Role of mitogen-activated protein kinases in hydrogen peroxide-induced cell death in osteoblastic cells

Oxidative stress is known to induce cell death in a wide variety of cell types, apparently by modulating intracellular signaling pathways. However, the underlying mechanism by which oxidants induce cell death remains unclear. The present study was undertaken to determine the role of the mitogen-acti...

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Published in:Toxicology (Amsterdam) 2005-11, Vol.215 (1), p.115-125
Main Authors: Park, Byung Guk, Yoo, Chong Il, Kim, Hui Taek, Kwon, Chae Hwa, Kim, Yong Keun
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptosis - drug effects
Bax
bcl-2-Associated X Protein - biosynthesis
Biological and medical sciences
Cell Line
Cell Survival - drug effects
Hydrogen peroxide
Hydrogen Peroxide - toxicity
MAPK
Medical sciences
Membrane Potentials - drug effects
Mice
Mitochondria - drug effects
Mitochondria - physiology
Mitochondrial membrane potential
Mitogen-Activated Protein Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinases - physiology
Osteoblasts
Osteoblasts - cytology
Osteoblasts - drug effects
Osteoblasts - enzymology
Osteoblasts - metabolism
Oxidants - toxicity
Oxidative Stress - drug effects
Receptor, Epidermal Growth Factor - metabolism
Toxicology
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Summary:Oxidative stress is known to induce cell death in a wide variety of cell types, apparently by modulating intracellular signaling pathways. However, the underlying mechanism by which oxidants induce cell death remains unclear. The present study was undertaken to determine the role of the mitogen-activated protein kinase subfamilies in hydrogen peroxide (H 2O 2)-induced cell death of osteoblastic cells. H 2O 2 resulted in a time- and dose-dependent cell death, which was, in part, attributed to apoptosis. H 2O 2-induced cell death was prevented by iron chelator, hydroxyl radical scavengers. But H 2O 2-induced cell death was not affected by 3-aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase activation. H 2O 2 treatment caused a transient activation of extracellular signal-regulated kinase (ERK), followed by sustained activation. Cell death induced by H 2O 2 was prevented by PD98059, an inhibitor of ERK upstream kinase MEK1/2. But H 2O 2 induced a transient activation of p38 and c-Jun N-terminal kinase (JNK) without sustained activation and inhibitors of these kinses were not effective in preventing the cell death. H 2O 2 increased Bax expression and produced hyperpolarization of mitochondrial membrane potential and its effect was prevented by PD98059. The ERK activation and cell death induced by H 2O 2 were not dependent on the phosphorylation of epidermal growth factor receptor. Taken together, these findings suggest that the ERK signaling pathway plays an active role in mediating H 2O 2-induced apoptosis of osteoblasts and functions upstream of mitochondria-dependent pathway to initiate the apoptotic signal.
ISSN:0300-483X
1879-3185
DOI:10.1016/j.tox.2005.07.003