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 activator protein 1 (AP-1) activation and have a fundamental role in the pathophysiology of arthritic diseases by degrading connective tissues. This study evaluates the effect of paclitaxel on AP-1 activation and examines 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, MMP-3, c-fos, and c-jun messenger RNA (mRNA) levels were measured in interleukin-1 (IL-1)-induced primary chondrocytes in the presence and absence of paclitaxel. The effect of paclitaxel on AP-1 promoter activity was studied by chloramphenicol acetyltransferase assays in IL-1-stimulated chondrocytes. The same conditions were applied to studies of the effect of paclitaxel on binding at the AP-1 site by gel-shift mobility assays. The cytotoxicity effect of paclitaxel on chondrocytes was studied by examining cell viability and expression of the matrix molecules aggrecan and type II collagen.


RESULTS
IL-1-induced MMP-1 and MMP-3 mRNA levels were markedly reduced in paclitaxel-treated chondrocytes. Further, IL-1-induced AP-1 activation and AP-1 binding were inhibited by paclitaxel. However, there was no effect on the expression of c-fos or c-jun mRNA levels. Chondrocyte viability was not affected by paclitaxel, and there was no effect on the expression of housekeeping genes or the major cartilage matrix molecules aggrecan and type II collagen.


CONCLUSIONS
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 viability of chondrocytes or the expression of matrix molecules.
Hui
A
A
Mount Sinai Hospital, Toronto, Ontario, Canada.
Min
W X
WX
Tang
J
J
Cruz
T F
TF
D053674:Aggrecans; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002358:Cartilage, Articular / Q000201:enzymology; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D019902:Chondrocytes / Q000187:drug effects* / Q000201:enzymology; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000737:chemistry; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1 / Q000494:pharmacology*; D037181:Lectins, C-Type; D020781:Matrix Metalloproteinase 1; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*
D053674:Aggrecans; D000972:Antineoplastic Agents, Phytogenic; D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D037181:Lectins, C-Type; D011509:Proteoglycans; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D003094:Collagen; D015500:Chloramphenicol O-Acetyltransferase; D017364:Collagenases; D019278:Matrix Metalloproteinase 3; D020781:Matrix Metalloproteinase 1; D017239:Paclitaxel