Mesenchymal Stem Cell-Originated Exosomal Circular RNA circFBXW7 Attenuates Cell Proliferation, Migration and Inflammation of Fibroblast-Like Synoviocytes by Targeting miR-216a-3p/HDAC4 in Rheumatoid Arthritis

J Inflamm Res. 2021 Nov 24;14:6157-6171. doi: 10.2147/JIR.S336099. eCollection 2021.

Abstract

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease of articular joint damage and elevated synovial hyperplasia. Abnormal proliferation, invasion inflammatory response of rheumatoid fibroblast-like synoviocytes (RA-FLS) play a critical role in RA progression. Mesenchymal stem cell (MSC)-derived exosomal circular RNAs are promising therapeutic manner for disease treatment. This work aimed to decipher the role of exosomal circFBXW7 in RA.

Methods: The expression of circFBXW7, miR-216a-3p, and HDAC4 were detected in clinical RA samples. The RA rat model was established. Isolation and identification of exosomes from MSCs was conducted. The effects of exosomal circFBXW7 on RA was evaluated by qPCR, CCK-8, transwell assays, flow cytometry, Western blotting, ELISA, and immunohistochemical assay. Interaction between miR-216a-3p and circFBXW7 or HDAC4 was determined by luciferase reporter gene assay and RNA pulldown.

Results: Exosomal circFBXW7 treatment suppressed proliferation, migration and inflammatory response of RA-FLSs and damage of RA model. CircFBXW7 could directly sponge miR-216a-3p to upregulate the expression of HDAC4. Inhibition of HDAC4 or upregulation of miR-216a-3p abolished the therapeutic function of exosomal circFBXW7. Our data demonstrated that circFBXW7 and HDAC4 were decreased, and miR-216a-3p was elevated in clinical RA sample compared with healthy samples.

Conclusion: We concluded that MSC-derived exosomal circFBXW7 suppressed proliferation, migration and inflammatory response of RA-FLSs and damage of RA rats via sponging miR-216a-3p and release the activation of HDAC4. These findings may provide a novel therapeutic target for RA.

Keywords: HDAC4; circFBXW7; fibroblast-like synoviocytes; mesenchymal stem cell; miR-216a-3p; rheumatoid arthritis.