Mechanism of basic calcium phosphate crystal-stimulated matrix metalloproteinase-13 expression by osteoarthritic synovial fibroblasts: inhibition by prostaglandin E(2)

作者：Molloy E S^*; Morgan M P; Doherty G A; McDonnell B; O'Byrne J; Fitzgerald D J; McCarthy G M

来源：Annals of the Rheumatic Diseases, 2008, 67(12): 1773-1779.

DOI：10.1136/ard.2007.079582

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) E(2) 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 kappa B. Addition of exogenous PGE(2) downregulated BCP crystal-stimulated MMP-13 expression. In contrast, PGE(2) upregulated, and had no effect, on BCP crystal stimulated MMP-3 and MMP-1 mRNA expression, respectively. These effects of PGE(2) 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 kB; this upregulation of MMP-13 may contribute to the accelerated cartilage breakdown in BCP crystal-associated osteoarthritis. PGE(2) had contrasting effects on BCP crystal-stimulated MMP- 3 and MMP- 13 mRNA expression, mediated in an EP2/EP4/cAMP-dependent manner, suggesting that PGE(2) may have beneficial as well as deleterious effects in BCP crystal-associated osteoarthritis.

• 出版日期2008-12