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Mechanism of basic calcium phosphate crystal-stimulated matrix metalloproteinase-13 expression in osteoarthritic synovial fibroblasts: inhibition by prostaglandin E2
  1. E S Molloy (eamonn.molloy{at}
  1. Royal College of Surgeons in Ireland, Eire
    1. M P Morgan (mmorgan{at}
    1. Royal College of Surgeons in Ireland, Eire
      1. G A Doherty (glen.doherty{at}
      1. University College Dublin, Eire
        1. B McDonnell (bmcdonnell{at}
        1. Royal College of Surgeons in Ireland, Eire
          1. J O'Byrne (jmobyrne{at}
          1. Cappagh National Orthopaedic Hospital, Eire
            1. D J Fitzgerald (des.fitzgerald{at}
            1. University College Dublin, Eire
              1. G M McCarthy (gmccarthy{at}
              1. Royal College of Surgeons in Ireland, Eire


                Objective: To determine the mechanism of MMP-13 upregulation in osteoarthritic synovial fibroblasts (OASF) in response to stimulation with basic calcium phosphate (BCP) crystals and to investigate the effect of PGE2 on BCP crystal-stimulated MMP expression.

                Methods: Primary OASF were stimulated with BCP crystals; mRNA expression was measured by real-time RT-PCR and protein levels were assessed by western blotting.

                Results: BCP crystals upregulated MMP-13 mRNA expression over 20-fold and increased MMP-13 protein production in OASF. BCP crystal-stimulated MMP-13 mRNA expression was blocked by inhibition of the extracellular regulated kinase (ERK1/2) and p38 mitogen activated protein kinase (MAPK) pathways and inhibition of activation of nuclear factor kB. Addition of exogenous PGE2 downregulated BCP crystal-stimulated MMP-13 expression. In contrast, PGE2 upregulated, and had no effect, on BCP crystal stimulated MMP-3 and MMP-1 mRNA expression, respectively. These effects of PGE2 were diminished by L-161,982, a selective EP4 receptor antagonist, and mimicked by CAY10399, a selective EP2 receptor agonist, and forskolin, an adenylate cyclase activator.

                Conclusions: These data suggest that BCP crystal induction of MMP-13 expression may involve the ERK1/2 and p38 MAPK pathways and activation of NFkB; this upregulation of MMP-13 may contribute to the accelerated cartilage breakdown in BCP crystal-associated OA. PGE2 had contrasting effects on BCP crystal-stimulated MMP-3 and MMP-13 mRNA expression, mediated in an EP2/EP4/cAMP dependent manner, suggesting that PGE2 may have beneficial as well as deleterious effects in BCP crystal-associated OA.

                • basic calcium phosphate crystals
                • matrix metalloproteinase-13
                • osteoarthritis
                • prostaglandin E2
                • synovial fibroblasts

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