Long non-coding RNA PVT1 knockdown suppresses fibroblast-like synoviocyte inflammation and induces apoptosis in rheumatoid arthritis through demethylation of sirt6

Abstract

Abstract Background As a type of chronic autoimmune joint disease, rheumatoid arthritis (RA) is a disorder, characterized by a variety of physical symptoms as well as RA fibroblast-like synoviocyte (RA-FLS) proliferation. More recently, long non-coding RNAs (lncRNAs) have been implicated in the progression of various diseases including the progression of RA. Hence, the aim of the current study was to investigate the role by which the lncRNA, plasmacytoma variant translocation 1 (PVT1), influences RA-FLSs and its ability to modulate the methylation of sirtuin 6 (sirt6). Methods RA rat models were initially established to determine the expression of PVT1 and sirt6 in synovial tissues and RA-FLSs. Elevation or depletion of PVT1 or sirt6 was achieved by means of transformation with plasmids in order to investigate their effects on RA-FLS proliferation, inflammation and apoptosis. The localization of PVT1 and its binding ability to the sirt6 promoter region were also explored in an attempt to elucidate the correlation between PVT1 and sirt6 methylation. Results High expression of PVT1 and low expression of sirt6 were detected in the synovial tissues and RA-FLSs of the rat models. RA-FLSs treated with sh-PVT1 or oe-sirt6 exhibited suppressed cell proliferation, inflammation and induced apoptosis. PVT1 was predominately localized in the nucleus while evidence was obtained indicating that it could bind to the sirt6 promoter to induce sirt6 methylation, thus inhibiting sirt6 transcription. PVT1 knockdown was observed to restore sirt6 expression through decreasing sirt6 methylation, thereby alleviating RA. Conclusion The key findings of the study provide evidence suggesting that, PVT1 knockdown is able to restrain RA progression by inhibiting sirt6 methylation to restore its expression.

Keywords

• Long non-coding RNA plasmacytoma variant translocation 1
• Sirtuin 6
• Rheumatoid arthritis
• Methylation
• Inflammation
• Apoptosis