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-activated protein kinase subfamilies in hydrogen peroxide (H2O2)-induced cell death of osteoblastic cells. H2O2 resulted in a time- and dose-dependent cell death, which was, in part, attributed to apoptosis. H2O2-induced cell death was prevented by iron chelator, hydroxyl radical scavengers. But H2O2-induced cell death was not affected by 3-aminobenzamide, an inhibitor of poly (ADP-ribose) polymerase activation. H2O2 treatment caused a transient activation of extracellular signal-regulated kinase (ERK), followed by sustained activation. Cell death induced by H2O2 was prevented by PD98059, an inhibitor of ERK upstream kinase MEK1/2. But H2O2 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. H2O2 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 H2O2 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 H2O2-induced apoptosis of osteoblasts and functions upstream of mitochondria-dependent pathway to initiate the apoptotic signal.
Park
Byung Guk
BG
Department of Orthopedic Surgery, College of Medicine, Pusan National University, Pusan 602-739, Republic of Korea.
Yoo
Chong Il
CI
Kim
Hui Taek
HT
Kwon
Chae Hwa
CH
Kim
Yong Keun
YK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
C494827:Bax protein, mouse; D016877:Oxidants; D051028:bcl-2-Associated X Protein; D006861:Hydrogen Peroxide; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases