Abstract
A hallmark of rheumatoid- and osteoarthritis (OA) is proinflammatory cytokine-induced degeneration of cartilage collagen and aggrecan by matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS). Effects of the Chinese herb, Tripterygium wilfordii Hook F (TWHF), on cartilage and its anti-arthritic mechanisms are poorly understood. This study investigated the impact of a purified derivative of TWHF, PG490 (triptolide), on cytokine-stimulated expression of the major cartilage damaging proteases, MMP-3, MMP-13, and ADAMTS4. PG490 inhibited cytokine-induced MMP-3, MMP-13 gene expression in primary human OA chondrocytes, bovine chondrocytes, SW1353 cells, and human synovial fibroblasts. Triptolide was effective at low doses and blocked the induction of MMP-13 by IL-1 in human and bovine cartilage explants. TWHF extract and PG490 also suppressed IL-1-, IL-17-, and TNF-alpha-induced expression of ADAMTS-4 in bovine chondrocytes. Thus, PG490 could protect cartilage from MMP- and aggrecanase-driven breakdown. The immunosuppressive, cartilage protective, and anti-inflammatory properties could make PG490 potentially a new therapeutic agent for arthritis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins
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ADAMTS4 Protein
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Animals
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Cartilage / drug effects
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Cartilage / metabolism
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Cattle
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Cells, Cultured
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Chondrocytes / drug effects*
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Chondrocytes / metabolism
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Collagenases / genetics*
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Collagenases / metabolism
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Cytokines / antagonists & inhibitors*
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Cytokines / pharmacology
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Diterpenes / pharmacology*
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Dose-Response Relationship, Drug
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Down-Regulation / drug effects
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Epoxy Compounds
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Gene Expression Regulation / drug effects*
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Humans
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Inflammation / genetics
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Inflammation / metabolism
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Interleukin-1 / pharmacology
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Interleukin-17 / pharmacology
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Matrix Metalloproteinase 13
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Matrix Metalloproteinase 3 / genetics*
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Matrix Metalloproteinase 3 / metabolism
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Matrix Metalloproteinase Inhibitors
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Metalloendopeptidases / genetics*
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Phenanthrenes / pharmacology*
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Plant Extracts / pharmacology
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Procollagen N-Endopeptidase
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RNA, Messenger / genetics
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Tripterygium / chemistry
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Cytokines
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Diterpenes
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Epoxy Compounds
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Interleukin-1
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Interleukin-17
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Matrix Metalloproteinase Inhibitors
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Phenanthrenes
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Plant Extracts
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RNA, Messenger
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Tumor Necrosis Factor-alpha
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triptolide
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ADAM Proteins
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Collagenases
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MMP13 protein, human
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Matrix Metalloproteinase 13
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Metalloendopeptidases
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Procollagen N-Endopeptidase
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Matrix Metalloproteinase 3
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ADAMTS4 Protein
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ADAMTS4 protein, human