N-Cadherin-Mediated Activation of PI3K/Akt-GSK-3β Signaling Attenuates Nucleus Pulposus Cell Apoptosis Under High-Magnitude Compression

Li, Pei; Liang, Zherui; Hao, Gang; Song, Lei; Zhang, Ruijie; Ye, Gan; Zhang, Chengmin; Xu, Yang; Zhou, Qiang

doi:10.1159/000484649

Cited by 35 publications

(31 citation statements)

References 43 publications

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“…Previous studies demonstrated that N-CDH played an important role in maintaining normal NP cell phenotype and NP matrix biosynthesis [14, 15]. N-CDH-mediated signaling can protect against NP cell apoptosis under mechanical loading [16, 17]. However, whether N-CDH can protect against NP cell senescence under high glucose conditions is not clear.…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…Due to its adverse impulsion on either individuals or society, IDD has been a highlighted research field, and many factors have been found to contribute to the development of IDD, including age, metabolism, nutrition, and mechanical loading [37]. Among those damaging factors, excessive/abnormal mechanical loading on IVD has been determined to be a primary incentive [38]. Moreover, the underlying mechanism of pressure-induced IDD has now been clarified to a great extent, and many singling pathways have been demonstrated to be involved in the progress, such as TGF-β, PI3K/Akt pathway, and p38-MAPK pathway [37,38].…”

Section: Discussionmentioning

confidence: 99%

“…Among those damaging factors, excessive/abnormal mechanical loading on IVD has been determined to be a primary incentive [38]. Moreover, the underlying mechanism of pressure-induced IDD has now been clarified to a great extent, and many singling pathways have been demonstrated to be involved in the progress, such as TGF-β, PI3K/Akt pathway, and p38-MAPK pathway [37,38].…”

Section: Discussionmentioning

confidence: 99%

“…The PI3K/Akt pathway is a vital intracellular pathway that regulates the cell cycle, which reveals its significant influence on cellular proliferation, aging, cancer development, and apoptosis [47][48][49]. Compression has been reported to induce NPC apoptosis by downregulating N-cadherin and inhibiting the PI3K/Akt signaling pathway [38]. Activation of the PI3K/Akt signaling pathway might be an approach to rescue cell apoptosis [50].…”

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confidence: 99%

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Puerarin Relieved Compression-Induced Apoptosis and Mitochondrial Dysfunction in Human Nucleus Pulposus Mesenchymal Stem Cells via the PI3K/Akt Pathway

Huang

Peng

et al. 2020

Stem Cells International

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Puerarin (PUR), an 8-C-glucoside of daidzein extracted from Pueraria plants, is closely related to autophagy, reduced reactive oxygen species (ROS) production, and anti-inflammatory effects, but its effects on human nucleus pulposus mesenchymal stem cells (NPMSCs) have not yet been identified. In this study, NPMSCs were cultured in a compression apparatus to simulate the microenvironment of the intervertebral disc under controlled pressure (1.0 MPa), and we found that cell viability was decreased and apoptosis level was gradually increased as compression duration was prolonged. After PUR administration, apoptosis level evaluated by flow cytometry and caspase-3 activity was remitted, and protein levels of Bas as well as cleaved caspase-3 were decreased, while elevated Bcl-2 level was identified. Moreover, ATP production detection, ROS, and JC-1 fluorography as well as quantitative analysis suggested that PUR could attenuate intercellular ROS accumulation and mitochondrial dysfunction. Besides, the rat tail compression model was utilized, which indicated that PUR could restore impaired nucleus pulposus degeneration induced by compression. The PI3K/Akt pathway was identified to be deactivated after compression stimulation by western blot, and PUR could rescue the phosphorylation of Akt, thus reactivating the pathway. The effects of PUR, such as antiapoptosis, cell viability restoration, antioxidation, and mitochondrial maintenance, were all counteracted by application of the PI3K/Akt pathway inhibitor (LY294002). Summarily, PUR could alleviate compression-induced apoptosis and cell death of human NPMSCs in vitro as well as on the rat compression model and maintain intracellular homeostasis by stabilizing mitochondrial membrane potential and attenuating ROS accumulation through activating the PI3K/Akt pathway.

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“…Many adverse factors contribute to IVD degeneration, such as adverse microenvironment, cytokines. Previous studies indicated that activation of PI3K/AKT signaling attenuated NP cells apoptosis induced by high-magnitude compression [23] or hyperosmotic conditions [24]. In addition, PI3K/AKT could protect NP cells against apoptosis induced by some cytokines, such as IL-1β [25] and TNF-ɑ [26].…”

Section: Introductionmentioning

confidence: 99%

The protective effects of PI3K/Akt pathway on human nucleus pulposus mesenchymal stem cells against hypoxia and nutrition deficiency

Tian

Chen

et al. 2020

J Orthop Surg Res

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Background: To study the effects of hypoxia and nutrition deficiency mimicking degenerated intervertebral disc on the biological behavior of human nucleus-derived pulposus mesenchymal stem cells (hNP-MSCs) and the role of PI3K/Akt pathway in the process in vitro. Methods: hP-MSCs were isolated from lumbar disc and were further identified by their immunophenotypes and multilineage differentiation. Then, cells were divided into the control group, hypoxia and nutrition deficiency group, the LY294002 group, and insulin-like growth factor 1 (IGF-1) group. Then cell apoptosis, the cell viability, the caspase 3 activity, and the expression of PI3K, Akt, and functional genes (aggrecan, collagen I, and collagen II) were evaluated. Result: Our work showed that isolated cells met the criteria of International Society for cellular Therapy. Therefore, cells obtained from degenerated nucleus pulposus were definitely hNP-MSCs. Our results showed that hypoxia and nutrition deficiency could significantly increase cell apoptosis, the caspase 3 activity, and inhibit cell viability. Gene expression results demonstrated that hypoxia and nutrition deficiency could increase the relative expression of PI3K and Akt gene and inhibit the expression of functional genes. However, when the PI3K/Akt pathway was inhibited by LY294002, the cell apoptosis and caspase 3 activity significantly increased while the cell viability was obviously inhibited. Quantitative real-time PCR results showed that the expression of functional genes was more significantly inhibited. Our study further verified that the abovementioned biological activities of hNP-MSCs could be significantly improved by IGF1. Conclusions: PI3K/Akt signal pathway may have protective effects on human nucleus pulposus-derived mesenchymal stem cells against hypoxia and nutrition deficiency.

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N-Cadherin-Mediated Activation of PI3K/Akt-GSK-3β Signaling Attenuates Nucleus Pulposus Cell Apoptosis Under High-Magnitude Compression

Cited by 35 publications

References 43 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

Puerarin Relieved Compression-Induced Apoptosis and Mitochondrial Dysfunction in Human Nucleus Pulposus Mesenchymal Stem Cells via the PI3K/Akt Pathway

The protective effects of PI3K/Akt pathway on human nucleus pulposus mesenchymal stem cells against hypoxia and nutrition deficiency

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