Mechanisms involved in prostaglandin-induced increase in bone resorption in neonatal mouse calvaria

Abstract Prostaglandins (PG) E 1 , E 2 and F 2 α induce bone resorption in isolated neonatal parietal bone cultures, and an associated increase in interleukin-6 (IL-6) production. Indomethacin had little effect on the response to PGE 2 , or the relatively non-selective EP receptor agonists 11-deoxy PGE 1 and misoprostol, but blocked the effects of PGF 2 α and the F receptor agonist fluprostenol, indicating an indirect action via release of other prostaglandins. It is more likely that there is positive autoregulation of prostaglandins production in this preparation mediated via stimulation of F receptors. The effects of selective EP receptor agonists sulprostone (EP1,3) and 17-phenyl trinor PGE 2 (EP1), indicated the involvement of EP2 and/or EP4 receptors, which signal via cAMP. The relatively weak increase in IL-6 production by misoprostol (with respect to resorption) suggests that these responses are controlled by different combination of EP2 and EP4 receptors. The PKA activator, forskolin, induced small increases in bone resorption at lower concentrations (50–500 ng/ml) but a reversal of this effect, and inhibition of resorption induced by other stimuli (PTH, PGE 2 ), at higher concentrations (0.5–5 μg/ml). IL-6 production was markedly increased only at the higher concentrations. The inhibitory effect of forskolin may be a calcitonin-mimetic effect. PMA induced both resorption and IL-6 production which were both blocked by indomethacin, indicating a role for PKC in the control of prostaglandin production.