| Project/Area Number |
16591865
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional basic dentistry
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| Research Institution | Showa University |
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Principal Investigator |
MIYAMOTO Yoichi Showa University, School of Dentistry, Associate Professor, 歯学部, 助教授 (20295132)
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| Co-Investigator(Kenkyū-buntansha) |
KATAGIRI Takenobu Saitama Medical School, Research Center for Genomic Medicine, Associate Professor, ゲノム医学研究センター, 助教授 (80245802)
MASAMICHI Takami Showa University, School of Dentistry, Lecturer, 歯学部, 講師 (80307058)
SHINKI Toshimasa Nihon Pharmaceutical University, Department of Biochemistry, Professor, 薬学部, 教授 (90138420)
MORIMURA Naoko Riken, Brain Science Institute, Researcher, 脳科学総合研究センター, 研究員 (00349044)
KAMIJO Ryutaro Showa University, School of dentistry, Professor, 歯学部, 教授 (70233939)
赤池 孝章 熊本大学, 大学院・医学薬学研究部, 助教授 (20231798)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | nitric oxide / chondrocytes / synoviocytes / cell death / rheumatoid arthritis / osteoarthritis / NADPH-oxidase / radicals / 細胞・組織 / シグナル伝達 / ストレス / 生体分子 / 生理活性 / 軟骨 / インターロイキン-1 / スーパーオキサイド / パーオキシナイトライト / ミトコンドリア / ネクローシス |
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| Research Abstract |
It is known that nitric oxide production is up-regulated both in synovial tissues and articular cartilages in the joints of rheumatoid arthritis (RA) and osteoarthritis (OA) patients. NO is regarded as one of the important molecules to regulate cell death and survival, whereas the regulatory mechanism has not been fully elucidated. On the other hand, interleukin-1 (IL-1) acts as a key mediator of the degeneration of articular cartilage in RA and OA, where chondrocyte death is observed. In this study, the viability of mouse chondrocyte-like ATDC5 cells was reduced by the treatment with IL-1β for 48 h or longer. IL-1β augmented the expression of the catalytic subunit of NADPH-oxidase gp91^<phox> as well as inducible NO synthase in ATDC5 cells. Generation of nitrated guanosine and tyrosine suggested the formation of reactive nitrogen species including peroxynitrite (ONOO^-), a reaction product of NO and superoxide in ATDC5 cells and rat primary chondrocytes treated with IL-1β. Death of AT
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DC5 cells after IL-1β treatment was prevented by an NADPH-oxidase inhibitor 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), a NO synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME), and a ONOO^- scavenger uric acid. The viability of ATDC5 cells was reduced by a ONOO^- generator 3-(4-morpholinyl)sydnonimine hydrochloride but not by either a NO donor 1-hydroxy-2-oxo-3-(N-methyl-2-aminopropyl)-3-methyl-1-triazene or S-nitrosoglutathione. Disruption of mitochondrial membrane potential and ATP deprivation were observed in IL-1β-treated ATDC5 cells, both of which were restored by L-NAME, AEBSF, or uric acid. On the other hand, any morphological or biochemical sign indicating apoptosis was not observed in these cells. These results suggest that the death of chondrocyte-like ATDC5 cells was mediated at least in part by mitochondrial dysfunction and energy depletion through ONOO^- formation after IL-1β treatment. We have also succeeded in the establishment of a fibroblastic cell line from the synoviocytes obtained from an RA patient. Less
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