circFADS2 protects LPS-treated chondrocytes from apoptosis acting as an interceptor of miR-498/mTOR cross-talking

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Abstract
We aimed to investigate the regulation of circular RNAs in lipopolysaccharide (LPS)-treated chondrocytes isolated from SD rat. In this study, we analyzed how circFADS2 was regulated in LPS-treated chondrocytes and isolates from Rheumatoid arthritis (RA) patients and found that circFADS2 and mTOR were highly expressed whereas miR-498 expression was significantly reduced. We then silenced circFADS2 in LPS-treated chondrocytes; this resulted in a declined expression of type II collagen, but an increase in the expression of MMP-13, COX-2, and IL-6. Overall, silencing circFADS2 caused a significant reduction in the proliferative rate of LPS-treated chondrocytes, increased apoptotic levels, miR-498 upregulation, and mTOR downregulation. Dual-luciferase reporter assay indicated that circFADS2 directly targeted miR-498. In contrast, miR-498 down-regulation affected circFADS2 silencing, promoting extracellular matrix (ECM) degradation and apoptosis. The 3' UTR of the mTOR gene is targeted by miR-498, and consequently, in cells transfected with miR-498, there was a significant reduction of mTOR expression at the protein and mRNA levels. Silencing mTOR had a similar effect to circFADS2 silencing on type II collagen, MMP-13, COX-2, and IL-6 expression, as well as cell proliferation and apoptosis. In conclusion, circFADS2 may affect LPS-induced chondrocytes properties by regulating the ECM catabolism, inflammation, and apoptosis in chondrocytes.

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