid Arthritis ◽  
Joint Destruction ◽  
Synovial Fibroblasts

FRI0020 BMP-2 and TGF-B Inhibit IL-34 Expression in Rheumatoid Arthritis Synovial Fibroblasts

2016 ◽  
Vol 75 (Suppl 2) ◽  
pp. 432.3-433
Author(s):  
M. Chemel-Mary ◽  
B. Legoff ◽  
Y. Maugars ◽  
D. Heymann ◽  
F. Verrechia
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fibroblasts

scholarly journals The activin-follistatin anti-inflammatory cycle is deregulated in synovial fibroblasts

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Magnus Diller ◽  
Klaus Frommer ◽  
Berno Dankbar ◽  
Ingo Tarner ◽  
Marie-Lisa Hülser ◽  
...  
Keyword(s):  
Synovial Fibroblasts ◽  
Anti Inflammatory

scholarly journals OP0036 IL-6 ACTIVATES YES-ASSOCIATED PROTEIN (YAP) IN FIBROBLASTS AND INDUCES YAP-SNAIL COMPLEX FORMATION TO DRIVE SYNOVIAL LINING PATHOLOGY IN INFLAMMATORY ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 19.1-19
Author(s):  
R. Symons ◽  
F. Colella ◽  
F. Collins ◽  
A. Roelofs ◽  
C. De Bari
Keyword(s):  
Transcription Factor ◽  
Complex Formation ◽  
Inflammatory Arthritis ◽  
Normal Mouse ◽  
Joint Destruction ◽  
Proximity Ligation Assay ◽  
Synovial Lining ◽  
Arthritis Severity ◽  
Marginal Erosions

Background:In rheumatoid arthritis (RA), the fibroblast-like synoviocytes (FLS) in synovial lining become invasive and cause joint destruction. The molecular mechanisms underpinning this pathogenic FLS phenotype are incompletely understood. The FLS descend from Growth differentiation factor 5 (Gdf5)-expressing joint interzone cells in the embryo, and we showed that conditional ablation of the transcriptional co-activator Yes associated protein (Yap) in Gdf5-lineage cells prevents synovial lining hyperplasia after traumatic cartilage injury in mice [1].Objectives:Here, we investigated a potential role for Yap in pathogenic FLS in immune-mediated inflammatory arthritis.Methods:Immunohistochemistry was used to detect Yap in human RA synovium and Yap, Snail and Ctgf in mouse synovium following antigen-induced arthritis (AIA). To determine the effect of Yap knockout (KO) in synovial stromal cells, AIA was induced in Gdf5-Cre;tdTomato;Yapfl/fl (Yap cKO) and Gdf5-Cre;tdTomato;Yapwt/wt (control) mice, or in Pdgfrα-CreER;Yapfl/fl (Yap ciKO, targeting Pdgfrα-expressing fibroblasts) and Yapfl/fl or YapWT/fl (control) mice after adult tamoxifen induction. Yap KO in both models was confirmed by immunohistochemistry. After nine days, arthritis severity was determined by histological scoring of synovial lining hyperplasia, immune infiltrates, cellular exudate, and marginal erosions. TdTomato+ Gdf5-lineage cells in synovium were quantified. In vitro, Yap reporter cells were treated with inflammatory cytokines to evaluate their ability to stimulate Yap-induced GFP expression by flow cytometry. Snail overexpression, siRNA-mediated Yap knockdown, and IL-6/sIL-6R stimulation were performed on normal mouse FLS, AIA-FLS or human RA-FLS, and cell invasion through a matrigel-coated transwell was quantified. A proximity ligation assay was utilised to detect Yap/Snail complex formation.Results:Average expression levels of Yap (p<0.0001), its transcription factor partner Snail (p=0.002), and their downstream target Ctgf (p=0.0003), were increased in mouse synovium after AIA (n=5), and Yap was highly expressed by FLS in human RA synovium. Yap cKO mice (n=24) showed a significantly decreased arthritis severity (p=0.002) after AIA compared to controls (n=22), with significant reductions in synovial lining hyperplasia (p<0.001), synovial immune cell infiltrates (p=0.026) and marginal erosions (p=0.002). Similarly, Yap ciKO mice (n=6) showed a significant decrease in arthritis score (p=0.039) after AIA compared to controls (n=9). However, both control mice (p<0.001) and Yap cKO mice (p<0.001) showed an extensive expansion of tdTomato+ Gdf5-lineage synovial cells after AIA, with no significant difference between control and Yap cKO mice. In vitro, Yap knockdown prevented IL-6/sIL-6R-induced invasion of normal mouse FLS (p=0.037) and decreased the invasiveness of AIA-FLS (p=0.0057). Using Yap reporter cells, we found that Yap was activated by IL-6/sIL-6R (p=0.016), but not TNFα or IL-1β. Finally, IL-6/sIL-6R treatment of normal mouse FLS (p=0.033) or human RA-FLS (p=0.036) induced Yap-Snail complex formation, and Yap knockdown prevented FLS invasion induced by Snail overexpression (p=0.027).Conclusion:These data demonstrate that via activation by IL-6, and co-operation with the transcription factor Snail, Yap acts as a key modulator of the invasive and destructive phenotype of FLS in inflammatory arthritis. Therapeutic targeting of Yap could reduce joint destruction in RA.References:[1]A. J. Roelofs et al., “Joint morphogenetic cells in the adult mammalian synovium,” Nat. Commun., vol. 8, no. May, p. 15040, 2017. DOI: 10.1136/annrheumdis-2018-213799Acknowledgements:This work was funded by the Medical Research Council (MR/L020211/1 and MR/L022893/1) and Versus Arthritis (20775 and 21156).Disclosure of Interests:None declared

Notch‐1 and Notch‐3 Mediates Hypoxia‐Induced Synovial Fibroblasts Activation in Rheumatoid Arthritis

2021 ◽  
Author(s):  
Jianhai Chen ◽  
Wenxiang Cheng ◽  
Jian Li ◽  
Yan Wang ◽  
Jingqin Chen ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fibroblasts ◽  
Notch 1 ◽  
Notch 3
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