Abstract
BackgroundLong 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.ResultsHOTAIR 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.ConclusionsActivation 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.
Highlights
Long noncoding RNAs are recently found to be critical regulators of the epigenome
Effect of HOX antisense intergenic RNA (HOTAIR) inhibition and over-expression on gene expression in SW1353 cells When HOTAIR function was inhibited in SW1353 cells by small interfering RNA (siRNA)-mediated knockdown of HOTAIR, the Messenger RNA (mRNA) expression of HOTAIR was significantly reduced in these cells (Fig. 2a, left)
This was accompanied by gene expression changes opposite to those observed for HOTAIR inhibition, that is, significant increase in the expression of Matrix metalloproteinase (MMP)-13, ADAMTS5 and BMP-2, as well as significant decrease in the expression of TIMP3, ACAN and SOX9 (Fig. 2b, right)
Summary
Long noncoding RNAs (lncRNAs) are recently found to be critical regulators of the epigenome. There are two major groups of noncoding RNAs based on their length, short noncoding RNAs and long noncoding RNAs. MicroRNAs are the most commonly studied short noncoding RNAs with a range of roles in affecting cell fate and disease pathophysiology [6]. The role of long noncoding RNAs (lncRNAs) as critical regulators of biological processes, and their effects on tissue development and disease has only begun to emerge within the last decade. LncRNAs are known to be differentially expressed in many human diseases including metabolic, cardiovascular, neurodegenerative and psychiatric diseases [8], as well as cancer [9]. To date, limited studies have revealed the regulatory roles of specific lncRNAs in OA, including GAS5 [15], lncRNA-CIR [16], and H19 [17] as the top candidates
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