Cholesterol Induces Pyroptosis and Matrix Degradation via mSREBP1-Driven Endoplasmic Reticulum Stress in Intervertebral Disc Degeneration.

Jiansen Yan,Yangyang Zhang,Jiajun Wu,Tianyu Qin,Wei Ye,Jie Zhou,Zhihuai Deng,Yin Xiao,Zhengqi Huang,Kang Xu,Shuangxing Li

doi:10.3389/fcell.2021.803132

Abstract

Intervertebral disc degeneration (IDD) is closely associated with low back pain, but its underlying mechanism remains unclear. Cholesterol is an essential nutrient in mammalian cells. Alterations in cholesterol levels lead to impairments in cell physiology, such as cell proliferation and signal transduction. Previous clinical studies demonstrated that hypercholesterolemia could be a potential risk factor for IDD, but how cholesterol induces IDD remains unknown. The current study aimed to explore the regulatory role of cholesterol in IDD development and the potential underlying mechanisms. It was found that different forms of cholesterol levels were elevated in degenerative nucleus pulposus (NP) tissues in both humans and Sprague–Dawley rats. Rats fed a high cholesterol diet (HCD) exhibited degenerative features in the lumbar intervertebral disc compared with those fed a standard diet. Interestingly, this effect could be abolished by cholesterol-lowering drug atorvastatin. In NP cells treated with TNF-α and IL-1β, a significantly higher level of cholesterol was observed. These results suggested a pivotal role of cholesterol in the progression of IDD. We also observed accelerated pyroptosis in NP cells and extracellular matrix (ECM) degradation in the rat NP cells treated with exogenous cholesterol. We further demonstrated that endoplasmic reticulum stress was responsible for cholesterol-induced pyroptosis and ECM degradation. Moreover, RNA-seq analysis revealed that the mature form of SREBP1 (mSREBP1), an important regulator of lipid metabolism, is involved in regulating endoplasmic reticulum stress in knockdown experiments. In conclusion, this study demonstrated that cholesterol could induce pyroptosis in NP cells and ECM degradation by activating endoplasmic reticulum stress through stimulating mSREBP1 in IDD.

Highlights

Low back pain (LBP) is a common musculoskeletal disorder and the most predominant cause of disability (Knezevic et al, 2021)
Filipin staining demonstrated that inflammatory cytokine stimulation resulted in free cholesterol accumulation compared with that in unstimulated nucleus pulposus (NP) cells (Figure 1G), which was coincident with increases in total cholesterol and free cholesterol, as measured by spectrophotometry (Figure 1H)
We first found that metabolism of cholesterol was disturbed and different forms of cholesterol accumulated as Intervertebral disc degeneration (IDD) progressed

Summary

Introduction

Low back pain (LBP) is a common musculoskeletal disorder and the most predominant cause of disability (Knezevic et al, 2021). The etiology and pathology are complicated and not well understood, IDD is believed to play a vital role in the process of LBP (Livshits et al, 2011). During IDD, NP tissues undergo the most dramatic changes and are characterized by dysfunctional and reduced numbers of NP cells, as well as degradation of the extracellular matrix (ECM), including collagen II (COL2A) and aggrecan. NP cells, which are the predominant cell type within the NP region, regulate ECM homeostasis by controlling anabolism and catabolism.

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