Rat Notochordal Cells Undergo Premature Stress-Induced Senescence by High Glucose

Park, Jong-Beom; Byun, Chu-Hwan; Park, Eun Young

doi:10.4184/asj.2015.9.4.495

Cited by 18 publications

(22 citation statements)

References 34 publications

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“…The present study found that high glucose obviously increased intracellular ROS generation and activated the downstream NF-κB pathway in NP cells, which indicates that high glucose induced an oxidative stress reaction in NP cells. This result is consistent with previous studies that demonstrated that oxidative stress may be a potential mechanism for high glucose-related disc degenerative changes [9, 33]. However, we found that N-CDH overexpression decreased ROS generation and NF-κB pathway activity in NP cells under the high glucose condition, which indicates that N-CDH may suppress high glucose-induced cellular oxidative stress in NP cells.…”

Section: Discussionsupporting

confidence: 78%

N-Cadherin Attenuates High Glucose-Induced Nucleus Pulposus Cell Senescence Through Regulation of the ROS/NF-κB Pathway

Hao¹,

Zhao²,

Teng³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Diabetes mellitus (DM) is a potential etiology of disc degeneration. N-cadherin (N-CDH) helps maintain the cell viability, cell phenotype and matrix biosynthesis of nucleus pulposus (NP) cells. Here, we mainly aimed to investigate whether N-CDH can attenuate high glucose-induced NP cell senescence and its potential mechanism. Methods: Rat NP cells were cultured in a base culture medium and base culture medium with a 0.2 M glucose concentration. Recombinant lentiviral vectors were used to enhance N-CDH expression in NP cells. Senescence-associated β-galactosidase (SA-β-Gal) activity was measured by SA-β-Gal staining. NP cell proliferation was evaluated by CCK-8 assay. Telomerase activity and intracellular reactive oxygen species (ROS) content were tested by specific chemical kits according to the manufacturer’s instructions. G0/G1 cell cycle arrest was evaluated by flow cytometry. Real-time PCR and Western blotting were used to analyze mRNA and protein expressions of senescence markers (p16 and p53) and matrix macromolecules (aggrecan and collagen II). Additionally, p-NF-κB expression was also analyzed by Western blotting to evaluate NF-κB pathway activity. Results: High glucose significantly decreased N-CDH expression, increased ROS generation and NF-κB pathway activity, and promoted NP cell senescence, which was reflected in the increase in SA-β-Gal activity and senescence marker (p16 and p53) expression, compared to the control group. High glucose decreased telomerase activity and cell proliferation potency. However, N-CDH overexpression partially attenuated NP cell senescence, decreased ROS content and inhibited the activation of the NF-κB pathway under the high glucose condition. Conclusion: High glucose decreases N-CDH expression and promotes NP cell senescence. N-CDH overexpression can attenuate high glucose-induced NP cell senescence through the regulation of the ROS/ NF-κB pathway. This study suggests that N-CDH is a potential therapeutic target to slow DM-mediated disc NP degeneration.

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Section: Discussionsupporting

confidence: 78%

N-Cadherin Attenuates High Glucose-Induced Nucleus Pulposus Cell Senescence Through Regulation of the ROS/NF-κB Pathway

Hao¹,

Zhao²,

Teng³

et al. 2018

Cell Physiol Biochem

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“…Given that NNPC are more metabolically active and sensitive to nutrient disturbances [Guehring et al, 2009;Park et al, 2015], the possibility exists that the notochordal cell resources are exhausted by excessive apoptosis or senescence while the cells attracted from the CEP mediate the fibrocartilaginous changes within the NP [Kim et al, 2003[Kim et al, , 2009]. Another limitation of our hypothesis is that the genetic inheritance of IVD degeneration is not covered by the equation P e = P m + P v .…”

Section: Significance and Limitations Of The Hypothesismentioning

confidence: 88%

Large Cytoplasmic Vacuoles within Notochordal Nucleus Pulposus Cells: A Possible Regulator of Intracellular Pressure That Shapes the Cytoskeleton and Controls Proliferation

