Acidic pH promotes nucleus pulposus cell senescence through activating the p38 MAPK pathway

Background: Nucleus pulposus (NP) cell senescence is an important cellular feature within the degenerative disc. It is known that a very acidic niche exists in the degenerative disc, which participates in regulating disc cell viability and matrix metabolism. Objective: The present study was aimed to investigate the role and potential signaling transduction pathway of an acidic pH in regulating NP cell senescence. Methods: Rat NP cells were cultured in an acidic pH of 7.2 close to that in a healthy disc (Control group) or in an acidic pH of 6.2 close to that in a severe degenerative disc (Experiment group) for 10 days. Additionally, the experimental NP cells were incubated along with the inhibitor SB203580 to analyze the role of p38 MAPK pathway in this process. Results: Compared with the control NP cells, experimental NP cells showed a suppressed cell proliferation potency, an increased G0/G1 phase fraction whereas a decreased S-phase fraction and a declined telomerase activity, an up-regulated expression of senescence-related molecules (p16 and p53), and a down-regulated expression of matrix-related moleucles (aggrecan and collagen II). Further analysis showed that inhibition of the p38 MAPK pathway partly reversed effects of acidic pH of 6.2 on the experimental NP cells. Conclusion: The very acidic niche identified in a severe degenerative disc promotes NP cell senescence through regulating the p38 MAPK pathway. The present study provides a new mechanism that drives NP cell senescence during disc degeneration.

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Osteogenic protein-1 attenuates apoptosis and enhances matrix synthesis of nucleus pulposus cells under high magnitude compression though inhibiting the p38 MAPK pathway

Bioscience Reports ◽

10.1042/bsr20180018 ◽

2018 ◽

Vol 38 (2) ◽

Cited By ~ 3

Author(s):

Haolin Fang ◽

Xianzhou Li ◽

Haiming Shen ◽

Buwei Sun ◽

Haijun Teng ◽

...

Keyword(s):

Nucleus Pulposus ◽

P38 Mapk ◽

Disc Degeneration ◽

Cell Apoptosis ◽

Caspase 3 ◽

Mapk Pathway ◽

High Magnitude ◽

P38 Mapk Pathway ◽

Regulated Expression ◽

Osteogenic Protein

Disc degeneration is correlated with mechanical load. Osteogenic protein-1 (OP-1) is potential to regenerate degenerative disc. To investigate whether OP-1 can protect against high magitude compression-induced nucleus pulposus (NP) cell apoptosis and NP matrix catabolism, and its potential mechanism; porcine discs were cultured in a bioreactor and compressed at a relatively high-magnitude mechanical compression (1.3 MPa at a frequency of 1.0 Hz for 2 h once per day) for 7 days. OP-1 was added along with the culture medium to investigate the protective effects of OP-1. NP cell apoptosis and matrix biosynthesis were evaluated. Additionally, activity of the p38 MAPK pathway is also analyzed. Compared with the control group, high magnitude compression significantly promoted NP cell apoptosis and decreased NP matrix biosynthesis, reflected by the increase in the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells and caspase-3 activity, the up-regulated expression of Bax and caspase-3 mRNA and down-regulated expression of Bcl-2 mRNA, and the decreased Alcian Blue staining intensity and expression of matrix proteins (aggrecan and collagen II). However, OP-1 addition partly attenuated the effects of high magnitude compression on NP cell apoptosis and NP matrix biosynthesis. Further analysis showed that inhibition of the p38 MAPK pathway partly participated in this process. OP-1 can attenuate high magnitude compression-induced NP cell apoptosis and promoted NP matrix biosynthesis, and inhibition of the p38 MAPK pathway may participate in this regulatory process. The present study provides that OP-1 may be efficient in retarding mechanical overloading-exacerbated disc degeneration.

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Role of p38–MAPK pathway in the effects of high-magnitude compression on nucleus pulposus cell senescence in a disc perfusion culture

Bioscience Reports ◽

10.1042/bsr20170718 ◽

2017 ◽

Vol 37 (5) ◽

Cited By ~ 14

Author(s):

Lianglong Pang ◽

Pei Li ◽

Ruijie Zhang ◽

Yuan Xu ◽

Lei Song ◽

...

