miR‐144‐3p ameliorates the progression of osteoarthritis by targeting IL‐1β: Potential therapeutic implications

Abstract

The pro‐inflammatory cytokine interleukin 1 beta (IL‐1β) plays a critical role in osteoarthritis (OA) disease pathogenesis. MicroRNA (miRNA) activity is related to inflammation in OA and some miRNAs specifically regulate IL‐mediated degradation of cartilage type II collagen. Previous studies have indicated that miR‐144‐3p is a useful target in the regulation of pro‐inflammatory cytokines in different diseases. However, the role of miR‐144‐3p in OA is unclear. In this study, we observed a negative correlation between miR‐144‐3p and IL‐1β expression in OA. miR‐144‐3p mimic transfection of OA synovial fibroblasts downregulated levels of IL‐1β expression, while blocking the MAPK, PI3K/Akt, and NF‐κB signaling pathways relating to IL‐1β production, and effectively increased miR‐144‐3p expression in OASFs. Findings from an anterior cruciate ligament transection rat model revealed that administration of miR‐144‐3p mimic effectively ameliorated OA progression and reduced the numbers of IL‐1β‐positive cells in synovial tissue. This study suggests that miR‐144‐3p is a useful therapeutic target in OA disease.

Nesfatin-1 facilitates IL-1β production in osteoarthritis synovial fibroblasts by suppressing miR-204-5p synthesis through the AP-1 and NF-κB pathways

“…Western blot and ELISA assays revealed that nesfatin-1 increased cellular and secreted IL-1β protein expression ( Figure 2B – 2D ). The PI3K and Akt signaling cascade mediates IL-1β expression during the progression of arthritis [ 25 ]. Treating OASFs with either a PI3K inhibitor (Ly294002) or an Akt inhibitor (Akti) markedly antagonized nesfatin-1-induced IL-1β synthesis ( Figure 3A and 3C ).…”

“…The mediation of IL-1β synthesis by miRNAs is crucial in the progression of OA [ 25 ]. Our search of online databases for miRNA target prediction data suggested that the three prime untranslated region (3′-UTR) of IL-1β mRNA includes 19 promising candidate miRNAs ( Figure 5A and 5B ).…”

“…PI3K/Akt activation is crucial in the adjustment of numerous cellular roles [ 43 ]. Notably, the PI3K/Akt signaling cascade mediates IL-1β expression during the progression of arthritis disease [ 25 , 44 , 45 ]. Our data show that nesfatin-1 promotes the phosphorylation of PI3K and Akt, while their respective inhibitors inhibit nesfatin-1-induced IL-1β production in human OASFs.…”

“…Numerous transcription factor binding elements have been reported in the promoter site of IL-1β [ 46 , 47 ]. In particular, AP-1 and NF-κB mediate IL-1β transcription and inflammatory responses [ 25 , 46 ]. We found that inhibitors of AP-1 (tanshinone IIA) and NF-κB (PDTC and TPCK) suppressed nesfatin-1-induced production of IL-1β in human OASFs.…”

“…As the progression of OA is regulated by numerous microRNAs (miRs), modulating miRNA-mediated proinflammatory cytokine expression represents one therapeutic strategy for OA [ 20 – 23 ]. We have previously described how several miRNAs (including miR-let-7c-5p, miR-149-5p and miR-144-5p) inhibit the progression of OA disease [ 24 , 25 ]. Similarly, other research has shown that the targeting of runt-related transcription factor 2 (Runx2) by miR-204-5p downregulates chondrocyte proliferation and ameliorates the OA development in rats [ 26 ].…”