Prostaglandins regulate acid-induced cell-mediated bone resorption

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Abstract
Metabolic acidosis induces bone calcium efflux initially by physicochemical dissolution and subsequently by cell-mediated mechanisms involving inhibition of osteoblasts and stimulation of osteoclasts. In rat kidney, acidosis increases endogenous prostaglandin synthesis, and in bone, prostaglandins are important mediators of resorption. To test the hypothesis that acid-induced bone resorption is mediated by prostaglandins, we cultured neonatal mouse calvariae in neutral or physiologically acidic medium with or without 0.56 μM indomethacin to inhibit prostaglandin synthesis. We measured net calcium efflux and medium PGE2 levels. Compared with neutral pH medium, acid medium led to an increase in net calcium flux and PGE2 levels after both 48 h and 51 h, a time at which acid-induced net calcium flux is predominantly cell mediated. Indomethacin inhibited the acid-induced increase in both net calcium flux and PGE2. Net calcium flux was correlated directly with medium PGE2 (r = 0.879,n = 29, P < 0.001). Exogenous PGE2, at a level similar to that found after acid incubation, induced net calcium flux in bones cultured in neutral medium. Acid medium also stimulated an increase in PGE2levels in isolated bone cells (principally osteoblasts), which was again inhibited by indomethacin. Thus acid-induced stimulation of cell-mediated bone resorption appears to be mediated by endogenous osteoblastic PGE2 synthesis.