Quercetin Suppresses Apoptosis and Attenuates Intervertebral Disc Degeneration via the SIRT1-Autophagy Pathway.

Zhuojing Luo,Zhen Sun,Liu Yang,Bo Gao,Di Wang,Chao Zheng,Han Wang,Qiliang Shang,Haoruo Jia,Xiaolong Xu,Xin He,Pandi Peng,Dong Wang

doi:10.3389/fcell.2020.613006

Abstract

Intervertebral disc degeneration (IDD) has been generally accepted as the major cause of low back pain (LBP), which causes an enormous socioeconomic burden. Previous studies demonstrated that the apoptosis of nucleus pulposus (NP) cells and the dyshomeostasis of extracellular matrix (ECM) contributed to the pathogenesis of IDD, and effective therapies were still lacking. Quercetin, a natural flavonoid possessing a specific effect of autophagy stimulation and SIRT1 activation, showed some protective effect on a series of degenerative diseases. Based on previous studies, we hypothesized that quercetin might have therapeutic effects on IDD by inhibiting the apoptosis of NP cells and dyshomeostasis of ECM via the SIRT1-autophagy pathway. In this study, we revealed that quercetin treatment inhibited the apoptosis of NP cells and ECM degeneration induced by oxidative stress. We also found that quercetin promoted the expression of SIRT1 and autophagy in NP cells in a dose-dependent manner. Autophagy inhibitor 3-methyladenine (3-MA) reversed the protective effect of quercetin on apoptosis and ECM degeneration. Moreover, SIRT1 enzymatic activity inhibitor EX-527, suppressed quercetin-induced autophagy and the protective effect on NP cells, indicating that quercetin protected NP cells against apoptosis and prevented ECM degeneration via SIRT1-autophagy pathway. In vivo, quercetin was also demonstrated to alleviate the progression of IDD in rats. Taken together, our results suggest that quercetin prevents IDD by promoting SIRT1-dependent autophagy, indicating one novel and effective therapeutic method for IDD.

Highlights

Low back pain (LBP) is one of the most common musculoskeletal diseases that leads to a low quality of life and high socioeconomic burden (Disease et al, 2016; Global Burden of Disease Cancer, Fitzmaurice et al, 2017; Hurwitz et al, 2018)
To evaluate the effect of quercetin and tert-butyl hydroperoxide (TBHP) on the viability of nucleus pulposus (NP) cells, cells were treated with various concentrations quercetin and TBHP for 24 h, and the viability was examined by CCK8 assay
After 100 μM TBHP treatment for 24 h, NP cells shrank in size, more floated cells were observed and less attached cells remained, while quercetin significantly reversed this phenomenon (Figure 1E)

Summary

Introduction

Low back pain (LBP) is one of the most common musculoskeletal diseases that leads to a low quality of life and high socioeconomic burden (Disease et al, 2016; Global Burden of Disease Cancer, Fitzmaurice et al, 2017; Hurwitz et al, 2018). Intervertebral disc degeneration (IDD) has been generally accepted as the major cause of LBP (Sun et al, 2013; Molladavoodi et al, 2019; Taylor and Bishop, 2019). Some previous studies suggested that NP dysfunction was closely related to IDD pathogenesis (Cheng et al, 2018; Ji et al, 2018) Some extracellular stimuli such as hypoxia, nutritional deprivation, inflammation or mechanical loading, could trigger the apoptosis and an imbalance between anabolic and catabolic activities of NP cell, and primed the process of IDD (Ma et al, 2013; Choi et al, 2016; Zhang et al, 2018b, 2019; Yurube et al, 2019; Zuo et al, 2019)

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Results

Conclusion