Inhibition of hyaluronan export reduces collagen degradation in interleukin-1 treated cartilageReport as inadecuate

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Arthritis Research and Therapy

, 10:R8

First Online: 18 January 2008Received: 31 July 2007Revised: 25 October 2007Accepted: 18 January 2008


BackgroundOsteoarthrosis 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.

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

ResultsThese 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.

ConclusionInhibition of hyaluronan over-production may be an appropriate target to attenuate IL-1-induced reactions in osteoarthritic cartilage.

AbbreviationsHABP= hyaluronan binding protein

HRPO= horseradish peroxidase

IL= interleukin

MMP= matrix metalloprotease

MRP= multidrug resistance-associated protein

ODQ = 1H-12,4-oxadiazolo 4,3aquinoxaline-1-one.

Electronic supplementary materialThe online version of this article doi:10.1186-ar2357 contains supplementary material, which is available to authorized users.

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Author: Barthold Deiters - Peter Prehm


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