Mechanosensitive Ion Channel Piezo1 Activated by Matrix Stiffness Regulates Oxidative Stress-Induced Senescence and Apoptosis in Human Intervertebral Disc Degeneration

Mechanical stimulation plays a crucial part in the development of intervertebral disc degeneration (IDD). Extracellular matrix (ECM) stiffness, which is a crucial mechanical microenvironment of the nucleus pulposus (NP) tissue, contributes to the pathogenesis of IDD. The mechanosensitive ion channel Piezo1 mediates mechanical transduction. This study purposed to investigate the function of Piezo1 in human NP cells under ECM stiffness. The expression of Piezo1 and the ECM elasticity modulus increased in degenerative NP tissues. Stiff ECM activated the Piezo1 channel and increased intracellular Ca2+ levels. Moreover, the activation of Piezo1 increased intracellular reactive oxygen species (ROS) levels and the expression of GRP78 and CHOP, which contribute to oxidative stress and endoplasmic reticulum (ER) stress. Furthermore, stiff ECM aggravated oxidative stress-induced senescence and apoptosis in human NP cells. Piezo1 inhibition alleviated oxidative stress-induced senescence and apoptosis, caused by the increase in ECM stiffness. Finally, Piezo1 silencing ameliorated IDD in an in vivo rat model and decreased the elasticity modulus of rat NP tissues. In conclusion, we identified the mechanosensitive ion channel Piezo1 in human NP cells as a mechanical transduction mediator for stiff ECM stimulation. Our results provide novel insights into the mechanism of mechanical transduction in NP cells, with potential for treating IDD.

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Nrf2 mediated ER-phagy protects against oxidative damage in intervertebral disc degeneration

10.1101/2021.11.21.469451 ◽

2021 ◽

Author(s):

zhen lin ◽

libin ni ◽

cheng teng ◽

zhao zhang ◽

xinlei lu ◽

...

Keyword(s):

Oxidative Stress ◽

Intervertebral Disc ◽

Oxidative Damage ◽

Er Stress ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Cellular Damage ◽

Nucleus Pulposus Cells

Intervertebral disc degeneration (IDD) increases the risk of low back pain (LBP). Oxidative stress may induce cellular damage and contribute to various diseases including IDD. Endoplasmic reticulum autophagy (ER-phagy) is a specific type of autophagy, its role in oxidative stress induced damage as well as in IDD is unknown. This study explores the role of ER-phagy in oxidative damage in intervertebral disc nucleus pulposus cells (NPCs), as well as the Nrf2/FAM134B axis in ER-phagy regulation and IDD therapy. We found ER-phagy was decreased in NPCs during oxidative stress; while FAM134B may promote ER-phagy and alleviate oxidative stress induced ER-stress and apoptosis. In addition, the nuclear transcription factor Nrf2 may promote the expression of FAM134B as well as ER-phagy, and suppress ER-stress and apoptosis in NPCs. Furthermore, overexpression of FAM134B and Nrf2 could effectively attenuate the progression of IDD in rats in vivo. These results suggest Nrf2/FAM134B mediated ER-phagy may combat oxidative damage in cells; meanwhile, ER-phagy as well as Nrf2 could be potential therapeutic targets for IDD.

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Restoration of Autophagic Flux Rescues Oxidative Damage and Mitochondrial Dysfunction to Protect against Intervertebral Disc Degeneration

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/7810320 ◽

2019 ◽

Vol 2019 ◽

pp. 1-27 ◽

Cited By ~ 5

Author(s):

