Enhancement of fetal rat limb bone resorption by phorbol ester (PMA) and ionophore A-23187

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Abstract
The present investigation was under-taken to determine if an interaction affecting45Ca release from prelabeled fetal rat long bones could be elicited by the Ca2+ ionophore, A-23187, and the phorbol ester, 12-myristate 13-acetate (PMA). Treatment with either A-23187 at a concentration of 0.3 μM or PMA at concentrations of 10−6 M, 10−7 M, and 10−8 M produced significant45Ca mobilization. When A-23187 and PMA were combined, enhanced45Ca release was observed on days 1 and 2 of culture. The stimulation of calcium mobilization noted on day 1 occurred when neither ionophore nor 10−6 M PMA treatments alone produced significant45Ca release. On day 2, cumulative45Ca release elicited by the combination of A-23187 plus 10−6 M PMA was slightly more than additive (15.9% for combination treatment vs. 13.7% for the sum of the individual treatments). Moreover, when A-23187 was combined with 10−7 M PMA on day 2, an enhancement of45Ca release was observed which was clearly more than additive (14.5% for combination treatment vs. 8.8% for the individual treatments), suggesting the possibility of a synergistic interaction between the two agents. These results were in marked contrast to those obtained with the inactive phorbol ester analog, phorbol 13-monoacetate. No stimulation of45Ca release was observed with 10−6 M and 10−7 M phorbol 13-monoacetate alone nor was enhanced45Ca release noted when the analog was combined with 0.3 μM A-23187. A synergistic enhancement of calcium mobilization by A-23187 and PMA could be indicative of mechanisms of bone resorption mediated by calcium-activated, calmodulin-dependent and C-kinase-dependent protein kinases.