期刊
EUROPEAN CELLS & MATERIALS
卷 30, 期 -, 页码 89-103出版社
AO RESEARCH INSTITUTE DAVOS-ARI
DOI: 10.22203/eCM.v030a07
关键词
oxidative stress; H2O2; intervertebral disc nucleus pulposus cells; MAPKs; Akt; Nrf2; NF-kappa B; ROS; ATM; senescence
资金
- European Union FP7 (GENODISC project) [HEALTH-F2-2008-201626]
Aged and degenerated intervertebral discs are characterised by a significant increase in the number of senescent cells, which may be associated with the deterioration of this tissue due to their catabolic phenotype. On the other hand, carboxymethyl-lysine has been found to be accumulated with ageing in the proteins of the disc, evidencing the existence of oxidative stress in this tissue. Accordingly, here we investigated the effect of oxidative stress on the physiology of human nucleus pulposus cells. Hydrogen peroxide (H2O2) at subcytotoxic concentrations transiently increased the intracellular levels of reactive oxygen species, activated the p38 MAPK, ERKs, JNKs and Akt signalling pathways and induced the nuclear translocation of NF-kappa B and Nrf2. It also provoked DNA damage and triggered a DNA repair response by activating the ATM-Chk2-p53-p21WAF1-pRb pathway, ultimately resulting in a G1 cell cycle delay and the decrease of cells' proliferation. Prolonged exposure to H2O2 led to premature cellular senescence, as characterised by the inhibition of proliferation, the enhanced senescence-associated beta galactosidase staining and the over-expression of known molecular markers, without though a significant decrease in the chromosome telomere length. H2O2-senescent cells were found to possess a catabolic phenotype, mainly characterised by the up-regulation of extracellular matrix-degrading enzymes (MMP-1, -2, -9 and ADAMTS-5) and the down-regulation of their inhibitors (TIMPs), as well as of several proteoglycans, including aggrecan, the major component of the nucleus pulposus. The senescent phenotype could be reversed by N-acetyl-L-cysteine, supporting the use of antioxidants for the improvement of disc physiology and the deceleration of disc degeneration.
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