Control of the chondrocyte fibrinolytic balance by the drug piroxicam: relevance to the osteoarthritic process.

OBJECTIVE

Since the plasminogen activator [PA/plasminogen activator inhibitor (PAI) system is believed to be involved in a breakdown of articular cartilage in osteoarthritis (OA), we studied the modulation of single components of the fibrinolytic system (urokinase-type plasminogen activator, u-PA; plasminogen activator inhibitor-1, PAI-1; the surface receptor for u-PA, u-PAR) in human chondrocytes in the presence of piroxicam.

METHODS

The drug was added to the chondrocyte culture medium either directly or by supplementing chondrocyte cultures with synovial fluid (SF) from patients with OA treated with piroxicam. We have shown u-PAR M(r) 55000 Da on human chondrocytes in suspension culture by cross linking chondrocyte lysates with 125I-labelled amino-terminal fragment (ATF) of human u-PA, which frames the sequence that specifically interacts with u-PAR.

RESULTS

Such receptors decrease upon incubation of chondrocytes with piroxicam or with SF from patients treated with piroxicam. The culture medium of treated chondrocytes showed decreased fibrinolytic activity when compared with untreated controls, while PAI activity was increased in both SF chondrocyte culture medium following piroxicam treatment. At the same time, internalization of u-PA/u-PAR complexes increased after incubation of chondrocytes with piroxicam or PAI-1 rich SF.

CONCLUSION

Our results indicate that the drug induces the surface clearance u-PAR by internalization of u-PA/PAI-/u-PAR complexes. Thus piroxicam reduces both the soluble fibrinolytic activity of human chondrocytes (increase of PAI activity and decrease of released u-PA) and the cell associated u-PA activity (clearance of u-PAR by internalization). The drug dependent changes in the fibrinolytic system suggest that piroxicam may be useful in preventing or limiting perilacunar cartilage damage in OA.