| Project/Area Number |
09835011
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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 |
老化(加齢)
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| Research Institution | TOKYO UNIVERSITY OF PHARMACY AND LIFE SCIENCE |
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Principal Investigator |
ITO Akira TOKYO UNIVERSITY OF PHARMACY AND LIFE SCIENCE,SCHOOL OF PHARMACY,DEPARTMENT OF BIOCHEMISTRY,PROFESSOR, 薬学部, 教授 (70096684)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 1998: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1997: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | AGING / CHONDROCYTES / MATRIX METALLOPROTEINASES / RHEUMATOID ARTHRITIS / OSTEOARTHRITIS / HUMAN URINARY TRYPSIN INHIBITOR / NOBILETIN / DIHYDROXYCOUMARIN / 関節軟骨細胞 / 関節滑膜細胞 / 柑橘フラボノイド / エスクレチン / プロテオグリカン / インターロイキン1 |
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| Research Abstract |
The relationship between aging and destruction of articular cartilage in rheumatoid arthritis (RA) and osteoarthritis (QA) was investigated using rabbit articular chondrocytes. Growth rate and proteoglycan synthesis in aged chondrocytes prepared from 1.5 years old were significantly lower than in the cells from 3 weeks and 6 months old rabbits. When the aged cells were treated with interleukin lalpha (IL-1alpha) the production of matrix metalloproteinases (MMPs) and concomitant release of proteoglycan were induced. These results strongly suggested that MMPs play an essential role in the destruction of proteoglycans and the suppression of MMPs as well as prostaglandins(PGs)is very likely to be effective to suppress the RA and OA.
From this point of view, effects of urinary trypsin inhibitor (UTI), dihydroxycoumarin and citrus flavonoid of nobiletin on the activation and production of proMMPs in rabbit chondrocytes were investigated. UTI effectively inhibited the plasminogen activator-mediated activation of plasminogen in rabbit chondrocytes co-treated with IL-1alpha and plasminogen, and eventually suppressed the activation of proMMP-1/procollagenase and proMMlP-3/prostromelysin and the release of proteoglycans. Both dihydroxycoumarin and nobiletin effectively suppressed the IL-1alpha-mediated production of proMMPs-1 and -3 in rabbit chondrocytes and synovial cells. Nobiletin also down-regulated the production of PGE2 in rabbit chondrocytes and synovial cells. Therefore, these three agents exert desirable effects on the maintenance of articular cartilage in RA and OA, and are novel candidate for the above forms of arthritis.
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