Abstract
Low back pain is tightly associated with intervertebral disc degeneration (IVDD) and aberrant nucleus pulposus (NP) is a critical cause. miRNAs N6-methyladenosine (m6A) modification accounts for the TNF-α-induced senescence of NP cells. The aim of this study was to investigate whether m6A modification regulates TNF-α-mediated cell viability, cell cycle arrest, and cell senescence and how it works. The results showed that METTL14 expression positively correlated with m6A and TNF-α expression in HNPCs. The knockdown of METTL14 led to the inhibition of the TNF-α-induced cell senescence. METTL14 overexpression promoted cell senescence. METTL14 regulated the m6A modification of miR-34a-5p and interacted with DGCR8 to process miR-34a-5p. The miR-34a-5p inhibitor inhibited the cell cycle senescence of HNPCs. miR-34a-5p was predicted to interact with the SIRT1 mRNA. SIRT1 overexpression counteracted the miR-34a-5p-promoted cell senescence. METTL14 participates in the TNF-α-induced m6A modification of miR-34a-5p to promote cell senescence in HNPCs and NP cells of IVDD patients. Downregulation of either METTL14 expression or miR-34a-5p leads to the inhibition of cell cycle arrest and senescence. SIRT1 mRNA is an effective binding target of miR-34a-5p, and SIRT1 overexpression mitigates the cell cycle arrest and senescence caused by miR-34a-5p.
Highlights
Lower back pain (LBP) is the most common chronic pain that affects at least 80% of Americans in their lifetime (Freburger et al, 2009)
To verify the relationship between tumor necrosis factor (TNF)-α and the m6A methylation in intervertebral disc degeneration (IVDD) patients, we first examined the level of m6A methylation in the nucleus pulposus (NP) tissues from the patients and discovered an increase in the level of m6A modification (Figure 1A)
The level of m6A modification significantly increased in the human NP cells (HNPCs), which was correlated with the level of TNF-α in IVDD patients. m6A modification has been characterized as the most prevalent internal mRNA modification in mammalian cells, which accounts for regulating various important biological processes (Zhang et al, 2019)
Summary
Lower back pain (LBP) is the most common chronic pain that affects at least 80% of Americans in their lifetime (Freburger et al, 2009). It has been revealed that LBP is strongly associated with intervertebral disc degeneration (IVDD) and degenerative disc disease is identified to be the main cause of LBP (Luoma et al, 2000; Morgan et al, 2014). Abnormal apoptosis of NP cells (NPCs) is correlated with the pathology of IVDD. The degeneration was mainly manifested by the apoptosis of NP cells, in which the levels of cleaved caspase-3 and Bax were upregulated while the expression of Bcl-2 was downregulated (Kepler et al, 2013; Jiao et al, 2018; Li Z. et al, 2019). Aberrant apoptosis and senescence of NP cells play significant roles in the process of IVDD (Zhao et al, 2006; Jiang et al, 2013; Chen et al, 2018). Through the PI3K/Akt signaling, TNF-α promoted senescence of NP cells
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