Suppression of circular RNA PTTG1 interacting protein (circPTTG1IP) decreases the progression of rheumatoid arthritis (RA) through the microRNA (MiRNA) miR-431-5p and follistatin-like 1 (FSTL1) glycoprotein signaling cascade within fibroblast-like synoviocytes (FLS), according to study results published in Transplant Immunology.
MiRNAs are short RNA molecules that regulate gene expression during translation or post-transcription and have been found to be involved in the progression of RA, possibly through interactions with FSTL1. Circular RNAs (CircRNAs) may also play a role in the pathogenesis of RA by absorbing MiRNAs. Previous studies have found enhanced expression circPTTG1IP in patients with RA.
Researchers sought to analyze the relationships between circPTTG1IP, miR-431-5p, and FSTL1 in the synovial tissues and FLS of patients with RA. They utilized reverse transcription-quantitative polymerase chain reaction and Western blot assays to measure RNA and protein expression. Cell proliferation was analyzed using colony formation and 5-Ethynyl-2’-deoxyuridine assays, cell motility was analyzed with transwell and wound healing assays, and cell apoptosis was analyzed using flow cytometry analysis. Dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA-pull down assays were performed to assess the interaction between miR-431-5p and circPTTG1IP or FSTL1.
Synovial specimens were obtained from 31 patients with RA and 31 healthy control participants. Expression of circPTTG1IP was markedly higher in the synovial tissues and FLS in patients with RA (RA-FLS) compared with healthy controls (HC-FLS). CircPTTG1IP negatively regulated miR-431-5p expression by directly binding to it in RA-FLS, indicating that circPTTG1IP serves as a molecular sponge for miR-431-5p.
Knockdown experiments showed that circPTTG1IP silencing suppressed the proliferation, migration, and invasion of RA-FLS and induced apoptosis. When the researchers added miR-431-5P, migration and invasion of RA-FLS was restored and apoptosis was attenuated. This suggested circPTTB1IP suppression up-regulated miR-431-5p.
FSTL1 was elevated in RA-FLS vs HC-FLS. Assays showed that miR-431-5p overexpression decreased FSTL1 and that miR-431-5p targets the 3’ untranslated region of FSTL1. Further, circPTTG1IP positively regulated FSTL1 expression by acting as a miR-431-5p sponge in RA-FLS.
The study authors conclude, “CircPTTG1IP promoted the proliferation, migration, and invasion and suppressed the apoptosis of RA-FLS by binding to miR-431-5p to up-regulate FSTL1 expression. CircPTTG1IP/miR-431-5p/FSTL1 axis might be a novel target for RA treatment.”
Yang C, Liu Q, Jiang Z. CircPTTG1IP knockdown suppresses rheumatoid arthritis progression by targeting miR-431-5p/FSTL1 axis. Transpl Immunol. Published online August 4, 2022. doi:10.1016/j.trim.2022.101685