Comorbid TNF-mediated heart valve disease and chronic polyarthritis share common mesenchymal cell-mediated aetiopathogenesis

Abstract

ObjectivesPatients 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.MethodsHistopathological 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.ResultsTg197 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.ConclusionsComorbidheart valve disease and chronic polyarthritis are efficiently modelled in the Tg197 arthritis model and share common TNF/TNFR1-mediated, mesenchymal cell-specific aetiopathogenic mechanisms.

Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis

“…By examining intestine, eyes and skin tissue during disease progression we did not observe any signs of pathology. However, we demonstrated with functional and immunohistochemical data a comorbid left-sided heart valve pathology con rming and expanding previous ndings (21). More speci cally, we observed that at 40 weeks of age, TgA86 mice displayed aortic valve thickening, consisting mainly of vimentin-positive mesenchymal cells and sparse Gr1-positive neutrophils (Additional le 1; Figure S2a, b).…”

Selective Sexual Dimorphisms in Musculoskeletal and Cardiopulmonary Pathologic Manifestations and Mortality Incidence in the Tumor Necrosis Factor–Transgenic Mouse Model of Rheumatoid Arthritis

“…Recently, Ntari et al described a strictly cardiovascular disease in the Tg197 line of TNF‐Tg mice , which is a murine model of more aggressive disease than that seen in the Tg3647 TNF‐Tg mouse line described herein. In the Tg197 mouse line, Ntari and colleagues found left‐sided aortic and mitral valve thickening and significant fibrosis, with no evidence of lung inflammation or right‐sided heart disease.…”

Prevalence of comorbidities and risk factors in spondyloarthritis: results of a cross-sectional study

“…[4][5][6] However, as for heart comorbidities, valvular heart disease was not mentioned in the ASAS-COMOSPA study, while it has been reported to be associated with SpA in a number of recent studies, based both on epidemiology and pathology. [7][8][9] As for risk factors for cardiovascular diseases, hyperuricaemia was not included as well, while uric acid has also been proven to be related to cardiovascular disease in the recent years. [10][11][12][13] Since there are still some comorbidities and risk factors to be evaluated, we proposed a research to include valvular heart disease as a comorbidity of SpA and hyperuricaemia as a risk factor of cardiovascular disease among patients with SpA.…”