title: Activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) induces cell death through MAPK-dependent mechanism in osteoblastic cells.
abstract: The present study was undertaken to determine the role of the mitogen-activated protein kinase (MAPK) subfamilies in cell death induced by PPARgamma agonists in osteoblastic cells. Ciglitazone and troglitazone, PPARgamma agonists, resulted in a concentration- and time-dependent cell death, which was largely attributed to apoptosis. But a PPARalpha agonist ciprofibrate did not affect the cell death. Ciglitazone caused reactive oxygen species (ROS) generation and ciglitazone-induced cell death was prevented by antioxidants, suggesting an important role of ROS generation in the ciglitazone-induced cell death. ROS generation and cell death induced by ciglitazone were inhibited by the PPARgamma antagonist GW9662. Ciglitazone treatment caused activation of extracellular signal-regulated kinase (ERK) and p38. Activation of ERK was dependent on epidermal growth factor receptor (EGFR) and that of p38 was independent. Ciglitazone-induced cell death was significantly prevented by PD98059, an inhibitor of ERK upstream kinase MEK1/2, and SB203580, a p38 inhibitor. Ciglitazone treatment increased Bax expression and caused a loss of mitochondrial membrane potential, and its effect was prevented by N-acetylcysteine, PD98059, and SB203580. Ciglitazone induced caspase activation, which was prevented by PD98059 and SB203580. The general caspase inhibitor z-DEVD-FMK and the specific inhibitor of caspases-3 DEVD-CHO exerted the protective effect against the ciglitazone-induced cell death. The EGFR inhibitors AG1478 and suramin protected against the ciglitazone-induced cell death. Taken together, these findings suggest that the MAPK signaling pathways play an active role in mediating the ciglitazone-induced cell death of osteoblasts and function upstream of a mitochondria-dependent mechanism. These data may provide a novel insight into potential therapeutic strategies for treatment of osteoporosis.
authors.affiliation: Department of Orthopedic Surgery, College of Medicine, Pusan National University, Pusan, Korea.
authors.forename: Sung Hun
authors.initials: SH
authors.lastname: Kim
authors.forename: Chong Il
authors.initials: CI
authors.lastname: Yoo
authors.forename: Hui Taek
authors.initials: HT
authors.lastname: Kim
authors.forename: Ji Yeon
authors.initials: JY
authors.lastname: Park
authors.forename: Chae Hwa
authors.initials: CH
authors.lastname: Kwon
authors.forename: Yong Keun
authors.initials: YK
authors.lastname: Kim
mesh_terms: D016475:3T3 Cells; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology; D002995:Clofibric Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058607:Fibric Acids; D007004:Hypoglycemic Agents / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D000975:Antioxidants; D002839:Chromans; D004791:Enzyme Inhibitors; D058607:Fibric Acids; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D045162:Thiazolidinediones; D002995:Clofibric Acid; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C019304:ciprofibrate; D000077288:Troglitazone; C039671:ciglitazone