Hong

Zhang

Wang

et al. 2018

Cells Tissues Organs

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Degeneration of the intervertebral disc, which is closely associated with the loss of vacuolated notochordal nucleus pulposus cells (NNPC), remains a major cause of lower-back pain and motor deficiency. Being the most defining characteristic of NNPC, large cytoplasmic vacuoles not only modulate the cytoskeleton and shape cell morphology but they also respond to the disc microenvironment and regulate the biological behavior of vacuolated cells as a potent reporter of the histocytological changes that occur at the beginning of disc aging and degeneration. Here we hypothesize a model in which large cytoplasmic vacuoles primarily function to maintain a reasonable intracellular pressure (P_v) that facilitates NNPC in resisting the extracellular mechanical loading (P_e), part of which is absorbed by the extracellular matrix (P_m), forming the equation P_e = P_m + P_v. By mimicking a situation of contact-induced growth inhibition, the crowded cytoplasmic vacuoles slow down the proliferation of NNPC and restrain the generation of nonvacuolated chondrocytic nucleus pulposus cells (CNPC), whereas increased mechanical loading (↑P_e) alters cytoskeletons and breaches cytoplasmic vacuoles, which in turn weakens the vacuoles-mediated proliferation check, increases the generation of CNPC that accumulates fibrocartilaginous matrix, and rebalances the increased loading with elevated P_m (↑P_m) and lowered P_v (↓P_v), equating to ↑P_e = ↑P_m + ↓P_v. By depicting the biological function and the disappearance of the cytoplasmic vacuoles, our model highlights a mechanical exhaustion of the notochordal cell resources, which might help to elucidate the histocytological changes that initiate disc aging and degeneration.

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“…During the transportation of electrons, a small proportion of electrons (1%–3%) leak and reduce O 2 to O 2 − rather than H 2 O [53, 54]. The mitochondrion-dependent ROS production has been reported in various disc cells derived from different species (Figure 1), including human NP cells, human AF cells, rat AF cells, rat notochordal cells, and rabbit NP cells [55–60]. Nonmitochondrial oxygen consumption through nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) or xanthine oxidase (XO) is one other main ROS production site (Figure 1) [61, 62].…”

Section: Ros Production In Healthy Ivdsmentioning

confidence: 99%

“…In this microenvironment, various exogenous stimuli, such as mechanical loading, high oxygen tension, high glucose stress, and proinflammatory cytokines, increase ROS production in disc cells (Figure 2). Furthermore, ROS themselves also enhance ROS production in disc cells, forming a positive feedback loop [14, 15, 20–24, 36, 44, 56–60]. …”

Section: Disturbed Redox Homeostasis In the Microenvironment Of Dementioning

confidence: 99%

“…Structurally, the mitochondrion of human AF cells from degenerative discs showed an abnormal morphology with small cristae, dark colour, and dense inclusion bodies [55]. Moreover, various stimuli have been shown to cause mitochondrion dysfunction in human, rat, and rabbit disc cells, including high oxygen tension, high glucose stress, and abnormal mechanical loading [56–60]. Compression induced the opening of MPTP and decreased MTMP in rabbit NP cells [56].…”

Section: Disturbed Redox Homeostasis In the Microenvironment Of Dementioning

confidence: 99%

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ROS: Crucial Intermediators in the Pathogenesis of Intervertebral Disc Degeneration

Feng

Yang

Lan

et al. 2017

Oxidative Medicine and Cellular Longevity

279

262

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Excessive reactive oxygen species (ROS) generation in degenerative intervertebral disc (IVD) indicates the contribution of oxidative stress to IVD degeneration (IDD), giving a novel insight into the pathogenesis of IDD. ROS are crucial intermediators in the signaling network of disc cells. They regulate the matrix metabolism, proinflammatory phenotype, apoptosis, autophagy, and senescence of disc cells. Oxidative stress not only reinforces matrix degradation and inflammation, but also promotes the decrease in the number of viable and functional cells in the microenvironment of IVDs. Moreover, ROS modify matrix proteins in IVDs to cause oxidative damage of disc extracellular matrix, impairing the mechanical function of IVDs. Consequently, the progression of IDD is accelerated. Therefore, a therapeutic strategy targeting oxidative stress would provide a novel perspective for IDD treatment. Various antioxidants have been proposed as effective drugs for IDD treatment. Antioxidant supplementation suppresses ROS production in disc cells to promote the matrix synthesis of disc cells and to prevent disc cells from death and senescence in vitro. However, there is not enough in vivo evidence to support the efficiency of antioxidant supplementation to retard the process of IDD. Further investigations based on in vivo and clinical studies will be required to develop effective antioxidative therapies for IDD.

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Rat Notochordal Cells Undergo Premature Stress-Induced Senescence by High Glucose

Cited by 18 publications

References 34 publications

N-Cadherin Attenuates High Glucose-Induced Nucleus Pulposus Cell Senescence Through Regulation of the ROS/NF-κB Pathway

N-Cadherin Attenuates High Glucose-Induced Nucleus Pulposus Cell Senescence Through Regulation of the ROS/NF-κB Pathway

Large Cytoplasmic Vacuoles within Notochordal Nucleus Pulposus Cells: A Possible Regulator of Intracellular Pressure That Shapes the Cytoskeleton and Controls Proliferation

ROS: Crucial Intermediators in the Pathogenesis of Intervertebral Disc Degeneration

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