Evaluation of the influence of prostaglandin E2 on recombinant equine interleukin-1β-stimulated matrix metalloproteinases 1, 3, and 13 and tissue inhibitor of matrix metalloproteinase 1 expression in equine chondrocyte cultures

Objective —To determine the effects of prostaglandin E 2 (PGE 2 ) on recombinant equine interleukin (IL)-1β-stimulated expression of matrix metalloproteinases (MMP 1, MMP 3, MMP 13) and tissue inhibitor of matrix metalloproteinase 1 (TIMP 1) in vitro. Sample Population —Cultured equine chondrocytes. Procedure —Stationary monolayers of first-passage chondrocytes were exposed to graduated concentrations of PGE 2 with or without a subsaturating dose (50 pg/ml) of recombinant equine IL-1β (reIL-1β) to induce expression of MMP 1, MMP 3, MMP 13, and TIMP 1, followed by RNA isolation and northern blotting. In subsequent experiments, gene expression was similarly quantified from mRNA isolated from cultures pretreated with phenylbutazone to quench endogenous PGE 2 synthesis, followed by exposure to reIL-1β and exogenous PGE 2 (5 mg/ml) with appropriate controls. Results —Exogenous PGE 2 (10 mg/ml) significantly reduced reIL-1β-induced expression of MMP 1, MMP 3, MMP 13, and TIMP 1. Abrogation of cytokine induction with this dose of PGE 2 was comparable to that for dexamethasone (10 –5 M ) control. Similarly, pretreatment with phenylbutazone, followed by exposure to reIL-1β and PGE 2 (5 mg/ml), was associated with a reduced expression of the genes of interest, an effect that was significant for MMP 1, MMP 13, and TIMP 1. Conclusions and Clinical Relevance —The MMP and TIMP 1 are important mediators in the pathophysiologic events in osteoarthritis. The potential for physiologically relevant regulation of expression of these genes by PGE 2 is a consideration in the use of drugs that inhibit prostanoid synthesis in the treatment of equine arthropathies. ( Am J Vet Res 2002;63:987–993)