Apoptotic insults to human chondrocytes induced by sodium nitroprusside are involved in sequential events,including cytoskeletal remodeling,phosphorylation of mitogen‐activated protein kinase kinase kinase‐1/c‐Jun N‐terminal kinase,and Bax‐Mitochondria‐Mediated caspase activation |
| |
| Authors: | Yih‐Giun Cherng Hua‐Chia Chang Yi‐Ling Lin Ming‐Liang Kuo Wen‐Ta Chiu Ruei‐Ming Chen |
| |
| Affiliation: | 1. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250 Wu‐Hsing St., Taipei 110, Taiwan, Republic of China;2. Core Laboratories, Department of Anesthesiology, Wan‐Fang Hospital, Taipei Medical University, Taipei, Taiwan, Republic of China;3. Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China;4. Center of Excellence for Clinical Trial and Research in Neurology, Wan‐Fang Hospital, Taipei Medical University, Taipei, Taiwan, Republic of China |
| |
| Abstract: | Nitric oxide (NO) can regulate chondrocyte activities. This study was aimed to evaluate the molecular mechanisms of NO donor sodium nitroprusside (SNP)‐induced insults to human chondrocytes. Exposure of human chondrocytes to SNP increased cellular NO levels but decreased cell viability in concentration‐ and time‐dependent manners. SNP time dependently induced DNA fragmentation and cell apoptosis. Treatment with 2‐phenyl‐4,4,5,5‐tetramethyl‐imidazoline‐1‐oxyl 3‐oxide, an NO scavenger, significantly lowered SNP‐induced cell injuries. Administration of SNP interrupted F‐actin and microtubule cytoskeletons and stimulated phosphorylation of mitogen‐activated protein kinase kinase kinase‐1 (MEKK1) and c‐Jun N‐terminal kinase (JNK). Similar to SNP, cytochalasin D, an inhibitor of F‐actin formation, disturbed F‐actin polymerization and increased MEKK1 and JNK activations. Overexpression of a dominant negative mutant of MEKK1 (dnMEK1) in human chondrocytes significantly ameliorated SNP‐induced cell apoptosis. Exposure to SNP promoted Bax translocation from the cytoplasm to mitochondria, but application of dnMEKK1 lowered the translocation. SNP time dependently decreased the mitochondrial membrane potential, complex I NADH dehydrogenase activity, and cellular ATP levels, but increased the release of cytochrome c from mitochondria to the cytoplasm. Activities of caspase‐9, ‐3, and ‐6 were sequentially increased by SNP administration. This study shows that SNP can induce apoptosis of human chondrocytes through sequential events, including cytoskeletal remodeling, activation of MEKK1/JNK, Bax translocation, mitochondrial dysfunction, cytochrome c release, caspase activation, and DNA fragmentation. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:1018–1026, 2008 |
| |
| Keywords: | human chondrocytes nitric oxide cytoskeletal remodeling MEKK1/JNK Bax translocation mitochondria‐dependent apoptotic mechanism |
|
|
