MiRNA-141 Induced Pyroptosis in Intervertebral Disk Degeneration by Targeting ROS Generation and Activating TXNIP/NLRP3 Signaling in Nucleus Pulpous Cells

Qiaolong Xu,Weishan Chen,Ning Zhang,Jiaqi Wu,Hongyuan Xing

doi:10.3389/fcell.2020.00871

Abstract

The role and mechanism of pyroptosis in intervertebral disk (IVD) degeneration are unclear. MicroRNAs (miRNAs) regulate the viability and function of nucleus pulposus cells (NPCs) in IVDs and are related to pyroptosis. We performed microarray analyses of normal and degenerated nucleus pulposus (NP) to assess the role of pyroptosis and identify key miRNAs in IVD degeneration. We also evaluated the underlying mechanism of miRNA-mediated pyroptosis in NPCs. In addition, we demonstrated the preventative effects of miRNAs on IVD degeneration in a rat model. The levels of the pyroptosis-related proteins cleaved caspase-1, N-terminal gasdermin D (GSDMD), interleukin (IL)-1β, and IL-18 in the degenerative NP were significantly higher than those in the normal NP. miRNA-141 was significantly upregulated in the degenerated NP. miR-141 mimic suppressed the matrix synthesis function of NPCs. By contrast, reactive oxygen species (ROS) generation, and the expression of TXNIP and NLRP3 were significantly downregulated by an miR-141 inhibitor. Furthermore, the miRNA-141 inhibitor prevented the degeneration of IVDs in vivo. Our findings suggest that miRNA-141 induces pyroptosis and extracellular matrix (ECM) catabolism in NPCs by increasing ROS generation and activating TXNIP/NLRP3 signaling. miRNA-141-regulated pyroptosis may be a novel therapeutic target for IVD degeneration.

Highlights

Intervertebral disk (IVD) degeneration and the consequent chronic low-back pain affect approximately 632 million people worldwide and exert social and economic effects on patients (Mathew et al, 2013)
We investigated the role of miR-141 in regulating pyroptosis in nucleus pulposus cells (NPCs) during intervertebral disk (IVD) degeneration
Healthy human NPCs were purchased from Procell (Procell Life Science & Technology, Hubei, China) and cultured in Dulbecco’s modified Eagle’s medium (DMEM)-high glucose supplemented with 10% fetal bovine serum (FBS), 4 mM L-glutamine, and 1% penicillin–streptomycin at 37◦C in 5% CO2

Summary

INTRODUCTION

Intervertebral disk (IVD) degeneration and the consequent chronic low-back pain affect approximately 632 million people worldwide and exert social and economic effects on patients (Mathew et al, 2013). Apoptosis is involved in several grades of IVD degeneration (Eser et al, 2017) Other factors, such as nutrients and aging, may regulate the viability of, and ECM synthesis by NPCs (Barakat et al, 2019). In IVDs, miRNAs regulate the viability and function of NPCs. miR532 induces NPC apoptosis by downregulating Wnt/β catenin signaling (Sun et al, 2018). MiR-7 modulates ECM degeneration of NPCs by targeting growth differentiation factor 5 (Liu W. et al, 2016). MiR-141 may be a key regulator in NPCs. miR-141 modulates cell migration, proliferation, and apoptosis (Zhao et al, 2013; Li et al, 2017; Qin et al, 2019). We investigated the role of miR-141 in regulating pyroptosis in NPCs during IVD degeneration. Discovery of the effect of miR-141 on pyroptosis in NPCs may provide a novel therapeutic target for IVD degeneration

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ETHICS STATEMENT