Keyword(s):

Nucleus Pulposus ◽

P38 Mapk ◽

Ex Vivo ◽

Mapk Pathway ◽

Cell Senescence ◽

Bioreactor Culture ◽

Pathological Feature ◽

High Magnitude ◽

P38 Mapk Pathway

Nucleus pulposus (NP) cell senescence is a typical pathological feature within the degenerative intervertebral disc. As a potential inducing and aggregating factor of disc degeneration, mechanical overloading affects disc biology in multiple ways. The present study was to investigate the NP cell senescence-associated phenotype under intermittent high compression in an ex vivo disc bioreactor culture, and the role of the p38–MAPK pathway in this regulatory process. Porcine discs were cultured in culture chambers of a self-developed mechanically active bioreactor and subjected to different magnitudes of dynamic compression (low-magnitude and high-magnitude: 0.1 and 1.3 MPa at a frequency of 1.0 Hz for 2 h per day respectively) for 7 days. Non-compressed discs were used as controls. The inhibitor SB203580 was used to study the role of the p38–MAPK pathway in this process. Results showed that intermittent high-magnitude compression clearly induced senescence-associated changes in NP cells, such as increasing β-galactosidase-positive NP cells, decreasing PCNA-positive NP cells, promoting the formation of senescence-associated heterochromatic foci (SAHF), up-regulating the expression of senescence markers (p16 and p53), and attenuating matrix production. However, inhibition of the p38–MAPK pathway partly attenuated the effects of intermittent high-magnitude (1.3 MPa) compression on those described NP cell senescence-associated parameters. In conclusion, intermittent high-magnitude compression can induce NP cell senescence-associated changes in an ex vivo disc bioreactor culture, and the p38–MAPK pathway is involved in this process.

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Mechano growth factor attenuates mechanical overload-induced nucleus pulposus cell apoptosis through inhibiting the p38 MAPK pathway

Bioscience Reports ◽

10.1042/bsr20182462 ◽

2019 ◽

Vol 39 (3) ◽

Cited By ~ 4

Author(s):

Qing Xu ◽

Haolin Fang ◽

Liang Zhao ◽

Cunxin Zhang ◽

Luo Zhang ◽

...

Keyword(s):

Growth Factor ◽

Protein Expression ◽

Nucleus Pulposus ◽

P38 Mapk ◽

Disc Degeneration ◽

Cell Apoptosis ◽

Caspase 3 ◽

Mapk Pathway ◽

P38 Mapk Pathway ◽

Mechanical Overload

Abstract Mechanical overload is a risk factor of disc degeneration. It can induce disc degeneration through mediating cell apoptosis. Mechano growth factor (MGF) has been reported to inhibit mechanical overload-induced apoptosis of chondrocytes. The present study is aimed to investigate whether MGF can attenuate mechanical overload-induced nucleus pulposus (NP) cell apoptosis and the possible signaling transduction pathway. Rat NP cells were cultured and subjected to mechanical overload for 7 days. The control NP cells did not experience mechanical load. The exogenous MGF peptide was added into the culture medium to investigate its protective effects. NP cell apoptosis ratio, caspase-3 activity, gene expression of Bcl-2, Bax and caspase-3, protein expression of cleaved caspase-3, cleaved PARP, Bax and Bcl-2 were analyzed to evaluate NP cell apoptosis. In addition, activity of the p38 MAPK pathway was also detected. Compared with the control NP cells, mechanical overload significantly increased NP cell apoptosis and caspase-3 activity, up-regulated gene/protein expression of pro-apoptosis molecules (i.e. Bax, caspase-3, cleaved caspase-3 and cleaved PARP) whereas down-regulated gene/protein expression of anti-apoptosis molecule (i.e. Bcl-2). However, exogenous MGF partly reversed these effects of mechanical overload on NP cell apoptosis. Further results showed that activity of the p38 MAPK pathway of NP cells cultured under mechanical overload was decreased by addition of MGF peptide. In conclusion, MGF is able to attenuate mechanical overload-induced NP cell apoptosis, and the p38 MAPK signaling pathway may be involved in this process. The present study provides that MGF supplementation may be a promising strategy to retard mechanical overload-induced disc degeneration.

