Alteration of telomere length and mtDNA copy number in interstitial lung disease associated with rheumatoid arthritis

Abstract

Interstitial lung disease (ILD) is a common extra-articular manifestation of rheumatoid arthritis (RA). The inflammatory response in lung disease is characterized by severe oxidative stress, which enhances cellular senescence. Telomeric shortening and mitochondria dysregulation represent two hallmarks of cellular senescence. The maintenance of telomere length (TL) and mitochondrial DNA (mtDNA) copy number is preserved by many proteins, such as TERF1 and TFAM, respectively. Our aim was to evaluate the TL, the mtDNA copy number and the expression of two regulator gene factors in RA patients with (RA-ILD) and without lung involvement (RA-NILD). Eighty-five RA patients and 21 healthy subjects were enrolled. Relative TL, mtDNA copy number, and expression analysis of TERF1 and TFAM genes were measured using qPCR assay. All RA patients present a statistically significant telomere shortening; in particular, RA-ILD patients show shorter TL compared to both controls and RA-NILD. Patients with Usual Interstitial Pneumonia pattern show a more evident shortening of TL. Lastly, both RA-ILD and RA-NILD patients present a significant decrease in mtDNA copy number compared to controls. The analysis of regulatory genes showed an increase in TERF1 expression in RA patients compared to controls, also after stratification in the two subgroups, and a decrease in TFAM expression in RA patients compared to controls. These results show that the alteration of TL and mtDNA copy number in RA patients is more evident in the presence of ILD. The hypothesis is that, in these patients, oxidative stress could accelerate the shortening of telomeres and the decrease of mtDNA copy number.

Keywords: Rheumatoid arthritis; gene expression; interstitial lung disease; mtDNA; telomere length.