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Abstract
We have examined the role of prostaglandins, nitric oxide (NO), and the NO induced
effector molecule cyclic-guanosine monophosphate (cGMP) as mediators of cytokine effects
on bone resorption in murine calvarial organ cultures. The combination of interleukin-1
beta (IL-1) and tumor necrosis factor alpha (TNF) stimulated NO production, PGE2 production,
and bone resorption. The increase in bone resorption was inhibited by the NO synthase
inhibitor L-NG-monomethyl arginine (LMMA) and by the cyclo-oxygenase inhibitor indomethacin,
indicating that both factors act as mediators of bone resorption induced by IL-1 and
TNF. In contrast, interferon gamma (IFN) inhibited bone resorption induced by IL-1,
markedly stimulated NO production, but had no effect on IL-1 induced PGE2 production.
The suppressive effect of IFN on bone resorption was reversed by LMMA, but enhanced
by indomethacin confirming that the inhibitory effect of IFN on cytokine induced resorption
is entirely attributable to high levels of NO production. While cytokine induced NO
production was accompanied by increased production of cyclic guanosine monophosphate
(cGMP), the cGMP agonist 8-bromo-cGMP had no significant effect on bone resorption,
suggesting the effects of NO in bone resorption are mediated by other pathways. We
conclude that the effect of cytokines on bone resorption are determined by a balance
between levels of NO and PGE2; high NO concentrations inhibit bone resorption and
antagonize the effects of PGE2, whereas lower concentrations act together with prostaglandins
to enhance bone resorption. These observations may be of relevance to the pathogenesis
of bone loss in inflammatory diseases such as rheumatoid arthritis (RA) where, IL-1
and TNF production are increased but IFN production is diminished, resulting in modest
increases in NO and large increase in PGE production that are pro-resorptive.