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Rheumatology Advance Access published online on April 30, 2008
Rheumatology, doi:10.1093/rheumatology/ken144
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

E. S. Molloy1, M. P. Morgan1, G. A. Doherty2, B. McDonnell1, M. Hilliard2, J. O’Byrne3, D. J. Fitzgerald2 and G. M. McCarthy1,2,3,4

1Department of Molecular and Cellular Therapeutics, Royal College of Surgeons of Ireland, 2Conway Institute, University College Dublin, 3National Orthopaedic Hospital, Cappagh and 4Department of Rheumatology, Mater Misericordiae University Hospital, Dublin, Ireland.

Correspondence to: E. S. Molloy, Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, 9500 Euclid Avenue, Desk A50, Cleveland, OH 44195, USA. E-mail: eamonn.molloy{at}ireland.com


  Abstract

Objectives. Basic calcium phosphate (BCP) crystals have been implicated in the pathogenesis of OA and stimulate cyclo-oxygenase (COX) expression and PGE2 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, PGE2 (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 PGF2{alpha}, thromboxane A2 or cyclopentanone PGs including 15d-PGJ2. 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.

KEY WORDS: Basic calcium phosphate crystals, Osteoarthritis, Cyclo-oxygenase-1, Prostaglandins, Synovial fibroblasts

Submitted 20 July 2007; revised version accepted 18 March 2008.
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