lncRNA HOTAIR upregulates autophagy to promote apoptosis and senescence of nucleus pulposus cells.

Intervertebral disc degeneration (IDD) is a complex and chronic disease that involves disc cell senescence, death, and extracellular matrix (ECM) degradation. HOTAIR, a long non-coding RNA (lncRNA) is reportedly associated with autophagy, whereas autophagy is shown to promote IDD. However, how it affects nucleus pulposus (NP) cells, the primary component of intervertebral discs is still unclear. We hypothesized that HOTAIR promotes NP cell apoptosis and senescence through upregulating autophagy. Thus, silencing HOTAIR should inhibit autophagy and exert a therapeutic effect on IDD. Our in vitro experiments in human NP cells revealed that HOTAIR expression positively correlated with IDD grade, and overexpression enhanced autophagy. Autophagy inhibition via 3-methyladenine reversed HOTAIR stimulatory effects on apoptosis, senescence, and ECM catabolism, while the AMP-activated protein kinase (AMPK) inhibitor Compound C suppressed HOTAIR-induced autophagy through regulating AMPK/mTOR/ULK1 pathways. Our in vivo experiment then illustrated that silencing HOTAIR ameliorates IDD in rats. Collectively, we demonstrated that HOTAIR stimulates autophagy to promote NP cell apoptosis, senescence, and ECM catabolism. Therefore, silencing HOTAIR has the potential to become a treatment option for IDD.

Zhan S ，Wang K ，Xiang Q ，Song Y ，Li S ，Liang H ，Luo R ，Wang B ，Liao Z ，Zhang Y ，Yang C ... -  《-》

Long non-coding RNA HOTAIR modulates intervertebral disc degenerative changes via Wnt/β-catenin pathway.

Zhan S ，Wang K ，Song Y ，Li S ，Yin H ，Luo R ，Liao Z ，Wu X ，Zhang Y ，Yang C ... -  《-》

Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo.

Chen D ，Xia D ，Pan Z ，Xu D ，Zhou Y ，Wu Y ，Cai N ，Tang Q ，Wang C ，Yan M ，Zhang JJ ，Zhou K ，Wang Q ，Feng Y ，Wang X ，Xu H ，Zhang X ，Tian N ... -  《Cell Death & Disease》

Inhibited microRNA-494-5p promotes proliferation and suppresses senescence of nucleus pulposus cells in mice with intervertebral disc degeneration by elevating TIMP3.

Chen G ，Zhou X ，Li H ，Xu Z ... -  《-》

The long noncoding RNA HOTAIR serves as a microRNA-34a-5p sponge to reduce nucleus pulposus cell apoptosis via a NOTCH1-mediated mechanism.

Intervertebral disc degeneration (IDD) is a major cause of lower back pain, but the specific molecular mechanisms governing its development are poorly characterized. This study sought to assess to what extent HOTAIR, a long non-coding (Lnc) RNA is expressed in IDD and regulates the apoptotic death of nucleus pulposus (NP) cells. We therefore used real-time qPCR to measure HOTAIR and microRNA(miR)-34a-5p in degenerative NP cells, and then validated their functional relevance via overexpressing them in these NP cells. We further verified the targets of these RNA constructs in 293 T cells through the use of a dual luciferase reporter assay. We further measured NP cell apoptosis via flow cytometry and Notch1 expression via western blotting. Our results indicated that IDD was linked with decreased HOTAIR expression relative to regular NP cells, and overexpressing this lncRNA was linked to reduced apoptotic NP cell death, whereas overexpressing miR-34a-5p had the opposite effect. We found that HOTAIR served as a miR-34a-5p sponge, sequestering this miRNA and thereby down regulating genes linked to apoptosis through the Notch signaling pathway. Even in naturally degenerated NP cells, HOTAIR delayed the onset of apoptosis. Together these results reveal that a HOTAIR/miR-34a-5p/Notch1 signaling pathway may regulate the development of IDD, potentially making HOTAIR a viable target for treatment of this disease.

Shao T ，Hu Y ，Tang W ，Shen H ，Yu Z ，Gu J ... -  《-》