Effects of forskolin on bone resorption in the absence and presence of parathyroid hormone and calcitonin

Summary Release of previously incorporated⁴⁵Ca from fetal rat long bones was determined with the diterpene forskolin, both in the absence and presence of parathyroid hormone (PTH) and calcitonin (CT). In the absence of hormone, increased bone resorption was observed with 10⁻⁷M forskolin, but biphasic responses, consisting of initial decreases in⁴⁵Ca release that were followed by increased calcium mobilization, were produced with 10⁻⁶M and 10⁻⁵M forskolin. Inhibition of⁴⁵Ca release was pronounced and delayed more with 10⁻⁵M forskolin while the greatest stimulation of bone resorption was elicited by 10⁻⁶M forskolin, a response that was inhibited by 100 mU/ml CT. In the presence of 250 ng/ml PTH, a synergistic enhancement of⁴⁵Ca release occurred with 10⁻⁷M forskolin treatment while, in contrast, calcium mobilization was inhibited by 10⁻⁶M and 10⁻⁵M forskolin. Inhibition by 10⁻⁶M forskolin was characterized by “escape” while that of 10⁻⁵M forskolin was continuous over a 5 day interval. Inhibition throughout the experimental period also was noted when 10⁻⁵M forskolin was combined with 2.5 ng/ml PTH, but no effect on calcium mobilization was observed upon addition of 10⁻⁷M forskolin and, rather than inhibition, an enhancement of⁴⁵Ca release occurred when 10⁻⁶M forskolin was combined with 2.5 ng/ml PTH. Inhibition of 250 ng/ml PTH, but lack of inhibition of 2.5 ng/ml PTH by 10⁻⁶M forskolin suggests a 10⁻⁶M forskolin-sensitive portion of PTH-mediated calcium efflux. Absence of “escape” when 10⁻⁵M forskolin is combined with 250 ng/ml PTH suggests that heterologous desensitization may not play a major role in the “escape” which occurs with 10⁻⁶M forskolin.