Inhibition of hyaluronan export reduces collagen degradation in interleukin-1 treated cartilage.
BACKGROUND
Osteoarthrosis is characterized by cartilage erosion, proteolysis of aggrecan and collagen, and disturbed rates of synthesis of aggrecan and hyaluronan by chondrocytes, with hyaluronan over-production being an early reaction. We considered that inhibition of hyaluronan export might prevent subsequent proteoglycan loss and collagen degradation.


METHODS
To test this hypothesis, we studied a tissue culture model using bovine cartilages explants activated with IL-1alpha to induce osteoarthritic reactions using the phosphodiesterase-5 inhibitors tadalafil, zaprinast and vardenafil.


RESULTS
These drugs inhibited hyaluronan export, but they did not inhibit hyaluronan synthase activity. Simultaneously, they inhibited proteoglycan loss and collagen degradation, but not their synthesis. They also reduced the release of gelatinases into the culture media and diffusion of the indicator protein horseradish peroxidase through the cartilage explants. The mechanism of action of these compounds may be through inhibition of hyaluronan exporter multidrug resistance-associated protein 5 (MRP5), because the effective drug concentrations were much higher than required for phosphodiesterase-5 inhibition and intracellular cGMP accumulation.


CONCLUSIONS
Inhibition of hyaluronan over-production may be an appropriate target to attenuate IL-1-induced reactions in osteoarthritic cartilage.
Deiters
Barthold
B
Muenster University Hospital, Institute of Physiological Chemistry and Pathobiochemistry, Waldeyerstr, 15, D-48129 Münster, Germany. bartholdd@yahoo.de
Prehm
Peter
P
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002358:Cartilage, Articular / Q000187:drug effects* / Q000378:metabolism*; D002417:Cattle; D003094:Collagen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004058:Diffusion / Q000187:drug effects; D018093:Gelatinases / Q000037:antagonists & inhibitors; D006735:Horseradish Peroxidase / Q000493:pharmacokinetics; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D066298:In Vitro Techniques; D007202:Indicators and Reagents / Q000493:pharmacokinetics; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D011506:Proteins / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism
D003094:Collagen; D018093:Gelatinases; D006735:Horseradish Peroxidase; D006820:Hyaluronic Acid; D007202:Indicators and Reagents; D007375:Interleukin-1; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011506:Proteins; D011509:Proteoglycans