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p38MAPK mediates IL-1-induced down-regulation of aggrecan gene expression in human chondrocytes
Ist Teil von
International journal of molecular medicine, 2006-04, Vol.17 (4), p.661-668
Ort / Verlag
Greece: D.A. Spandidos
Erscheinungsjahr
2006
Quelle
MEDLINE
Beschreibungen/Notizen
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.