RT Journal Article SR Electronic T1 Mechanism of basic calcium phosphate crystal-stimulated matrix metalloproteinase-13 expression by osteoarthritic synovial fibroblasts: inhibition by prostaglandin E2 JF Annals of the Rheumatic Diseases JO Ann Rheum Dis FD BMJ Publishing Group Ltd and European League Against Rheumatism SP 1773 OP 1779 DO 10.1136/ard.2007.079582 VO 67 IS 12 A1 E S Molloy A1 M P Morgan A1 G A Doherty A1 B McDonnell A1 J O’Byrne A1 D J Fitzgerald A1 G M McCarthy YR 2008 UL http://ard.bmj.com/content/67/12/1773.abstract AB Objective: To determine the mechanism of matrix metalloproteinase (MMP)-13 upregulation in osteoarthritic synovial fibroblasts (OASF) in response to stimulation with basic calcium phosphate (BCP) crystals and to investigate the effect of prostaglandin (PG)E2 on BCP crystal-stimulated MMP expression.Methods: Primary OASF were stimulated with BCP crystals; mRNA expression was measured by real-time reverse transcription–polymerase chain reaction 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 the activation of nuclear factor κB. 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 nuclear factor κB; this upregulation of MMP-13 may contribute to the accelerated cartilage breakdown in BCP crystal-associated osteoarthritis. 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 osteoarthritis.