Role of mitogen-activated protein kinase (MAPK) in troglitazone-induced osteoblastic cell death.
Troglitazone, a PPARgamma agonist, has been reported to induce cell death on different cell types. However, its mechanism of action remains unclear. The present study was undertaken to investigate the effect of troglitazone on cell death and to determine its underlying mechanism in MC3T3-E1 cells, an established osteoblast cell line. Troglitazone induced loss of cell viability in a dose- and time-dependent manner, which was accompanied by apoptosis. Troglitazone increased reactive oxygen species (ROS), but troglitazone-induced cell death was not affected by the antioxidant N-acetylcysteine, suggesting that the ROS generation is not involved in the cytotoxicity of troglitazone. Troglitazone-induced cell death was prevented by the PPARgamma antagonist GW9662. Troglitazone treatment inhibited activation of extracellular signal-regulated protein kinase (ERK) and stimulated p38 activation. Troglitazone-induced cell death was increased by the ERK inhibitor U0126 and prevented by transfection with constitutively active MEK1 and the p38 inhibitor SB203580. Troglitazone induced depolarization of mitochondrial membrane potential and its effect was blocked by SB203580 and GW9662. Caspase-3 was activated by troglitazone treatment and pharmacological inhibition of caspase blocked troglitazone-induced cell death. Taken together, these data suggest that troglitazone induces apoptosis via a caspase-dependent mechanism associated with down-regulation of ERK and up-regulation of p38.
Jung
Ju Young
JY
Department of Orthopedic Surgery, College of Medicine, Pusan National University, Pusan, Republic of Korea.
Yoo
Chong Il
CI
Kim
Hui Taek
HT
Kwon
Chae Hwa
CH
Park
Ji Yeon
JY
Kim
Yong Keun
YK
D016475:3T3 Cells; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D007004:Hypoglycemic Agents / Q000633:toxicity; D007093:Imidazoles / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D045162:Thiazolidinediones / Q000633:toxicity*; D000077288:Troglitazone
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D002070:Butadienes; D061945:Caspase Inhibitors; D002839:Chromans; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007093:Imidazoles; D009570:Nitriles; D047495:PPAR gamma; D011725:Pyridines; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; C113580:U 0126; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D053148:Caspase 3; D000077288:Troglitazone; C093642:SB 203580