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Identifier 000425793
h
Title The interplay between mechanisms involving aging, rheumatoid arthritis and related comorbidities
Alternative Title H αλληλεπίδραση μεταξύ των μηχανισμών της γήρανσης, της ρευματοειδούς αρθρίτιδας και των σχετιζόμενων συννοσηροτήτων
Author Ντάρη, Λυδία
Thesis advisor Τσατσάνης, Χρήστος
Reviewer Γαρίνης, Γεώργιος
Σιδηρόπουλος, Πρόδρομος
Κόλλιας, Γεώργιος
Μπερτσιάς, Γεώργιος
Παπαδάκη, Ελένη
Κοχιαδάκης, Γεώργιος
Abstract Patients with rheumatoid arthritis and spondyloarthritis show higher mortality rates, mainly caused by cardiac comorbidities and premature aging of their immune system. The TghuTNF (Tg197) arthritis model develops tumor necrosis factor (TNF)-driven and mesenchymal synovial fibroblast (SF)-dependent polyarthritis. Here, we investigate whether this model develops, similarly to human patients, comorbid heart pathology and we explore the cellular and molecular mechanisms linking arthritis to cardiac comorbidities. We also investigate whether these pathologies are affected by premature aging which is caused by accumulation of DNA damage in the synovium and in the heart valve. For these reasons, we used the TghuTNF (Tg197) arthritis model, which overexpresses huTNF and develops chronic polyarthritis, as well as systemic or tissue-specific Ercc1 KO mice, which lack Ercc1 protein and develop a premature aging phenotype. Furthermore, synovial fibroblasts (SFs) and Valve interstitial cells (VICs) were targeted by mice carrying the ColVI-Cre transgene. Clinical and histopathological evaluation of arthritis features were performed in the above animals and echocardiographic evaluation of cardiac function was performed in the Tg197 model. In vitro analysis of cultured SFs and VICs was also performed to investigate possible similarities of these two mesenchymal cellular populations. Tnfr1fl/fl and Tnfr1cneo/cneo mutant mice were used to explore the role of mesenchymal TNF signaling in the development of heart valve disease. Pathogenic VICs and SFs were further analysed by comparative RNA-sequencing analysis. The pathology of Tg197 was not affected by either systemic loss of Ercc1 or mesenchymal-specific ablation of the protein. Similarly, the arthritogenic phenotype of SFs derived from these mice was not affected by the premature aging phenotype. Interestingly, mesenchymal-specific Ercc1 deletion caused muscle atrophy leading to reduced body weight of ColVI-Cre Ercc1fl/- mice compared to their littermates. It also ameliorated induced arthritis. Furthermore, Tg197 mice were found to develop left-sided heart valve disease, characterised by valvular fibrosis with minimal signs of inflammation. Thickened valve areas consisted almost entirely of hyperproliferative ColVI-expressing mesenchymal VICs. Development of pathology resulted in valve stenosis and left ventricular dysfunction, accompanied by arrhythmic episodes and, occasionally, valvular insufficiency. TNF dependency of the pathology was indicated by disease modulation following pharmacological inhibition or mesenchymal-specific genetic ablation or activation of TNF/TNFR1 signaling. 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. Interestingly, heart-valve pathology of Tg197 mice was completely abolished by systemic Ercc1 ablation, but not by mesenchymal-specific Ercc1 deletion. This has to be due to additional mechanisms which are beyond the scope of this study. In conclusion, comorbid heart valve disease and chronic polyarthritis are efficiently modelled in the Tg197 arthritis model and share common TNF/TNFR1-mediated, mesenchymal cell-specific aetiopathogenic mechanisms. Chronic polyarthritis was not affected by premature aging phenotype, suggesting that the mechanisms driving the pathology of Tg197 act independently of the DNA damage caused by Ercc1 deletion.
Language English
Subject ERCC1
Fibroblasts
Heart valve disease
Tumor necrosis factor (TNF)
Βαλβιδοπάθεια
Ινοβλάστες
Παράγοντας νέκρωσης όγκου
Issue date 2019-12-11
Collection   Faculty/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
Permanent Link https://elocus.lib.uoc.gr//dlib/4/0/5/metadata-dlib-1573125802-663457-28863.tkl Bookmark and Share
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