Liang Kang ◽

Qian Xiang ◽

Shengfeng Zhan ◽

Yu Song ◽

Kun Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Intervertebral Disc ◽

Oxidative Damage ◽

Mitochondrial Dysfunction ◽

Disc Degeneration ◽

Cell Apoptosis ◽

Intervertebral Disc Degeneration ◽

Autophagic Flux ◽

Ecm Degradation

Oxidative stress-induced mitochondrial dysfunction and nucleus pulposus (NP) cell apoptosis play crucial roles in the development of intervertebral disc degeneration (IDD). Increasing studies have shown that interventions targeting impaired autophagic flux can maintain cellular homeostasis by relieving oxidative damage. Here, we investigated the effect of curcumin (CUR), a known autophagy activator, on IDD in vitro and in vivo. CUR suppressed tert-butyl hydroperoxide- (TBHP-) induced oxidative stress and mitochondrial dysfunction and thereby inhibited human NP cell apoptosis, senescence, and ECM degradation. CUR treatment induced autophagy and enhanced autophagic flux in an AMPK/mTOR/ULK1-dependent manner. Notably, CUR alleviated TBHP-induced interruption of autophagosome-lysosome fusion and impairment of lysosomal function and thus contributed to the restoration of blocked autophagic clearance. These protective effects of CUR in TBHP-stimulated human NP cells resembled the effects produced by the autophagy inducer rapamycin, but the effects were partially eliminated by 3-methyladenine- and compound C-mediated inhibition of autophagy initiation or chloroquine-mediated obstruction of autophagic flux. Lastly, CUR also exerted a protective effect against puncture-induced IDD progression in vivo. Our results showed that suppression of excessive ROS production and mitochondrial dysfunction through enhancement of autophagy coupled with restoration of autophagic flux ameliorated TBHP-induced human NP cell apoptosis, senescence, and ECM degradation. Thus, maintenance of the proper functioning of autophagy represents a promising therapeutic strategy for IDD, and CUR might serve as an effective therapeutic agent for IDD.

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Celastrol reduces IL-1β induced matrix catabolism, oxidative stress and inflammation in human nucleus pulposus cells and attenuates rat intervertebral disc degeneration in vivo

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2017.04.093 ◽

2017 ◽

Vol 91 ◽

pp. 208-219 ◽

Cited By ~ 24

Author(s):

Jian Chen ◽

Jun Xuan ◽

Yun-Tao Gu ◽

Ke-Si Shi ◽

Jun-Jun Xie ◽

...

Keyword(s):

Oxidative Stress ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Nucleus Pulposus Cells

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Therapeutic Potential of Naringin for Intervertebral Disc Degeneration: Involvement of Autophagy Against Oxidative Stress-Induced Apoptosis in Nucleus Pulposus Cells

The American Journal of Chinese Medicine ◽

10.1142/s0192415x18500805 ◽

2018 ◽

Vol 46 (07) ◽

pp. 1561-1580 ◽

Cited By ~ 4

Author(s):

Zengjie Zhang ◽

Chenggui Wang ◽

Jialiang Lin ◽

Haiming Jin ◽

Ke Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Intervertebral Disc ◽

Nucleus Pulposus ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Therapeutic Potential ◽

Nucleus Pulposus Cells ◽

Induced Apoptosis

Intervertebral disc degeneration (IDD) is a major cause of lower back pain, but few efficacious medicines have been developed for IDD. Increased nucleus pulposus cells apoptosis is a dominant pathogenesis of IDD and is considered a therapeutic target. Previously, our group proved that autophagy may protect nucleus pulposus cells against apoptosis. As one of the major bioflavonoids of citrus, naringin activates autophagy. Therefore, we hypothesize that naringin may have therapeutic potential for IDD by activating autophagy in nucleus pulposus cells. In this study, we evaluated the effects of naringin on TBHP-induced oxidative stress in nucleus pulposus cells in vitro as well as in puncture-induced rat IDD model in vivo. Our results showed that naringin could reduce the incidence of oxidative stress-induced apoptosis in nucleus pulposus cells and promoted the expression of autophagy markers LC3-II/I and beclin-1. Meanwhile, inhibition of autophagy by 3-MA may partially reverse the anti-apoptotic effect of naringin, indicating that autophagy was involved in the protective effect of naringin in nucleus pulposus cells. Further study showed that autophagy regulation of naringin may be related to AMPK signaling. Also, we found that naringin treatment can regulate the expression of collagen II, aggrecan and Mmp13 to sustain the extracellular matrix. Furthermore, our in vivo study showed that naringin can ameliorate IDD in puncture-induced rat model. In conclusion, our study suggests that naringin can protect nucleus pulposus cells against apoptosis and ameliorate IDD in vivo, the mechanism may relate to its autophagy regulation.

