Abstract
Accumulating evidence indicated that inhibiting the expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 ameliorate cartilage degradation, suggesting ADAMTS-5 as an effective target for treating osteoarthritis (OA). A recent study has identified long noncoding RNA (lncRNA) HOTAIR and ADAMTS-5 as the most up-regulated lncRNA and the most upregulated gene, respectively, in human OA cartilage compared with normal cartilage. In the present study, we explored the regulatory effect of HOTAIR on the expression of ADAMTS-5 as well as the underlying mechanisms in human normal and OA articular chondrocytes. We found that human OA articular chondrocytes had significantly higher basal expression levels of HOTAIR and ADAMTS-5 than normal articular chondrocytes. Tumor necrosis factor (TNF)-α significantly enhanced the basal expression of HOTAIR and ADAMTS-5 in OA but not in normal articular chondrocytes. Lentiviral overexpression and knockdown of HOTAIR markedly increased and decreased the expression of ADAMTS-5, respectively, in OA but not in normal articular chondrocytes in the presence or absence of TNF-α. Neither overexpression/ knockdown of HOTAIR nor TNF-α showed a significant effect on the ADAMTS-5 gene promoter in OA articular chondrocytes. Although HOTAIR showed no significant effect on the stability of ADAMTS-5 mRNA in normal articular chondrocytes, HOTAIR overexpression and knockdown respectively increased and decreased the ADAMTS-5 mRNA stability in OA articular chondrocytes. TNF-α enhanced the protective effect of HOTAIR on the ADAMTS-5 mRNA stability. In conclusion, this study provides the first evidence supporting that HOTAIR strongly promotes the expression of ADAMTS-5 by increasing its mRNA stability in human OA articular chondrocytes; this effect is enhanced by TNF-α. It adds new insights into the pathogenesis of OA and suggests that HOTAIR could be a new therapeutic target for ADAMTS-5 inhibition in human OA cartilage.
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