Radons, Jürgen and Bosserhoff, Anja Katrin and Grässel, Susanne and Falk, Werner and Schubert, Thomas E. O. (2006) p38MAPK mediates IL-1-induced down-regulation of aggrecan gene expression in human chondrocytes. International journal of molecular medicine 17 (4), pp. 661-668.
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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.
|Institutions:|| Medicine > Lehrstuhl für Innere Medizin I|
Medicine > Abteilung für Hämatologie und Internistische Onkologie
|Keywords:||chondrocytes; IL-1, IL-6; p38MAPK; signal transduction; aggrecan; PI3K, JNK, ERK1/2|
|Subjects:||600 Technology > 610 Medical sciences Medicine|
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Yes|
|Deposited On:||02 Mar 2007|
|Last Modified:||20 Jul 2011 20:51|