Metformin alleviates intervertebral disc degeneration by upregulating MMP-1 expression via the KDM6A/SOX9/miR-202-3p/MMP-1 signaling pathway

Archives of Medical Science ◽

10.5114/aoms/117427 ◽

2021 ◽

Author(s):

Xin-yao Hu ◽

Dong-zi Cao ◽

Zhi-hua Wang

Keyword(s):

Intervertebral Disc ◽

Signaling Pathway ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Methylation Status ◽

Inhibitory Effect ◽

Luciferase Assay ◽

Downstream Target ◽

Neuronal Precursor Cells

IntroductionMiR-202-3p is involved in the pathogenesis of intervertebral disc degeneration (IDD) via regulating MMP-1 expression in neuronal precursor cells (NPCs). As an activator of miR-202-3p and KDM6A expression, metformin (MET) may regulate the expression of SOX9 via regulating the methylation status of SOX9 promoter. However, the role of MET in the treatment of IDD remains to be explored.Material and methodsQuantitative real-time PCR was performed to analyze the expression of KDM66, SOX9, MMP-1 and miR-202-3p in NPCs and IDD rabbits. Western blot was carried out to evaluate the expression of KDM6A, SOX9 and MMP-1 protein under different conditions. Bisulfite sequencing PCR was used to analyze the DNA methylation of SOX9 promoter. Luciferase assay was carried out to explore the inhibitory effect of miR-202-3p upon MMP-1.ResultsThe expression of KDM6A, SOX9 and MMP-1 was abnormal in IDD cells and rabbits, while the MET treatment restored the normal expression of KDM6A, SOX9 and MMP-1 and miR-202-3p. Mechanistically, MET treatment reduced the level of hypermethylation of SOX9 promoter, thus restoring the expression of SOX9 in IDD cells and rabbits. The elevation in SOX9 expression promoted the expression of miR-202-3p, therefore inhibiting the expression of MMP-1, a downstream target of miR-202-3p.ConclusionsIn this study, we set up cellular and animal models of IDD and treated them with MET to probe the effect of MET on IDD and the signaling pathway of KDM6A/SOX9/miR-202-3p/MMP-1. Our work provided deep insight into the molecular mechanism underlying the therapeutic role of MET in the treatment of IDD.

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Melatonin Protects Intervertebral Disc from Degeneration by Improving Cell Survival and Function via Activation of the ERK1/2 Signaling Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/5120275 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Jun Ge ◽

Quan Zhou ◽

Junjie Niu ◽

Yingjie Wang ◽

Qi Yan ◽

...

Keyword(s):

Cell Cycle ◽

Intervertebral Disc ◽

Signaling Pathway ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Nucleus Pulposus Cell ◽

Cell Physiology ◽

Cell Degeneration

Melatonin, a neuroendocrine hormone secreted by the pineal body, has a positive effect on intervertebral disc degeneration. The present study is aimed at investigating the biological role of melatonin in intervertebral disc degeneration and its underlying mechanism. A human nucleus pulposus cell (NPC) line was exposed to melatonin at different concentrations. Cell proliferation was measured by CCK-8 assay. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was performed to measure the protein expression of indicated genes. A rabbit model of intervertebral disc degeneration was established to detect the role and mechanism of melatonin on intervertebral disc degeneration. Our study showed that melatonin promoted NPC viability and inhibited cell arrest. Furthermore, melatonin treatment led to the upregulation of collagen II and aggrecan and downregulation of collagen X. Moreover, melatonin significantly elevated the activity of the ERK signaling pathway. Inhibition of the ERK1/2 signals reversed the role of melatonin in the regulation of NPCs both in vitro and in vivo. Melatonin increased NPC viability through inhibition of cell cycle arrest and apoptosis. Moreover, melatonin promoted the secretion of functional factors influencing the nucleus pulposus cell physiology and retarded cell degeneration. Our results suggest that melatonin activated the ERK1/2 signaling pathway, thereby affecting the biological properties of the intervertebral disc degeneration.

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