EZH2 upregulates the expression of MAPK1 to promote intervertebral disc degeneration via suppression of miR‐129‐5p

Abstract

Background This study was designed to verify whether enhancer of zeste homolog 2 (EZH2) affects intervertebral disc degeneration (IVDD) development through regulation of microRNA (miR)‐129‐5p/MAPK1. Methods Initially, we collected lumbar nucleus pulposus (NP) tissue samples from patients with juvenile idiopathic scoliosis (n = 14) and IVDD (n = 34). We measured the expression of related genes in clinical IVDD tissues and a lipopolysaccharide (LPS)‐induced NP cell model. After loss‐ and gain‐of‐function assays, NP cell proliferation and senescence were examined. The targeting relationship between miR‐129‐5p and MAPK1 was explored by dual luciferase reporter gene and RNA immunoprecipitation (RIP) assays. The enrichment of EZH2 and H3K27me3 in miR‐129‐5p promoter was verified by chromatin immunoprecipitation (ChIP). Finally, an IVDD rat model was established to test the effects of transduction with lentiviral vector carrying miR‐129‐5p agomir and/or oe‐EZH2 in vivo. Results miR‐129‐5p was underexpressed, and EZH2 and MAPK1 levels were overexpressed in lumbar nucleus pulposus from human IVDD patients and in LPS‐induced NP cells. miR‐129‐5p overexpression or silencing of MAPK1 promoted proliferation of NP cells, while inhibiting their senescence. EZH2 inhibited miR‐129‐5p through H3K27me3 modification in the miR‐129‐5p promoter. miR‐129‐5p could target the downregulation of MAPK1 expression. EZH2 overexpression increased the release of inflammatory factors and cell senescence factors, which was reversed by miR‐129‐5p agomir in vivo. Conclusions Taken together, EZH2 inhibits miR‐129‐5p through H3K27me3 modification, which upregulates MAPK1, thereby promoting the development of IVDD.

Identification of miRNA-mRNA Pairs in Relation to TNF-α/IL-1β Induced Inflammatory Response in Intervertebral Disc Degeneration

“…Chronic in ammation in the IVDs is connected with IVDD pathophysiology through triggering irreversible structural and biochemical changes (e.g., extracellular matrix degradation, vascular and nerve innervation) [4,5]. Meanwhile, a few previous researches demonstrated that the miRNA could target the downstream gene to primarily a ecting in ammatory signal response, thus involving in the development and progression of IVDD [6,7].…”

Identification and validation of ferroptosis-related gene signature in intervertebral disc degeneration

“…MAPK1, mitogen-activated protein kinase 1, is a core signal transductor of the MAPK/ERK signaling pathway, and it could facilitate ferroptosis through regulating ROS production ( 43 ). Evidence has shown that the MAPK1 expression was increased in the degenerated disc tissues and it could accelerate the development of disc degeneration ( 44 ). HSPA5, heat shock protein family A (Hsp70) member 5, was found to resist ferroptosis in cancer cells ( 45 ).…”

COVID-19 inhibits spermatogenesis in the testes by inducing cellular senescence

“…At the same time, we ran the protein interaction network analysis for the negative correlation genes of the three key enzymes in glycolysis. The results showed that in the top 20 hub genes negatively correlated with the three enzymes respectively, many genes had been reported to be related to cellular senescence, including MAPK1, MITF, JUP, COX5 A, RPL22, RPLP1, DNA2, RPL31 and LRRK2 ( Wang et al, 2016 ; Zhou et al, 2022 ). Interestingly, among these senescence-related genes, MAPK1 occupied the most core position of the key rate-limiting enzyme HK1 negative correlation genes in glycolysis, which proves that MAPK signaling pathway, especially MAPK1, plays an important core function in inhibiting glycolysis.…”