The proinflammatory cytokine interleukin-1β (IL-1β) is involved in the initiation and progression of osteoarthritis (OA) by stimulating the expression of matrix-degrading proteinases, such as a disintegrin metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), a key player in OA pathogenesis. However, how IL-1β induces ADAMTS-5 overexpression is poorly understood. We demonstrate that IL-1β regulates ADAMTS-5 expression by suppressing microRNA-30a (miR-30a). Bioinformatics was performed to predict miRNAs targeting ADAMTS-5. miR-30a inhibited ADAMTS-5 expression by directly targeting its 3'-untranslated region. miR-30a expression was downregulated in OA patients and was negatively correlated with ADAMTS-5 expression and positively correlated with Hospital for Special Surgery (HSS) scores. IL-1β suppressed miR-30a expression by recruiting the activator protein (AP-1) transcription factor c-jun/c-fos to the miR-30a promoter. IL-1β-induced c-jun/c-fos expression regulated ADAMTS-5 expression and cartilage matrix degradation via miR-30a in human chondrocytes. These data indicate that the IL-1β/AP-1/miR-30a/ADAMTS-5 pathway contributes to IL-1β-induced cartilage matrix degradation in human OA chondrocytes. miR-30a may act as a pivotal regulator of cartilage homeostasis and a potential diagnostic and therapeutic target for OA.
Key messages: ADAMTS-5 was identified as a novel direct target of miR-30a. IL-1β suppresses miR-30a expression through activation of AP-1 (c-jun/c-fos). AP-1/miR-30a is essential for IL-1β-induced ADAMTS-5 upregulation in OA. Downregulation of miR-30a in OA is negatively correlated with ADAMTS-5 expression.
Keywords: ADAMTS-5; AP-1; IL-1β; Osteoarthritis; miR-30a.