miR-548aj-3p and miR-3127-3p suppress RANKL-facilitated inflammatory cytokines and catabolic factor in osteoarthritis and rheumatoid arthritis.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are highly prevalent joint diseases globally. The common pathological features include synovial inflammation, swelling, joint destruction, and bone remodeling. Arthritis development is associated with joint inflammation, particularly in inflamed synovial cells. Synovial inflammation contributes to joint destruction. The receptor activator of nuclear factor kappa-B ligand (RANKL) is a vital factor that is linked to the activity of osteoclasts and the erosion of bone. Increased levels of RANKL play a role in the course of arthritis. Adverse effects and individual differences in therapeutic efficacy are limits of arthritis medications. More effective treatment and drug options are needed to improve disease progression. miRNAs directly modulate gene transcription as a potential option for arthritis therapeutics. The GEO dataset from the synovium of normal, OA, and RA patients indicated that the expression levels of RANKL were upregulated and related to arthritis features. We found that RANKL stimulation in OA and RA synovial fibroblasts decreased miR-548aj-3p and miR-3127-3p expression and enhanced interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and matrix metalloproteinase-13 (MMP-13) production by using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). miRNA sequencing analysis and target prediction tools identified that miR-548aj-3p and miR-3127-3p regulate IL-1β, IL-6, and MMP-13 expression and are inhibited by RANKL stimulation. Administration of miR-548aj-3p and miR-3127-3p mimics significantly inhibited RANKL-induced expression of IL-1β, IL-6, and MMP-13 at both the mRNA and protein levels. We propose a potentially efficacious miRNA therapeutic approach for the treatment of arthritis, with a specific focus on OA and RA.