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. 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/β-catenin pathway. Activation of Wnt/β-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.

中文翻译：

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长链非编码 RNA HOTAIR 通过抑制 WIF-1 表达和激活 Wnt 通路促进骨关节炎中的软骨降解。


最近发现长非编码 RNA (lncRNA) 是表观基因组的关键调节因子。然而，我们对其在骨关节炎 (OA) 发展中的作用的了解有限。本研究探讨了 HOTAIR（一种在 OA 中表达升高的关键 lncRNA）影响 OA 疾病进展的机制。与正常软骨细胞相比，骨关节炎中的 HOTAIR 表达显着升高。 SW1353细胞中HOTAIR的沉默和过度表达分别减少和增加与OA软骨退化相关的基因的表达。分子通路研究表明，HOTAIR 通过增加 WIF-1 启动子中的组蛋白 H3K27 三甲基化直接作用于 Wnt 抑制因子 1 (WIF-1)，导致 WIF-1 抑制，有利于 Wnt/β-连环蛋白通路的激活。 HOTAIR 通过抑制骨关节炎软骨细胞中的 WIF-1 来激活 Wnt/β-catenin 信号传导，从而增加分解代谢基因的表达并促进软骨退化。这是第一项证明 HOTAIR、WIF-1 和 OA 进展之间直接联系的研究，这可能有助于未来对疾病生物标志物或治疗靶点的研究。