Inhibition of cyclo-oxigenase-2 activity does not abolish the anabolic effect of prostaglandin E2 in vivo or in vitro
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It was previously reported that the expression of cyclo-oxigenase-2 (COX-2) is induced by prostaglandin E(2) (PGE(2)) in vitro in an osteogenic cell line and organ culture, suggesting an autoamplification mechanism. In this study, we first tested whether this phenomenon also occurs in bone tissue in vivo and found that a single anabolic dose of PGE(2) (5 mg/kg) induced (between 30 and 120 min) in rat tibiae, an increase in the mRNA level of COX-2 (2.5- to 9-fold) but not that of COX-1. Secondly, to test whether COX-2 activity in generating endogenous prostaglandins (PGs) is required for the in vivo anabolic properties of PGE(2), young male rats were injected daily with either vehicle (8% ethanol) or 5 mg/kg PGE(2) for 21 days. PGE(2)-injected rats received, 45 min prior to PGE(2), either dimethyl sulphoxide (as vehicle) or one of two doses of NS-398, a selective COX-2 inhibitor: a low dose (3 mg/kg) or a high dose (10 mg/kg). PGE(2) increased bone formation (measured as cancellous mineralizing surface, mineral apposition rate and bone formation rate) and bone mass (measured as cancellous bone area and surface and cortical width). None of these increases was suppressed by pre-administration of NS-398. In contrast, the high dose of NS-398 effectively suppressed an increase in rat hind-paw volume induced by a local carrageenan injection. Furthermore, since COX-2 inactivation may affect PG receptor expression, we found that pre-administration of NS-398 did not abolish the induction in EP(4) receptor mRNA levels, caused by PGE(2) in rat bone tissue. For in vitro testing, rat femoral bone marrow stromal cell cultures were initiated and were incubated in the absence or presence of PGE(2) at 100 nM (as an inducer) and with increasing concentrations of NS-398 (10(-8) M to 10(-5) M) for 21 days, after which time mineralized (Von-Kossa positive) nodules were counted. PGE(2) increased nodule formation as previously reported; however, NS-398 reduced nodule formation in both control and PGE(2)-treated cultures to the same extent. We conclude that while the level of COX-2 mRNA is increased in vivo by administration of PGE(2), inhibition of its activity (i.e. generation of endogenous PGs) does not abolish the anabolic effect of PGE(2).
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