Effects of nonsteroidal anti-inflammatory drugs on the expression of urokinase plasminogen activator and inhibitor and gelatinases in the early osteoarthritic knee of humans.
OBJECTIVE
The purpose of this study was to examine the ex vivo effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the expression of urokinase-type plasminogen activator (u-PA), PA inhibitor-1 (PAI-1) and gelatinases [matrix metalloproteinase (MMP)-2 and MMP-9] in the early knee osteoarthritis (OA) of humans.


METHODS
Samples of articular cartilage, meniscus and synovium of OA patients were obtained and cultured ex vivo in the presence or absence of NSAIDs (diclofenac sodium, nimesulide, celecoxib, valdecoxib, rofecoxib and etoricoxib).


RESULTS
Gelatin zymography showed that all NSAIDs generally decreased MMP-2 secretion in chondral, meniscal and synovial cultures as well as MMP-9 production in meniscal and synovial cultures. ELISA showed the inhibitions of u-PA secretion in chondral cultures by diclofenac and rofecoxib as well as in chondral and synovial cultures by nimesulide, celecoxib and etoricoxib at 48 h. On PAI-1 secretion, rofecoxib in synovial cultures and diclofenac, nimesulide, celecoxib and etoricoxib in chondral and synovial cultures had significantly suppressive effects at 48 h.


CONCLUSIONS
This study clearly demonstrates that NSAIDs can down-regulate the PA/plasmin system and gelatinases expression during the early stage of knee OA, thereby possibly affect the structural progression of the disease. This inhibition seems to be independent selection of COX-1 and COX-2.
Yang
Shun-Fa
SF
Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan.
Hsieh
Yih-Shou
YS
Lue
Ko-Huang
KH
Chu
Shu-Chen
SC
Chang
I-Chang
IC
Lu
Ko-Hsiu
KH
D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D007719:Knee Joint / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D013583:Synovial Membrane / Q000201:enzymology / Q000378:metabolism; D013997:Time Factors; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D017395:Plasminogen Activator Inhibitor 1; D014568:Urokinase-Type Plasminogen Activator; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9