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,
*
Department of Rheumatology, Hospital for Joint Diseases, New York, NY 10003; and Departments of
Pathology and
Medicine, New York University Medical Center, New York, NY 10016
Tetracyclines (doxycycline and minocycline) augmented (one- to
twofold) the PGE2 production in human
osteoarthritis-affected cartilage (in the presence or absence of
cytokines and endotoxin) in ex vivo conditions. Similarly, bovine
chondrocytes stimulated with LPS showed (one- to fivefold) an increase
in PGE2 accumulation in the presence of doxycycline. This
effect was observed at drug concentrations that did not affect nitric
oxide (NO) production. In murine macrophages (RAW 264.7) stimulated
with LPS, tetracyclines inhibited NO release and increased
PGE2 production. Tetracycline(s) and
L-N-monomethylarginine (L-NMMA)
(NO synthase inhibitor) showed an additive effect on inhibition of NO
and PGE2 accumulation, thereby uncoupling the effects of
tetracyclines on NO and PGE2 production. The enhancement of
PGE2 production in RAW 264.7 cells by tetracyclines was
accompanied by the accumulation of both cyclooxygenase (COX)-2 mRNA and
cytosolic COX-2 protein. In contrast to tetracyclines,
L-NMMA at low concentrations (
100 µM) inhibited the
spontaneous release of NO in osteoarthritis-affected explants and
LPS-stimulated macrophages but had no significant effect on the
PGE2 production. At higher concentrations,
L-NMMA (500 µM) inhibited NO release but augmented
PGE2 production. This study indicates a novel mechanism of
action of tetracyclines to augment the expression of COX-2 and
PGE2 production, an effect that is independent of
endogenous concentration of NO.
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