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Cilostazol protects rat chondrocytes against nitric oxide-induced apoptosis in vitro and prevents cartilage destruction in a rat model of osteoarthritis

Authors
 Sung Won Lee  ;  Yeon Suk Song  ;  Sang Hwa Shin  ;  Kyung Taek Kim  ;  Young Chul Park  ;  Bong Soo Park  ;  Il Yun  ;  Kunhong Kim  ;  Sang Yeob Lee  ;  Won Tae Chung  ;  Hye Jeong Lee  ;  Young Hyun Yoo 
Citation
 Arthritis & Rheumatism, Vol.58(3) : 790-800, 2008 
Journal Title
 Arthritis & Rheumatism 
ISSN
 0004-3591 
Issue Date
2008
MeSH
Animals ; Apoptosis/drug effects* ; BH3 Interacting Domain Death Agonist Protein/metabolism ; Cartilage, Articular/drug effects ; Cartilage, Articular/metabolism ; Cartilage, Articular/pathology* ; Casein Kinase II/metabolism ; Caspases/metabolism ; Cells, Cultured ; Chondrocytes/drug effects ; Chondrocytes/metabolism ; Chondrocytes/pathology* ; Cilostazol ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Nitric Oxide/adverse effects ; Nitric Oxide/pharmacology* ; Nitric Oxide Synthase Type II/metabolism ; Osteoarthritis, Knee/metabolism ; Osteoarthritis, Knee/pathology ; Osteoarthritis, Knee/prevention & control* ; Phosphodiesterase Inhibitors/pharmacology* ; Phosphodiesterase Inhibitors/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Tetrazoles/pharmacology* ; Tetrazoles/therapeutic use ; Tumor Suppressor Protein p53/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism
Keywords
Animals ; Apoptosis/drug effects* ; BH3 Interacting Domain Death Agonist Protein/metabolism ; Cartilage, Articular/drug effects ; Cartilage, Articular/metabolism ; Cartilage, Articular/pathology* ; Casein Kinase II/metabolism ; Caspases/metabolism ; Cells, Cultured ; Chondrocytes/drug effects ; Chondrocytes/metabolism ; Chondrocytes/pathology* ; Cilostazol ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Nitric Oxide/adverse effects ; Nitric Oxide/pharmacology* ; Nitric Oxide Synthase Type II/metabolism ; Osteoarthritis, Knee/metabolism ; Osteoarthritis, Knee/pathology ; Osteoarthritis, Knee/prevention & control* ; Phosphodiesterase Inhibitors/pharmacology* ; Phosphodiesterase Inhibitors/therapeutic use ; Rats ; Rats, Sprague-Dawley ; Tetrazoles/pharmacology* ; Tetrazoles/therapeutic use ; Tumor Suppressor Protein p53/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism
Abstract
OBJECTIVE: To examine whether cilostazol, a selective phosphodiesterase type III inhibitor, protects rat articular chondrocytes against nitric oxide (NO)-induced apoptosis and prevents cartilage destruction in mono-iodoacetate-induced osteoarthritis (OA) in a rat model in which inducible nitric oxide synthase (iNOS) is expressed. METHODS: The NO donor sodium nitroprusside was administered to rat articular chondrocytes that had been pretreated with cilostazol. Induction of apoptosis was evaluated by DNA electrophoresis and pulsed-field gel electrophoresis. The expression level and the subcellular location of apoptosis-associated factors were examined by Western blot analysis and confocal microscopy, respectively. Protein kinase CK2 (PKCK2) activity was also assayed. To examine whether orally administered cilostazol prevents cartilage destruction in vivo, cartilage samples obtained from rats with experimentally induced OA were subjected to hematoxylin and eosin, Safranin O, and TUNEL staining and immunohistochemical analysis of iNOS expression. RESULTS: Cilostazol prevented NO-induced reduction in viability, in a dose-dependent manner. It also prevented the up-regulation of phosphorylated p53 and p38, the down-regulation of heme oxygenase 1, the subcellular translocation of apoptosis-inducing factor and cytochrome c, and the activation of caspases 3, 7, and 8 induced by NO treatment, indicating that cilostazol prevented NO-induced cell death by blocking apoptosis. In addition, cilostazol prevented NO-induced translocation of cleaved Bid onto mitochondria, and caused phosphorylated Bid to accumulate in the nucleus and cytosol. Cilostazol prevented the down-regulation of PKCK2 and the reduction in PKCK2 activity induced by NO, indicating that its apoptosis-preventing activity was mediated via PKCK2. It also prevented chondrocyte apoptosis and cartilage destruction in a rat model of experimentally induced OA. CONCLUSION: Our findings indicate that cilostazol prevents NO-induced apoptosis of chondrocytes via PKCK2 in vitro and prevents cartilage destruction in a rat model of OA.
Files in This Item:
T200801662.pdf Download
DOI
10.1002/art.23220
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kun Hong(김건홍) ORCID logo https://orcid.org/0000-0001-5639-6372
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/108004
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