Hsa-miR-21-5p is induced by interleukin-6 and affects multiple pathogenic factors associated with fibroblast-like synoviocytes in rheumatoid arthritis

• Published in: Scientific reports Vol. 15; no. 1; pp. 19416 - 15
• Main Authors: Araki, Kei, Mokuda, Sho, Kohno, Hiroki, Oka, Naoya, Watanabe, Hirofumi, Ishitoku, Michinori, Sugimoto, Tomohiro, Yoshida, Yusuke, Masumoto, Junya, Hirata, Shintaro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.06.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 692/4017; 692/699/1670/498; Apoptosis; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Cell death; Cell proliferation; Cells, Cultured; Female; Fibroblast-like synoviocytes; Fibroblasts; Fibroblasts - metabolism; Fibroblasts - pathology; Gene expression; Gene Expression Regulation; hsa-miR-21-5p; Humanities and Social Sciences; Humans; Interleukin 6; Interleukin-6 - metabolism; Interleukin-6 - pharmacology; Male; microRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; multidisciplinary; Next-generation sequencing; Osteoprotegerin; Pathogenesis; Post-transcription; Rheumatoid arthritis; Rheumatoid synovitis; Science; Science (multidisciplinary); Synoviocytes; Synoviocytes - metabolism; Synoviocytes - pathology; Synovitis; Therapeutic targets; microRNA; Fibroblast-like synoviocytes; Next-generation sequencing; hsa-miR-21-5p; Rheumatoid arthritis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-025-02840-z

Fibroblast-like synoviocytes (FLS) contribute significantly to the pathogenesis of rheumatoid arthritis (RA), particularly through their roles in synovitis and joint destruction. The microRNAs (miRNAs) are short non-coding RNA that regulate gene expression post-transcriptionally. Although more than 2000 human miRNAs are registered, comprehensive analyses of miRNA expression in FLS are limited. Herein, we investigated the relationship between miRNAs and FLS. Next-generation sequencing (small RNA-seq) was performed on primary cultured FLS derived from patients with RA to analyze the mature miRNA expression pattern. To assess inflammation-induced changes in miRNA levels, FLS were cultured with cytokines and evaluated by RT-qPCR. MiRNA mimics were transfected into FLS and an immortalized synovial fibroblast cell line (MH7A cells), and validated using conventional RNA-seq. Out of 2861 mature miRNAs, 297 mature miRNAs were detected and intronic miRNAs were predominated. Notably, hsa-miR-21-5p was abundantly expressed and its expression was enhanced by IL-6 stimulation. The induction of miR-21-5p mimic decreased the expression of Programmed Cell Death 4 (PDCD4) and Osteoprotegerin (OPG), while upregulating Semaphorin 5A (SEMA5A). MiR-21-5p mimic led to enhanced cell proliferation. These data suggest that hsa-miR-21-5p in FLS may exacerbate the pathophysiology of rheumatoid synovitis by promoting FLS proliferation, highlighting its potential as a therapeutic target in RA.