Autophagy is activated in compression-induced cell degeneration and is mediated by reactive oxygen species in nucleus pulposus cells exposed to compression

Ma, Kuo‐Hsing; Shao, Zengwu; Yang, Shuai; Wang, J.; Wang, B.-C.; Xiong, Liming; Wu, Qiang; Chen, S.-F.

doi:10.1016/j.joca.2013.10.002

Cited by 121 publications

(131 citation statements)

References 41 publications

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“…Although the causative relationship between disc degeneration and autophagy is not yet clear, alterations in the level of autophagy have been observed in degenerated IVDs, IVDs of aged or diabetic rats [37][38][39] and NP cells derived from degenerative human discs. 40 In addition, various stresses such as high glucose, 41,42 aberrant mechanical compression, 43 lactate overload, 44 glucosamine, 45 and reactive oxygen species (ROS), 43 activate autophagy in NP cells, further implicating autophagy modulation as a possible contributor to disc pathologies. However, studies investigating the mechanisms of how basal autophagy is controlled in NP cells and the role of physiological stimuli in this process are mostly lacking.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

et al. 2016

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Nucleus pulposus (NP) cells reside in the avascular and hypoxic microenvironment of intervertebral discs. Importantly, many activities related to survival and function of NP cells are controlled by the HIF-family of transcription factors. We hypothesize that NP cells adapt to their hypoxic niche through modulation of macroautophagy/autophagy. In various cell types, hypoxia induces autophagy in a HIF1A-dependent fashion; however, little is known about hypoxic regulation of autophagy in NP cells. Hypoxia increases the number of autophagosomes as seen by TEM analysis and LC3-positive puncta in NP cells. Hypoxic induction of autophagy was also demonstrated by a significantly higher number of autophagosomes and smaller change in autolysosomes in NP cells expressing tandem-mCherry-EGFP-LC3B. Increased LC3-II levels were not accompanied by a concomitant increase in BECN1 or the ATG12-ATG5 complex. In addition, ULK1 phosphorylation at Ser757 and Ser777 responsive to MTOR and AMPK, respectively, was not affected in hypoxia. Interestingly, when MTOR activity was inhibited by rapamycin or Torin1, LC3-II levels did not change, suggesting a novel MTOR-independent regulation. Noteworthy, while silencing of HIF1A affected hypoxic induction of BNIP3, it did not affect LC3-II levels, indicating hypoxia-induced autophagy is HIF1-independent. Importantly, there was no change in the number of LC3-positive autophagosomes in NP-specific Hif1a null mice. Finally, inhibition of autophagic flux did not affect the glycolytic metabolism of NP cells, suggesting a possible nonmetabolic role of autophagy. Taken together, our study for the first time shows that NP cells regulate autophagy in a noncanonical fashion independent of MTOR and HIF1A signaling.

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Section: Introductionmentioning

confidence: 99%

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

et al. 2016

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“…Hostile environments induce cells to upregulate autophagy to remove toxic protein aggregates and provide amino acids and fatty acids. It has also been suggested that autophagy plays a role in the onset of IDD and that controlling the autophagy response in NP cells under oxidative stress should be beneficial for the survival of the cells and would likely delay the process of disc degeneration [2, 51-53]. …”

Section: Discussionmentioning

confidence: 99%

Sestrin-Mediated Inhibition of Stress-Induced Intervertebral Disc Degradation Through the Enhancement of Autophagy

et al. 2018

Cell Physiol Biochem

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Background/Aims: Intervertebral disc degeneration (IDD) is a pathological process that is the primary cause of low back pain and is potentially mediated by compromised stress defense. Sestrins (Sesn) promote cell survival under stress conditions and regulate AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling. Here, we investigated the expression of Sesn in normal and degraded nucleus pulposus (NP) cells and its potential roles during IDD pathogenesis. Methods: Sesn expression in normal and degraded NP cells was determined by quantitative polymerase chain reaction and immunoblotting and immunohistochemistry, respectively. Sesn function was investigated by using Sesn knockdown and overexpression techniques with analysis of extracellular matrix (ECM), cell apoptosis, autophagy, AMPK, and mTOR activation. Results: In human cultured NP cells, Sesn expression was significantly decreased in degraded NP cells at both the RNA and protein levels. The expression of Sesn1, 2, and 3 increased after stimulation by 2-deoxyglucose (2-DG), an endoplasmic reticulum stress inducer. 2-DG could also increase cell apoptosis, promote extracellular matrix (ECM) degradation, and positively regulate autophagy in NP cells. Sesn knockdown by small interfering RNA increased NP cell apoptosis and ECM degradation under basal culture conditions and in the presence of 2DG. Conversely, Sesn overexpression mediated by plasmid transfection repressed IDD by enhancing autophagy, which was associated with changes in mTOR but not AMPK activation. Conclusions: Sesn expression is suppressed in degraded NP cells. In addition, Sesn inhibits stress-induced cell apoptosis and ECM degradation by enhancing autophagy, which is modulated though mTOR activity. Suppression of Sesn might therefore represent an important cellular dysfunction mechanism in the process of IDD.

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“…Ma et al (110) found that autophagy triggered by compression in rat NP cells was associated with apoptosis and intracellular ROS production. However, elucidation of the exact role of autophagy and the precise mechanism mediating autophagy activation require further investigation.…”

Section: Mechanical Stressmentioning

confidence: 99%

Responses and adaptations of intervertebral disc cells to microenvironmental stress: a possible central role of autophagy in the adaptive mechanism

Jiang

Yuan

Yin

et al. 2014

Connective Tissue Research

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Intervertebral discs comprise the largest avascular cartilaginous organ in the body, and its nutrient condition can be impaired by degeneration, aging and even metabolic disease. The unique microenvironment brings special stresses to various disc cell types, including nucleus pulposus cells, notochordal cells, annulus fibrosus cells and endplate chondrocytes. These cells experience nutrient starvation, acidic stress, hypoxic stress, hyperglycemic stress, osmotic stress and mechanical stress. Understanding the detailed responses and complex adaptive mechanisms of disc cells to various stresses might provide some clues to guide therapy for disc degeneration. By reviewing the published literatures describing disc cells under different hostile microenvironments, we conclude that these cells exhibit different responses to microenvironmental stresses with different mechanisms. Moreover, the interaction and combination of these stresses create a complex environment that synergistically increase or decrease influences on disc cells, compared with the effects of a single stress. Interestingly, most of these stresses activate autophagy, a self-protective mechanism by which dysfunctional protein and organelles are degraded. It is becoming clear that autophagy facilitates the cellular adaptation to stresses and might play a central role in regulating the adaptation of disc cells under stress. Therefore, autophagy modulation might be a potential therapeutic method to treat disc degeneration.

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Autophagy is activated in compression-induced cell degeneration and is mediated by reactive oxygen species in nucleus pulposus cells exposed to compression

Abstract: Enhanced degradation of damaged components of NP cells by autophagy may be a crucial survival response against mechanical overload, and extensive autophagy may trigger autophagic cell death. Regulating autophagy and reducing the generation of intracellular ROS may retard IVD degeneration.

Cited by 121 publications

References 41 publications

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

Hypoxia promotes noncanonical autophagy in nucleus pulposus cells independent of MTOR and HIF1A signaling

Sestrin-Mediated Inhibition of Stress-Induced Intervertebral Disc Degradation Through the Enhancement of Autophagy

Responses and adaptations of intervertebral disc cells to microenvironmental stress: a possible central role of autophagy in the adaptive mechanism

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