Abstract
transient transfection experiments, respectively. The role of the PGD2 receptors, D prostanoid receptor 1 (DP1) and chemoattractant-receptorlike molecule expressed on Th2 cells (CRTH2), was evaluated using specific agonists and antibody blocking experiments. The contribution of the cAMP/PKA pathway was determined using cAMP elevating agents and PKA inhibitors. Results: PGD2 dose-dependently decreased Il-1-induced MMP-1 and MMP-13 protein and mRNA expression as well as MMP-1 and -13 promoter activation. DP1 and CRTH2 are expressed and functional in chondrocytes. The effect of PGD2 was mimicked by the selective DP1 agonist BW245C, but not by the CRTH2 selective agonist DK-PGD2. Furthermore, treatment with an anti-DP1 antibody reversed the effect of PGD2, indicating that the inhibitory effect of PGD2 is mediated by DP1. The cAMP elevating agents, 8-Br-cAMP and forskolin, suppressed Il-1induced MMP-1 and MMP-13 expression, and the PKA inhibitors, KT5720 and H-89, reversed the inhibitory effect of PGD2, suggesting that the effect of PGD2 is mediated by the cAMP/PKA pathway. Conclusions: PGD2 inhibits Il-1-induced MMP-1 and MMP-13 production by chondrocytes through the DP1/cAMP/PKA signalling pathway. This suggest that modulation of PGD2 levels in the joint may have therapeutic potential in the prevention of cartilage degradation.
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