MiR-145-5p mitigates dysregulated Wnt1/β-catenin signaling pathway in rheumatoid arthritis

Fibroblast-like synoviocytes (FLS) lining the arthritic synovial joint region have been implicated to be a key player in bone remodeling. The uncontrolled proliferation of this cell subtype is strictly regulated by various molecular elements including microRNAs (miRNAs). The Wnt1/beta-catenin signaling pathway plays a crucial role in the survival of FLS cells. This study explores the underlying mechanism of miR-145-5p towards the Wnt1/beta-catenin pathway. MiR-145-5p depicted a strong binding affinity towards frizzled class receptor 4 (FZD4) 3' UTR, a key receptor complex essential for recognizing circulating Wnt1 molecules. Adjuvant induced arthritic fibroblast-like synoviocytes (AA-FLS) isolated from rats stimulated with Wnt1 (10 ng/ml) elicited active Wnt1/beta-catenin signaling. Transfection of miR-145-5p mimic (50 pmol) to AA-FLS stimulated with Wntl elicited reduced expression levels of various factors of Wnt1/beta-catenin signaling including low-density lipoprotein receptor-related protein 5 (LRP5), dishevelled segment polarity protein 1 (Dvl1) and beta-catenin transcription factor. Moreover, pro-inflammatory cytokines (TNF alpha, IL-1 beta, IL-6 and IL-23) were regulated compared to the diseased groups. Furthermore, miR-145-5p counterbalanced the levels of receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) at the cellular level, essential for bone remodeling. Hence, we suggest that miR-145-5p regulates the survival/proliferation of FLS cells in RA disease condition through attenuation of Wnt1/beta-catenin signaling.