Background/Purpose: Osteoarthritis (OA) is a chronic degenerative joint disease in which multiple factors contribute to cartilage degradation. It is widely accepted that excess production of proinflammatory cytokine, interlukin-1β (IL-1β), is associated with in the initiation and progression of cartilage destruction. In OA cartilage, IL-1β-stimulated COX-2 expresssion strongly contributes to the inflammation and cartilage destruction via upregulating PGE2 production. The objective of this study was to address whether miR-558, one of IL-1β-responsive microRNAs, can control IL-1β-mediated induction of COX-2 and catabolic effects in human articular chondrocytes.

Methods: Total RNA was extracted from the cartilage tissues of normal and OA donors or cultured human articular chondrocytes. The expression of miR-558 was quantified by TaqMan assay. To investigate the repressive effect of miR-558 on COX-2 expression, human chondrocytes and chondrogenic SW1353 cells were transfected with mature miR-558 or their antisense inhibitor (anti-miR-558). The expression of COX-2 protein was determined by western blot anaysis and the involvement of miR-558 on IL-1β-induced catabolic effects was examined by western blot anaysis and ELISA. Direct interaction between miR-558 and the putative site in the 3’-UTR of COX-2 mRNA was validated by luciferase reporter assay.

Results: Normal human articular cartilages expressed miR-558, and this expression was significantly suppressed in OA cartilages. Stimulation with IL-1β caused a significant reduction of miR-558 expression in normal and OA chondrocytes. IL-1β-induced activation of MAPK and NF-κB decreased miR-558 expression and induced COX-2 expression in chondrocytes. The overexpression of miR-558 directly suppressed the luciferase activity of a reporter construct containing the 3’-UTR of human COX-2 mRNA and significantly inhibited IL-1β-induced upregulation of COX-2, while treatment with anti-miR-558 enhanced IL-1β-induced COX-2 expression and reporter activity in chondrocytes. Interestingly, IL-1β-induced activation of NF-κB and expression of MMP-1 and MMP-13 were significantly inhibited by miR-558 overexpression.

Conclusion: These findings demonstrated that cartilage homeostasis is modulated by an elaborate network of functional microRNAs such as miR-558 that directly targets COX-2 and regulates IL-1β-stimulated catabolic effects in human chondrocytes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/microrna-558-regulates-the-expression-of-cyclooxygenase-2-and-il-1beta-responses-in-human-articular-chondrocytes/