ATP is a potent stimulator of the activation and formation of rodent osteoclasts.

1. There is increasing evidence that extracellular ATP acts directly on bone cells via P2 receptors. In normal rat osteoclasts, ATP activates both non-selective cation channels and Ca2+-dependent K+ channels. In this study we investigated the action of ATP on the formation of osteoclasts and on the ultimate function of these cells, namely resorption pit formation. 2. We found that ATP stimulated resorption pit formation up to 5.6-fold when osteoclast-containing bone cell populations from neonatal rats were cultured for 26 h on ivory discs, with a maximum effect occurring at relatively low concentrations (0.2-2 microM). The stimulatory effect of ATP was amplified greatly when osteoclasts were activated by culture in acidified media (pH 6.9-7.0). Pit formation by acid-activated osteoclasts in the absence of ATP was inhibited by apyrase, an ecto-ATPase and by suramin, an antagonist of P2 receptors. 3. Over the same concentration range at which rat osteoclast activation occurred (0.2-2 microM), ATP also enhanced osteoclast formation in 10 day mouse marrow cultures, by up to 3.3-fold, with corresponding increases in resorption pit formation. Higher concentrations of ATP (20-200 microM) reduced or blocked osteoclast formation. Adenosine, a P1 receptor agonist, was without effect on either osteoclast activation or formation. 4. These results suggest that low levels of extracellular ATP may play a fundamental role in modulating both the resorptive function and formation of mammalian osteoclasts.