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Inflammatory cytokines induce caveolin-1/β-catenin signalling in rat nucleus pulposus cell apoptosis through the p38 MAPK pathway

Cell Proliferation ◽

10.1111/cpr.12254 ◽

2016 ◽

Vol 49 (3) ◽

pp. 362-372 ◽

Cited By ~ 40

Author(s):

Jianxi Wang ◽

Huajiang Chen ◽

Peng Cao ◽

Xiaodong Wu ◽

Fazhi Zang ◽

...

Keyword(s):

Nucleus Pulposus ◽

P38 Mapk ◽

Inflammatory Cytokines ◽

Cell Apoptosis ◽

Mapk Pathway ◽

Nucleus Pulposus Cell ◽

Caveolin 1 ◽

P38 Mapk Pathway

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HtrA1 is induced by oxidative stress and enhances cell senescence through p38 MAPK pathway

Experimental Eye Research ◽

10.1016/j.exer.2013.04.013 ◽

2013 ◽

Vol 112 ◽

pp. 79-92 ◽

Cited By ~ 20

Author(s):

Supanji ◽

Mari Shimomachi ◽

Md.Zobaer Hasan ◽

Masashi Kawaichi ◽

Chio Oka

Keyword(s):

Oxidative Stress ◽

P38 Mapk ◽

Mapk Pathway ◽

Cell Senescence ◽

P38 Mapk Pathway

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Research on Roles of Mongolian Medical Warm Acupuncture in Inhibiting p38 MAPK Activation and Apoptosis of Nucleus Pulposus Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/6571320 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8

Author(s):

Sha Li ◽

Lidao Bao ◽

Lengge Si ◽

Xiaohui Wang ◽

Agula Bo

Keyword(s):

Oxidative Stress ◽

Gene Expression ◽

Extracellular Matrix ◽

Matrix Metalloproteinase ◽

Nucleus Pulposus ◽

P38 Mapk ◽

Mapk Pathway ◽

Active Oxygen ◽

Nucleus Pulposus Cells ◽

P38 Mapk Pathway

Background. Mongolian medical warm acupuncture has a desirable therapeutic effect on sciatica. Apoptosis of the nucleus pulposus cells is considered to play an important role in sciatica. Evidence has demonstrated that oxidative stress and its induced activation of the signaling pathways play important roles in sciatica. However, further research is expected to reveal whether Mongolian medical warm acupuncture can inhibit the apoptosis of nucleus pulposus cells and oxidative stress. Objective. To study the effect of the p38 MAPK pathway activated by the generated ROS on apoptosis and the expression of the genes related to the balance of the extracellular matrix metabolism during treatment of sciatica with Mongolian medical warm acupuncture. Method. The volume of the active oxygen generated in the nucleus pulposus cells was detected following intervention of Mongolian medical warm acupuncture. The p38 MAPK phosphorylation level was detected with Western blot. The genes are related to the metabolism of the nucleus pulposus extracellular matrix. Result. Mongolian medical warm acupuncture reduced the active oxygen within the nucleus pulposus cells and inhibited the activation of the p38 MAPK pathway (P=0.013). Meanwhile, it upregulated the gene expression of Type II collagen, aggrecan, Sox-9, and tissue matrix metalloproteinase reagent 1 (P-0.015; P=0.025; P=0.031; P=0.045) and downregulated the gene expression of matrix metalloproteinase 3 (P=0.015). Conclusion. Mongolian medical warm acupuncture may inhibit apoptosis of nucleus pulposus cells and activation of the extracellular matrix decomposition metabolism pathway and promote its anabolism. This process may rely on the oxidative stress matrix of the p38 MAPK pathway.

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