Abstract
The pleiotropic cytokine interleukin 1 (IL-1) is considered to be the principal inducer of mediators of cartilage degradation in both, osteoarthritis (OA) and rheumatoid arthritis (RA). IL-1 activates numerous signaling pathways involved in cartilage destruction and dedifferentiation of chondrocytes. In this study, we analyzed expression and functional effects of IL-1 in human chondrocytes. We found an IL-1-induced reduction in the expression of the cartilage specific proteoglycan aggrecan as an indicator for the IL-1-mediated dedifferentiation of chondrocytes. To block the IL-1-induced signaling pathways specifically, we incubated human chondrocytes and cartilage explants with IL-1 in the presence of different signal transduction inhibitors and analyzed their effect on aggrecan mRNA expression and IL-6 secretion. IL-6 has been found to act synergistically in the IL-1-induced suppression of the proteoglycan synthesis in chondrocytes. Our results led to the identification of p38MAPK and/or PI3K/JNK as being crucial for IL-1-induced IL-6 secretion by chondrocytes. IL-1-induced down-regulation of aggrecan expression was found to be mediated by p38MAPK and/or ERK1/2. The identification and characterization of these signaling pathways will enable us to develop new modulation strategies for therapeutic use in inflammatory joint diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aggrecans
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Cell Line, Tumor
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Cells, Cultured
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Chondrocytes / cytology
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Chondrocytes / drug effects*
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Chondrocytes / metabolism
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Chondroitin Sulfate Proteoglycans / genetics*
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Extracellular Matrix Proteins / genetics*
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Flavonoids / pharmacology
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Gene Expression / drug effects
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Humans
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Imidazoles / pharmacology
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Interleukin-1 / genetics
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Interleukin-1 / pharmacology*
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Lectins, C-Type / genetics*
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Leukocytes, Mononuclear / cytology
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / metabolism
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Male
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Middle Aged
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Pyridines / pharmacology
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Interleukin-1 / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Aggrecans
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Chondroitin Sulfate Proteoglycans
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Extracellular Matrix Proteins
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Flavonoids
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Imidazoles
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Interleukin-1
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Lectins, C-Type
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Pyridines
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RNA, Messenger
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Receptors, Interleukin-1
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one