A long non-coding RNA, HOTAIR, promotes cartilage degradation in osteoarthritis by inhibiting WIF-1 expression and activating Wnt pathway

Background: Long noncoding RNAs (lncRNAs) are recently found to be critical regulators of the epigenome. However, our knowledge of their role in osteoarthritis (OA) development is limited. This study investigates the mechanism by which HOTAIR, a key lncRNA with elevated expression in OA, affects OA disease progression. Results: HOTAIR expression was greatly elevated in osteoarthritic compared to normal chondrocytes. Silencing and over-expression of HOTAIR in SW1353 cells respectively reduced and increased the expression of genes associated with cartilage degradation in OA. Investigation of molecular pathways revealed that HOTAIR acted directly on Wnt inhibitory factor 1 (WIF-1) by increasing histone H3K27 trimethylation in the WIF-1 promoter, leading to WIF-1 repression that favours activation of the Wnt/beta-catenin pathway. Conclusions: Activation of Wnt/beta-catenin signalling by HOTAIR through WIF-1 repression in osteoarthritic chondrocytes increases catabolic gene expression and promotes cartilage degradation. This is the first study to demonstrate a direct link between HOTAIR, WIF-1 and OA progression, which may be useful for future investigations into disease biomarkers or therapeutic targets.