Abstract
Intervertebral disc degeneration (IVDD) is a main cause of low back pain that is associated with extracellular matrix (ECM) degradation and inflammation. This study aims to investigate the role of DNMT3B and its regulatory mechanisms in IVDD. IVDD rat models were constructed followed by transfections with oe-DNMT3B or oe-YAP in order to explore the role of DNMT3B in the development of IVDD. After that transfection, nucleus pulposus (NP) cells were isolated and transfected with oe-DNMT3B, oe-TRPA1, si-YAP, oe-YAP or oe-COX2 in order to investigate the functions of DNMT3B in NP cells. DNMT3B was poorly expressed in IVDD tissues and NP cells whereas TRPA1, COX2, and YAP were highly expressed. The proliferation or apoptosis of NP cells was detected through CCK-8 assay or flow cytometry, respectively. Overexpression of DNMT3B promoted the proliferation of NP cells, inhibited their apoptosis, as well as increasing the expression of collagen II and aggrecan and decreasing expression of MMP3 and MMP9. Besides, DNMT3B suppressed inflammation and alleviated IVDD. Mechanistically, DNMT3B modified the TRPA1 promoter by methylation to inhibit the expression of COX2. Overexpression of COX2 promoted the apoptosis of NP cells and decreased the expression of YAP, which was reversed by upregulating DNMT3B. DNMT3B may promote the proliferation of NP cells and prevent their ECM degradation through the TRPA1/COX2/YAP axis, thereby alleviating IVDD in rats.
Highlights
Human intervertebral disc degeneration (IVDD) is a multifactorial process that is caused by both genetic factors and mechanical stress [1]
IVDD is mainly attributed to the decrease in the number of Nucleus pulposus (NP) cells, current treatment strategies still cannot increase the number NP cells or reverse the pathology [23]
We clarified that inducing the expression of DNA Methyltransferase 3 Beta (DNMT3B) increased proliferation and reduced apoptosis of NP cells, extracellular matrix (ECM) degradation, and inflammation
Summary
Human intervertebral disc degeneration (IVDD) is a multifactorial process that is caused by both genetic factors and mechanical stress [1]. IVDD is asymptomatic in most cases, and is often correlated with sciatica, spondylolisthesis, disc herniation, and degenerative scoliosis [2]. Nucleus pulposus (NP) cells play critical roles in generating aggrecan, type II collagen, and other components of the extracellular matrix (ECM), thereby exerting its important effects on maintaining IVD integrity [4]. During IVDD, pro-inflammatory cytokines such as TNF-α and IL-1β can accelerate NP cell degeneration by promoting the release of matrix metalloproteinases (MMPs) and inflammatory cytokines [5, 6]. ECM degradation and inflammation in NP cells have been shown to accelerate the progression of IVDD. The underlying factors or mechanisms involved in this process are not yet fully understood
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