Inhibition of interleukin-1β-induced matrix metalloproteinases 1 and 13 production in human osteoarthritic chondrocytes by prostaglandin D 2

Nadia Zayed, Hassan Afif, Nadir Chabane, Leandra Mfuna-Endam, Mohamed Benderdour, Johanne Martel-Pelletier, Jean Pierre Pelletier, Rajender K. Motiani, Mohamed Trebak, Nicolas Duval, Hassan Fahmi

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44 Scopus citations

Abstract

Objective. To investigate the effects of prostaglandin D2 (PGD2) on interleukin-1β (IL-1β)-induced matrix metalloproteinase 1 (MMP-1) and MMP-13 expression in human chondrocytes and the signaling pathways involved in these effects. Methods. Chondrocytes were stimulated with IL-1 in the presence or absence of PGD2, and expression of MMP-1 and MMP-13 proteins was evaluated by enzyme-linked immunosorbent assay. Messenger RNA (mRNA) expression and promoter activity were analyzed by real-time reverse transcription-polymerase chain reaction and transient transfections, respectively. The role of the PGD2 receptors D prostanoid receptor 1 (DP1) and chemoattractant receptor-like molecule expressed on Th2 cells (CRTH2) was evaluated using specific agonists and antibody-blocking experiments. The contribution of the cAMP/protein kinase A (PKA) pathway was determined using cAMP-elevating agents and PKA inhibitors. Results. PGD2 decreased in a dose-dependent manner IL-1-induced MMP-1 and MMP-13 protein and mRNA expression as well as their promoter activation. DP1 and CRTH2 were expressed and functional in chondrocytes. The effect of PGD2 was mimicked by BW245C, a selective agonist of DP1, but not by 13,14-dihydro-15-keto-PGD2, a selective agonist of CRTH2. Furthermore, treatment with an anti-DP1 antibody reversed the effect of PGD 2, indicating that the inhibitory effect of PGD2 is mediated by DP1. The cAMP-elevating agents 8-Br-cAMP and forskolin suppressed IL-1-induced MMP-1 and MMP-13 expression, and the PKA inhibitors KT5720 and H89 reversed the inhibitory effect of PGD2, suggesting that the effect of PGD2 is mediated by the cAMP/PKA pathway. Conclusion. PGD 2 inhibits IL-1-induced production of MMP-1 and MMP-13 by chondrocytes through the DP1/cAMP/PKA signaling pathway. These data also suggest that modulation of PGD2 levels in the joint may have therapeutic potential in the prevention of cartilage degradation.

Original languageEnglish (US)
Pages (from-to)3530-3540
Number of pages11
JournalArthritis and rheumatism
Volume58
Issue number11
DOIs
StatePublished - Nov 2008

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)

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