Differential regulation of cytokine-induced MMP-1 and MMP-13 expression by p38 kinase inhibitors in human chondrosarcoma cells: potential role of Runx2 in mediating p38 effects
OsteoArthritis Research Society International. Published by Elsevier Ltd.
Doi
Abstract
SummaryObjectiveTo investigate mitogen activated protein (MAP) kinase pathways for their ability to differentially regulate the expression of matrix metalloprotease (MMP)-1 and -13 in human chondrosarcoma cells using pathway-selective inhibitors.DesignHuman chondrosarcoma cell lines (SW1353 and JJ012) and human articular chondrocytes (HACs) were treated with cytokines (IL-1β and TNFα) and the expression of MMP-1 and -13 was analyzed. The effects of MAP kinase inhibitors on cytokine-induced expression of MMP-1 and -13 were evaluated using ELISA and Western blot analyses. The possible involvement of the Runx2 pathway in mediating p38 effects on MMP-13 expression was analyzed using promoter–reporter assays, ELISA and immunoprecipitation analyses.ResultsIL-1β and TNFα strongly induced the expression of MMP-1 and -13 in SW1353 cells and HACs, whereas only TNFα was found to induce the expression of these two MMPs in JJ012 cells. Cytokine treatment did not result in a significant increase in the activity of MMPs because of the excess production of endogenous tissue inhibitors of metalloproteases (TIMPs). Treatment with p38 kinase inhibitors (SB203580 and SB242235) strongly inhibited cytokine-induced MMP-13 expression in a dose-dependent fashion while having a somewhat weaker inhibitory effect on MMP-1 expression. In contrast, inhibitors of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways did not inhibit the expression of either MMP. Overexpression of Runx2 robustly stimulated the transcriptional activation of MMP-13 but had no effect on MMP-1 expression. Furthermore, IL-1β induced the phosphorylation of Runx2, and this effect was blocked by a p38 kinase inhibitor. Our data suggest that Runx2 is likely to be a key downstream mediator of p38 effects in the differential regulation of IL-1β induced MMP-13 expression.ConclusionsThese studies demonstrate the differential inhibition of cytokine-induced MMP-1 and -13 expression by p38 kinase inhibitors in human chondrosarcoma cells. Our studies also suggest the involvement of Runx2, at least in part, in mediating the effects of p38 on MMP-13 expression
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