Abstract
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.
Highlights
Destruction of joint cartilage is the major outcome of arthritic diseases such as osteoarthrosis and rheumatoid arthritis
The mechanism of action of these compounds may be through inhibition of hyaluronan exporter multidrug resistanceassociated protein 5 (MRP5), because the effective drug concentrations were much higher than required for phosphodiesterase-5 inhibition and intracellular cGMP accumulation
Chondrocytes represent only 5% of the tissue, these cells are responsible for cartilage matrix synthesis, which consists of two main components: the network of type II collagen, which provides the tensile strength and stiffness; and the large aggregating proteoglycan aggrecan, which is responsible for the osmotic swelling capability and elasticity
Summary
Destruction of joint cartilage is the major outcome of arthritic diseases such as osteoarthrosis and rheumatoid arthritis. Hyaluronan is polymerized at the inner side of plasma membranes [1,2,3,4] and was originally thought to be exported by the synthase itself [5,6], but recently the ATPbinding cassette transporter multidrug resistance protein (MRP) was identified as a hyaluronan exporter [7,8]. Both components aggregate in the extracellular matrix [9], with up to 200 aggrecan molecules decorating one hyaluronan chain [10]. We considered that inhibition of hyaluronan export might prevent subsequent proteoglycan loss and collagen degradation
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