Abstract
Intervertebral disc degeneration (IVDD) has been reported to be a major cause of low back pain. Studies have demonstrated that IVDD may be dysregulated at the transcriptional level; however, whether post-transcriptional regulation is involved is still unknown. The current study aimed to illustrate the role of Human antigen R (HuR), an RNA binding protein involved in post-transcriptional regulation, in IVDD. The results showed that the expression of HuR was decreased in degenerative nucleus pulposus (NP) tissues as well as in TNF-α-treated NP cells. Downregulation of HuR may lead to increased inflammation and extracellular matrix (ECM) degradation in TNF-α-treated NP cells; however, these effects were not reversed in HuR overexpressed NP cells. Inhibition of the NF-κB signaling pathway attenuates inflammation and ECM degradation in HuR-deficient NP cells. A mechanism study showed that HuR prompted NKRF mRNA stability via binding to its AU-rich elements, and upregulation of NKRF suppressed inflammation and ECM degradation in HuR-deficient NP cells. Furthermore, we found that NKRF, but not HuR, overexpression ameliorated the process of IVDD in rats in vivo. In conclusion, HuR suppressed inflammation and ECM degradation in NP cells via stabilizing NKRF and inhibiting the NF-κB signaling pathway; NKRF, but not HuR, may serve as a potential therapeutic target for IVDD.
Highlights
Low back pain is a common disorder in the population, and up to 25% of people in the United States suffer from back and neck pain (Martin et al, 2008; Hoy et al, 2010; Zheng et al, 2018)
We evaluated the expression of Human antigen R (HuR) in nucleus pulposus (NP) cells during intervertebral disc degeneration (IVDD); we upregulated and downregulated its expression via lentivirus to explore the role of HuR in IVDD; inflammatory genes were screened to demonstrate its working mechanism; HuR and NKRF overexpressing lentiviruses were injected into NP tissues to assess their therapeutic effect on IVDD
It was found from dataset GSE27494 that ELAVL1(HuR) gene level was depressed in NP cells under inflammatory factor stimulation (Figure 1C)
Summary
Low back pain is a common disorder in the population, and up to 25% of people in the United States suffer from back and neck pain (Martin et al, 2008; Hoy et al, 2010; Zheng et al, 2018). Severe low back pain can lead to disability, which affects the quality of life for individuals and causes a serious burden to society; the socio-economic burden caused by low back pain has been reported to exceed 85 billion dollars (Martin et al, 2008). Studies have shown that up to 40% of lower back pain is related to intervertebral disc degeneration (IVDD) (Freemont, 2009). The jelly-like NP tissue is the major tissue of intervertebral disc to combat against loading, while the dysfunction of NP cells is considered to be the initiating cause of IVDD (Sakai and Grad, 2015; Gorth et al, 2020)
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