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An in vivo study of the effect of c-Jun on intervertebral disc degeneration in rats

Bioengineered ◽

10.1080/21655979.2021.1946459 ◽

2021 ◽

Vol 12 (1) ◽

pp. 4320-4330

Author(s):

Ming Lei ◽

Kangcheng Zhao ◽

Wenbin Hua ◽

Kun Wang ◽

Shuai Li ◽

...

Keyword(s):

Intervertebral Disc ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

In Vivo Study

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Krüppel like factor 10 prevents intervertebral disc degeneration via TGF-β signaling pathway both in vitro and in vivo

Journal of Orthopaedic Translation ◽

10.1016/j.jot.2021.04.003 ◽

2021 ◽

Vol 29 ◽

pp. 19-29

Author(s):

Tongde Wu ◽

Xinhua Li ◽

Xuebing Jia ◽

Ziqi Zhu ◽

Jiawei Lu ◽

...

Keyword(s):

Intervertebral Disc ◽

Signaling Pathway ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration

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Recovery of Intervertebral Disc Degeneration Post Enzymatic Treatment is Mediated by Matrix Metalloproteinases

ASME 2011 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2011-53887 ◽

2011 ◽

Author(s):

Nadeen Chahine ◽

Nate Stetson ◽

Neena Rajan ◽

Daniel Grande ◽

Mitchell Levine

Keyword(s):

Intervertebral Disc ◽

Disc Degeneration ◽

Enzymatic Degradation ◽

Intervertebral Disc Degeneration ◽

Biomechanical Properties ◽

Enzymatic Treatment ◽

Disc Injury ◽

Herniated Discs ◽

Dose Dependent

Enzymatic degradation of the intervertebral disc (IVD) with chondroitinase ABC (ChABC) reduces proteoglycan content of the IVD, thus simulating the GAG loss seen clinically in patients suffering from disc degeneration. This approach has been employed in models of disc injury in rats, rabbits and goats when administered over a large range of dosages [1–3]. Moreover, ChABC has also been used to induce repair of herniated discs in rabbits via chemonucleolysis [4, 5]. Despite the effectiveness of ChABC treatment to reduce the GAG content of the IVD, several recent studies including our own, have shown that this GAG loss is reversible at extended time points post enzymatic treatment [2,6,7]. The goal of the current study is to examine the dose dependent response of IVDs to degradation by ChABC in vivo. We hypothesize that administration of ChABC will result in dose dependent GAG loss and reduced mechanical properties. We administered ChABC at 0.1 U/ml, 1.0 U/ml and 10 U/ml and examined the changes in biomechanical properties, biochemical content, and gene expression in order to examine the biophysical and molecular mechanism by which GAG loss occurs in this model.

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A novel in vivo mouse intervertebral disc degeneration model induced by compressive suture

Experimental Cell Research ◽

10.1016/j.yexcr.2020.112359 ◽

2021 ◽

Vol 398 (1) ◽

pp. 112359

Author(s):

Zhuochao Liu ◽

Qi Zhou ◽

Jiancheng Zheng ◽

Changwei Li ◽

Weibin Zhang ◽

...

Keyword(s):

Intervertebral Disc ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration

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

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.613006 ◽

2020 ◽

Vol 8 ◽

Author(s):

Dong Wang ◽

Xin He ◽

Di Wang ◽

Pandi Peng ◽

Xiaolong Xu ◽

...

Keyword(s):

Intervertebral Disc ◽

Protective Effect ◽

Disc Degeneration ◽

Intervertebral Disc Degeneration ◽

Specific Effect ◽

Therapeutic Effects ◽

Dependent Manner ◽

Autophagy Pathway ◽

Dose Dependent

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.

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