Activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) induces cell death through MAPK-dependent mechanism in osteoblastic cells.
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.
Kim
Sung Hun
SH
Department of Orthopedic Surgery, College of Medicine, Pusan National University, Pusan, Korea.
Yoo
Chong Il
CI
Kim
Hui Taek
HT
Park
Ji Yeon
JY
Kwon
Chae Hwa
CH
Kim
Yong Keun
YK
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
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