skip to main content

Title: Activation of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) 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 PPAR{gamma} agonists in osteoblastic cells. Ciglitazone and troglitazone, PPAR{gamma} agonists, resulted in a concentration- and time-dependent cell death, which was largely attributed to apoptosis. But a PPAR{alpha} 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 PPAR{gamma} 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 cellmore » 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.« less
Authors:
 [1] ;  [1] ;  [2] ;  [1] ;  [2] ;  [3] ;  [3] ;  [4]
  1. Department of Orthopedic Surgery, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of)
  2. (Korea, Republic of)
  3. Department of Physiology, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of)
  4. Department of Physiology, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of) and Medical Research Institute, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of) and MRC for Ischemic Tissue Regeneration, College of Medicine, Pusan National University, Pusan, 602-739 (Korea, Republic of). E-mail: kim430@pusan.ac.kr
Publication Date:
OSTI Identifier:
20850407
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 215; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2006.03.001; PII: S0041-008X(06)00089-5; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIOXIDANTS; APOPTOSIS; CONNECTIVE TISSUE CELLS; GROWTH FACTORS; MEMBRANES; MITOCHONDRIA; OSTEOPOROSIS; OXYGEN; RECEPTORS; TIME DEPENDENCE