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Mechanism of basic calcium phosphate crystal-stimulated cyclo-oxygenase-1 up-regulation in osteoarthritic synovial fibroblasts.

Molloy ES, Morgan MP, Doherty GA, McDonnell B, Hilliard M, O'Byrne J, Fitzgerald DJ, McCarthy GM

Department of Molecular and Cellular Therapeutics, Royal College of Surgeons of Ireland. eamonn.molloy@ireland.com

OBJECTIVES: Basic calcium phosphate (BCP) crystals have been implicated in the pathogenesis of OA and stimulate cyclo-oxygenase (COX) expression and PGE(2) production. This study aimed to elucidate the mechanism of COX-1 up-regulation by BCP crystals and to characterize the PGs produced in OA synovial fibroblasts (OASFs) in response to BCP crystals. METHODS: OASFs were stimulated with BCP crystals in vitro. mRNA expression was measured by real-time PCR, PG production by EIA and protein production by western blot. RESULTS: Maximal (19-fold) up-regulation of COX-1 mRNA occurred 32 h after stimulation with BCP crystals; increased COX-1 protein production was also seen. At 32 h post-stimulation with BCP crystals, PGE(2) (and prostacyclin) production was COX-1 dependent. In contrast, maximal (17-fold) up-regulation of COX-2, with corresponding COX-2-dependent PG production, occurred 4 h after BCP crystal stimulation. There was no appreciable increased production of other PGs such as PGF(2alpha), thromboxane A(2) or cyclopentanone PGs including 15d-PGJ(2). Inhibition of protein kinase C (PKC) and extracellular regulated kinase 1/2 (ERK1/2) signal transduction pathways blocked BCP crystal-induced COX-1 mRNA expression. Bafilomycin A1, an inhibitor of intra-lysosomal BCP crystal dissolution, diminished BCP crystal-induced COX-1 mRNA expression. CONCLUSIONS: These findings indicate that BCP crystals can augment PG production in OASF through induction of COX-1 and COX-2. Intra-lysosomal BCP crystal dissolution and activity of the PKC and ERK1/2 signal transduction pathways are required for BCP crystal-induced COX-1 up-regulation. These data add to the evidence suggesting that the constitutive COX-1/inducible COX-2 concept is an over-simplification and suggest that non-selective COX inhibition may be preferable to COX-2 selective inhibition in BCP crystal-associated OA.

Published 18 June 2008 in Rheumatology (Oxford), 47(7): 965-71.
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