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MicroRNA-15a/16/SOX5 axis promotes migration, invasion and inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes.

ABSTRACT: Fibroblast-like synoviocytes (FLSs) are key effector cells in the pathogenesis of rheumatoid arthritis (RA) and display a unique aggressive tumor-like phenotype with remarkable hyperplasia, increased cell migration and invasion. How FLSs undergo these changes in RA remains unknown. We previously reported a novel function of transcription factor SOX5 in RA-FLSs that promote cell migration and invasion. In this study, we found that miR-15a/16 directly targets the SOX5 3'UTR and suppresses SOX5 expression. Moreover, miR-15a/16 is significantly down-regulated in RA-FLSs, which negatively correlates with SOX5 expression. Transfection with miR-15a/16 mimics in RA-FLSs inhibits cell migration, invasion, IL-1β and TNFα expression. Overexpression SOX5 in RA-FLSs decreases miR-15a/16 expression and rescues miR-15a/16-mediated inhibitory effect. Furthermore, RA patients with the lower baseline serum miR-15a/16 level present poor response of 3 months disease-modifying antirheumatic drugs (DMARDs) therapy. Collectively, this study reveals that miR-15a/16/SOX5 axis functions as a key driver of RA-FLSs invasion, migration and inflammatory response in a mutual negative feedback loop and correlates with DMARDs treatment response in RA.

SUBMITTER: Wei H

PROVIDER: S-EPMC7425471 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionAnti-malarial drug artesunate can suppress inflammation and prevent cartilage and bone destruction in collagen-induced arthritis model in rats-suggesting it may be a potent drug for rheumatoid arthritis (RA) therapy. We aimed to investigate its effect on the invasive property of fibroblast-like synoviocytes (FLS) from patients with RA.MethodsSynovial tissues were obtained by closed needle biopsy from active RA patients, and FLS were isolated and cultured in vitro. RA-FLS were treated with artesunate at various concentrations, while methotrexate or hydroxychloroquine was employed as comparator drugs. Cell viability, proliferation, cell cycle, apoptosis, migration, invasion, and pseudopodium formation of RA-FLS were assessed by CCK-8 assays, EdU staining, Annexin V-FITC/PI staining, transwell assays, or F-actin staining, respectively. Further, relative changes of expressed proteases were analyzed by Proteome profiler human protease array and verified by quantitative real-time PCR (qPCR), Western blot, and ELISA. The expression of signaling molecules of MAPK, NF-κB, AP-1, and PI3K/Akt pathways were measured by qPCR and Western blot. PDK-1 knockdown by specific inhibitor AR-12 or siRNA transfection was used to verify the pharmacological mechanism of artesunate on RA-FLS.ResultsArtesunate significantly inhibited the migration and invasion of RA-FLS in a dose-dependent manner with or without TNF-α stimulation. The effect was mediated through artesunate inhibition of MMP-2 and MMP-9 production, and pre-treatment with exogenous MMP-9 reversed the inhibitory effect of artesunate on RA-FLS invasion. Artesunate had a stronger inhibitory effect on migration and invasion of RA-FLS as well as greater anti-inflammatory effect than those of hydroxychloroquine. Similar inhibitory effect was detected between artesunate and methotrexate, and synergy was observed when combined. Mechanistically, artesunate significantly inhibited PDK-1 expression as well as Akt and RSK2 phosphorylation-in a similar manner to PDK-1-specific inhibitor AR-12 or PDK-1 knockdown by siRNA transfection. This inhibition results in suppression of RA-FLS migration and invasion as well as decreased MMP-2 and MMP-9 expression.ConclusionsOur study demonstrates artesunate is capable of inhibiting migration and invasion of RA-FLS through suppression of PDK1-induced activation of Akt and RSK2 phosphorylation-suggesting that artesunate may be a potential disease-modifying anti-rheumatic drug for RA.

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MicroRNA-15a/16/SOX5 axis promotes migration, invasion and inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes.

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