| Activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) induces cell death through MAPK-dependent mechanism in osteoblastic cells. | |
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MedLine Citation:
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PMID: 16616945 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Sung Hun Kim; Chong Il Yoo; Hui Taek Kim; Ji Yeon Park; Chae Hwa Kwon; Yong Keun Kim |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2006-04-17 |
Journal Detail:
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Title: Toxicology and applied pharmacology Volume: 215 ISSN: 0041-008X ISO Abbreviation: Toxicol. Appl. Pharmacol. Publication Date: 2006 Sep |
Date Detail:
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Created Date: 2006-08-16 Completed Date: 2006-09-28 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0416575 Medline TA: Toxicol Appl Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 198-207 Citation Subset: IM |
Affiliation:
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Department of Orthopedic Surgery, College of Medicine, Pusan National University, Pusan, Korea. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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3T3 Cells Anilides / pharmacology Animals Antioxidants / pharmacology Apoptosis / drug effects, physiology* Cell Survival / drug effects Chromans / pharmacology Clofibric Acid / analogs & derivatives, pharmacology Dose-Response Relationship, Drug Drug Antagonism Enzyme Activation Enzyme Inhibitors / pharmacology Hypoglycemic Agents / pharmacology Mice Mitogen-Activated Protein Kinases / metabolism* Osteoblasts / drug effects, enzymology*, pathology PPAR gamma / antagonists & inhibitors, metabolism* Reactive Oxygen Species / metabolism Thiazolidinediones / pharmacology p38 Mitogen-Activated Protein Kinases / metabolism |
| Chemical | |
Reg. No./Substance:
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0/2-chloro-5-nitrobenzanilide; 0/Anilides; 0/Antioxidants; 0/Chromans; 0/Enzyme Inhibitors; 0/Hypoglycemic Agents; 0/PPAR gamma; 0/Reactive Oxygen Species; 0/Thiazolidinediones; 52214-84-3/ciprofibrate; 74772-77-3/ciglitazone; 882-09-7/Clofibric Acid; 97322-87-7/troglitazone; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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