INHIBITION OF ACTIVATOR PROTEIN-1 ACTIVITY BY PACLITAXEL SUPPRESSES INTERLEUKIN-1-INDUCED COLLAGENASE AND STROMELYSIN EXPRESSION BY BOVINE CHONDROCYTES

Objective. Cytokine-induced collagenase 1 (matrix metalloproteinase 1 [MMP-1]) and stromelysin 1 (MMP-3) expression is dependent on activato r protein 1 (AP-1) activation and have a fundamental role in the patho physiology of arthritic diseases by degrading connective tissues. This study evaluates the effect of paclitaxel on AP-1 activation and exami nes its effect on the expression of 2 major matrix metalloproteinases, MMP-1 and MMP-3, and its effect on AP-1 activation. Methods. MMP-1, M MP-3, c-fos, and c-jun messenger RNA (mRNA) levels were measured in in terleukin-l (IL-l)-induced primary chondrocytes in the presence and ab sence of paclitaxel, The effect of paclitaxel on AP-l promoter activit y was studied by chloramphenicol acetyltransferase assays in IL-1-stim ulated chondrocytes, The same conditions were applied to studies of th e effect of paclitaxel on binding at the AP-1 site by gel-shift mobili ty assays. The cytotoxicity effect of paclitaxel on chondrocytes was s tudied by examining cell viability and expression of the matrix molecu les aggrecan and type ZI collagen, Results. IL-l-induced MMP-1 and MMP -3 mRNA levels were markedly reduced in paclitaxel-treated chondrocyte s, Further, IL-1-induced AP-1 activation and AP-l binding were inhibit ed by paclitaxel. However, there was no effect on the expression of c- fos or c-jun mRNA levels. Chondrocyte viability was not affected by pa clitaxel, and there was no effect on the expression of housekeeping ge nes or the major cartilage matrix molecules aggrecan and type II colla gen. Conclusion, These studies demonstrate that paclitaxel is a potent inhibitor of MMP-1 and MMP-3 synthesis through the AP-1 site. However , inhibition of AP-1 activity by paclitaxel does not affect the viabil ity of chondrocytes or the expression of matrix molecules.