Differential effects of nonsteroidal antiinflammatory drugs on the IL-1 altered expression of plasminogen activators and plasminogen activator inhibitor-1 by articular chondrocytes.
OBJECTIVE
To determine the in vitro effects of several nonsteroidal antiinflammatory drugs on the IL-1 altered expression and activity of tPA, uPA and PAI-1 by articular chondrocytes.


METHODS
Bovine chondrocytes were cultured in alginate gel beads. Cells were treated with IL-1alpha in the presence or absence of drugs at various concentrations. Expression of mRNA for the plasminogen activators (uPA and tPA) and their inhibitor (PAI-1) were analyzed by RT-PCR-ELISA. The protein content of PAI-1 in culture media was deter mined by ELISA. PA activity was measured by a functional assay.


RESULTS
All tested NSAIDs dose dependently inhibited the IL-1 induced mRNA expression of tPA, whereas only indomethacin and tiaprofenic acid were also able to reduce the expression of uPA. Expression of PAI-1 was elevated by IL-1 without an accompanying increase in secreted amounts of the inhibitor. Indomethacin, naproxen and tiaprofenic acid stimulated the release of PAI-1 into culture media, whereas meloxicam also induced expression of PAI-1 above IL-1 stimulated levels.


CONCLUSIONS
In conclusion, our studies indicate that NSAIDs preferentially inhibit tPA expression by bovine articular chondrocytes. By increasing the production of PAI-1 at therapeutical concentrations meloxicam could reduce PA activity, whereas the other NSAIDs tested mainly enhanced the release of this inhibitor from the extracellular matrix. In how far this would affect the enzyme-inhibitor balance within cartilage has to be determined in further studies.
Sadowski
T
T
Institute of Pharmacology and Toxicology, University of Bonn, Germany. thorsten.sadowski@biochem.uni-kiel.de
Steinmeyer
J
J
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D004008:Diclofenac / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D000077239:Meloxicam; D009288:Naproxen / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013843:Thiazines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D011422:Propionates; D012333:RNA, Messenger; D013843:Thiazines; D013844:Thiazoles; D004008:Diclofenac; C021270:tiaprofenic acid; D009288:Naproxen; D010960:Plasminogen Activators; D001241:Aspirin; D000077239:Meloxicam; D007213:Indomethacin