Apoptosis, senescence, and autophagy in rat nucleus pulposus cells: Implications for diabetic intervertebral disc degeneration

Jiang, Libo; Zhang, Xiaolei; Zheng, Xiaoliang; Ru, Ao; Ni, Xiao; Wu, Yaosen; Tian, Naifeng; Huang, Yixing; Xue, Enxing; Wang, Xiangyang; Xu, Huazi

doi:10.1002/jor.22289

Cited by 150 publications

(150 citation statements)

References 64 publications

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“…The result of this research is consistent with our previous study, which indicated that autophagy was increased in rats with type I diabetes mellitus [2]. Generally, the appropriate increase of autophagy in the chondrocyte and annulus fibrosus cells is considered to be an adaptive reaction to different types of stresses and play a protective role maintaining the homeostasis within cells.…”

supporting

confidence: 92%

Comment on Park et al.: High glucose-induced oxidative stress promotes autophagy through mitochondrial damage in rat notochordal cells

Jiang

Yuan

Dong

2013

International Orthopaedics (SICOT)

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supporting

confidence: 92%

Comment on Park et al.: High glucose-induced oxidative stress promotes autophagy through mitochondrial damage in rat notochordal cells

Jiang

Yuan

Dong

2013

International Orthopaedics (SICOT)

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“…76,77 An altered level of autophagy during intervertebral disc degeneration and aging has been reported. [37][38][39][40]78 Our studies clearly show evidence of MTOR-independent, noncanonical autophagy in NP cells. In addition, hypoxic induction of autophagy is independent of HIF1 as well as increased oxidative stress.…”

Section: Discussionsupporting

confidence: 57%

“…1,33,36 Not surprisingly, changes in autophagy have also been associated with disc degeneration. 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.…”

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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“…The role of apoptosis and apoptosis-related genes in the development of degenerative diseases has garnered much attention in recent years. The excessive apoptosis of NP cells, which are capable of producing ECM components, is one of the most discernable cellular and biochemical changes credited to degeneration (17)(18)(19)(20)(21)(22). A previous study demonstrated that NP cells predominantly undergo apoptosis via the death receptor pathway, which contributes to degeneration of the intervertebral disc (23).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-2 is upregulated in patients with a prolapsed lumbar intervertebral disc and modulates cell proliferation, apoptosis and extracellular matrix metabolism of human nucleus pulposus cells

Wang

Zhu

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Previous studies have demonstrated that the expression levels of cytokines are increased in degenerated intervertebral disc tissues, and several cytokines are associated with the pathogenesis of intervertebral disc degeneration. However, the role of interleukin (IL)-2 in the cellular functions of intervertebral disc tissues remains unreported. The present study aimed to determine the expression levels of IL-2 in the nucleus pulposus (NP) tissues of patients with a prolapsed lumbar intervertebral disc; and to observe the changes in cell proliferation, apoptosis, extracellular matrix (ECM) metabolism and p38 mitogen-activated protein kinase (MAPK) signaling in human NP cells (HNPCs) following treatment with IL-2. The present study demonstrated that IL-2 expression levels were upregulated in the NP tissues of patients with a prolapsed lumbar intervertebral disc; and a subsequent MTT assay demonstrated that IL-2 inhibits the proliferation of HNPCs in a dose-dependent manner. Furthermore, as demonstrated by the increased protein expression levels of Fas cell surface death receptor and the induction of caspase-8 and caspase-3 activity, the death receptor pathway was activated by IL-2 in the HNPCs in order to promote cell apoptosis. In addition, IL-2 promoted ECM degradation in the HNPCs, as demonstrated by an increase in the expression levels of type I collagen, a disintegrin and metalloproteinase with thrombospondin motifs and matrix metalloproteinases, and decreased aggrecan and type II collagen expression levels. Furthermore, phosphorylated-p38 was significantly increased in the HNPCs following IL-2 treatment. In conclusion, the present study demonstrated that IL-2 inhibits cell proliferation, and induces cell apoptosis and ECM degradation, accompanied by the activation of p38 MAPK signaling in HNPCs. Therefore, IL-2 may be a potential therapeutic agent for the treatment of degenerative disc disease. IntroductionThe prolapse of a lumbar intervertebral disc is a common ailment that places pressure on the surrounding nerves and causes pain in the waist and leg. Intervertebral disc degeneration (IDD) has been demonstrated to be the main cause of lumbar intervertebral disc prolapse. Approximately 20% of teenage indiciduals have discs with mild signs of degeneration, while ~10% of 50-year-old individuals and ~60% of 70-year-old individuals posses discs that exhibit severe degeneration (1). However, the pathogenesis of IDD is associated with various cellular and biochemical alterations (2). IDD is associated with numerous risk factors, including lifestyle, co-morbidities, genetic predisposition and age (3).Previous studies have detected high expression levels of cytokines in degenerated intervertebral disc tissues, including interleukin (IL)-1, interferon (IFN)-γ and tumor necrosis factor (TNF)-α, and these cytokines are associated with the pathogenesis of IDD (4-6).IL-2, which is a pleiotropic cytokine primarily produced by T lymphocytes, has been implicated in the development and control of inflammatory disea...

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Apoptosis, senescence, and autophagy in rat nucleus pulposus cells: Implications for diabetic intervertebral disc degeneration

Cited by 150 publications

References 64 publications

Comment on Park et al.: High glucose-induced oxidative stress promotes autophagy through mitochondrial damage in rat notochordal cells

Comment on Park et al.: High glucose-induced oxidative stress promotes autophagy through mitochondrial damage in rat notochordal cells

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

Interleukin-2 is upregulated in patients with a prolapsed lumbar intervertebral disc and modulates cell proliferation, apoptosis and extracellular matrix metabolism of human nucleus pulposus cells

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