In vitro effects of interleukin 1 on the synthesis of metalloproteases, TIMP, plasminogen activators and inhibitors in human articular cartilage.
Degradation of cartilage matrix macromolecules depends on the increase of metalloprotease activity. It has been suggested that interleukin 1 (IL-1) contributes to cartilage break-down by modulating the synthesis of the elements favoring an activation of these metalloenzymes. We analyzed the effect of IL-1 on the synthesis of collagenase, stromelysin, and tissue inhibitor of metalloproteases (TIMP) in human cartilage explants and culture chondrocytes, as well as its effect on the secretion of plasminogen activators (t-PA, u-PA) and inhibitors (PAI-1, PAI-2) in cartilage explants. Messenger RNA levels of collagenase and TIMP were also analyzed following chondrocyte incubation in the presence or absence of IL-1. We demonstrate that IL-1 stimulates the secretion of metalloproteases and t-PA in a dose dependent manner. At a relatively low concentration (5 pg/ml), IL-1 induced collagenase and stromelysin synthesis in parallel with a decline in TIMP secretion. While IL-1 induced collagenase gene expression, no change in the TIMP mRNA level was noted. The increase in t-PA synthesis was accompanied by a decreased PAI-1 level, while the PAI-2 level remained unchanged. u-PA could not be detected in the culture medium. This study gives insight into the ways that the synthesis, activation and inhibition of metalloproteases are modulated by IL-1. These results support the importance of IL-1 in the etiology of cartilage degeneration.
Martel-Pelletier
J
J
Rheumatic Disease Unit Research Laboratory, Notre-Dame Hospital Research Center, Montreal, PQ, Canada.
Zafarullah
M
M
Kodama
S
S
Pelletier
J P
JP
D015152:Blotting, Northern; D002358:Cartilage, Articular / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D019278:Matrix Metalloproteinase 3; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D008667:Metalloproteins / Q000235:genetics / Q000378:metabolism*; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism*; D015849:Plasminogen Inactivators / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
D006023:Glycoproteins; D007375:Interleukin-1; D008667:Metalloproteins; D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D003012:Microbial Collagenase