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Abstract
Objectives Patients with rheumatoid arthritis and spondyloarthritisshow higher mortality rates, mainly caused by cardiac comorbidities. The TghuTNF (Tg197) arthritis model develops tumour necrosis factor (TNF)-driven and mesenchymalsynovial fibroblast (SF)-dependent polyarthritis. Here, we investigate whether this model develops, similarly to human patients, comorbid heart pathology and explore cellular and molecular mechanisms linking arthritis to cardiac comorbidities.
Methods Histopathological analysis and echocardiographic evaluation of cardiac function were performed in the Tg197 model. Valve interstitial cells (VICs) were targeted by mice carrying the ColVI-Cretransgene. Tg197 ColVI-Cre Tnfr1 fl/fl and Tg197 ColVI-Cre Tnfr1 cneo/cneo mutant mice were used to explore the role of mesenchymal TNF signalling in the development of heart valve disease. Pathogenic VICs and SFs were further analysed by comparative RNA-sequencing analysis.
Results Tg197 mice develop left-sided heart valve disease, characterised by valvular fibrosis with minimal signs of inflammation. Thickened valve areas consist almost entirely of hyperproliferative ColVI-expressing mesenchymal VICs. Development of pathology results in valve stenosis and left ventricular dysfunction, accompanied by arrhythmic episodes and, occasionally, valvular regurgitation. TNF dependency of the pathology was indicated by disease modulation following pharmacological inhibition or mesenchymal-specific genetic ablation or activation of TNF/TNFR1 signalling. Tg197-derived VICs exhibited an activated phenotype ex vivo, reminiscent of the activated pathogenic phenotype of Tg197-derived SFs. Significant functional similarities between SFs and VICs were revealed by RNA-seq analysis, demonstrating common cellular mechanisms underlying TNF-mediated arthritides and cardiac comorbidities.
Conclusions Comorbidheart valve disease and chronic polyarthritis are efficiently modelled in the Tg197 arthritis model and share common TNF/TNFR1-mediated, mesenchymal cell-specific aetiopathogenic mechanisms.
- tnf-alpha
- cardiovascular disease
- fibroblasts
- rheumatoid arthritis
- spondyloarthritis
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Footnotes
LN and MS contributed equally.
Handling editor Josef S Smolen
Contributors GK, LN, MS, NK and MCD designed the study and interpreted the experimental results. LN, MS, PC and IM performed the experiments and data analysis. AP contributed to the data analysis. LN and MCD wrote the first draft of the manuscript and all authors were involved in critically revising its final preparation. All authors approved the final version to be published.
Funding This work has been funded by the IMI project BTCure (GA no. 115142-2), the Advanced ERC grant MCs-inTEST (340217), and a ’Research Project for Excellence IKY/Siemens' (GA no. 3288) to GK, an ’IKY fellowship of Excellence for postgraduate studies in Greece – Siemens program' to MS, the Operational Program “Competitiveness, Entrepreneurship and Innovation 2014-2020”, co-financed by Greece and the European Union (European Regional Development Fund) (MIS 5002562-KRIPIS II) as well the grant GA 31354 (CodeAge) FP7 -PEOPLE-2011-ITN to LN. The authors also wish to thank the InfrafrontierGR Infrastructure (co-funded by the ERDF and Greek NSRF 2007-2013) for providing mouse hosting and phenotyping facilities, including histopathology, flow cytometry and advanced microscopy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.