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

Abstract

Release of previously incorporated 45Ca 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(-7)M forskolin, but biphasic responses, consisting of initial decreases in 45Ca release that were followed by increased calcium mobilization, were produced with 10(-6)M and 10(-5)M forskolin. Inhibition of 45Ca release was pronounced and delayed more with 10(-5)M forskolin while the greatest stimulation of bone resorption was elicited by 10(-6)M forskolin, a response that was inhibited by 100 mU/ml CT. In the presence of 250 ng/ml PTH, a synergistic enhancement of 45Ca release occurred with 10(-7)M forskolin treatment while, in contrast, calcium mobilization was inhibited by 10(-6)M and 10(-5)M forskolin. Inhibition by 10(-6)M forskolin was characterized by "escape" while that of 10(-5)M forskolin was continuous over a 5 day interval. Inhibition throughout the experimental period also was noted when 10(-5)M forskolin was combined with 2.5 ng/ml PTH, but no effect on calcium mobilization was observed upon addition of 10(-7)M forskolin and, rather than inhibition, an enhancement of 45Ca release occurred when 10(-6)M 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(-6)M forskolin suggests a 10(-6)M forskolin-sensitive portion of PTH-mediated calcium efflux. Absence of "escape" when 10(-5) M 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(-6) M forskolin.

Parathyroid hormone and prostaglandin E2 stimulate both inositol phosphates and cyclic AMP accumulation in mouse osteoblast cultures

“…The cellular effects of PTH on osteoblast-like cells include stimulation of proliferation (Plas et al, 1985;McDonald et al, 1986), inhibition of proliferation at high concentrations (Partridge et al, 1985), elevation of [Ca], in some but not all osteoblast-like cell lines (Lowik et al, 1985;Boland et al, 1986) and the activation of adenylate cyclase (Chase & Aurbach, 1970). The latter action is insufficient to account for all of the effects of PTH (Lerner et al, 1986a;Conaway et al, 1987;Ransjo & Lerner, 1987) and it has been proposed that osteoblasts possess two different receptors for PTH (Lowik et al, 1985). In support of this proposal, Yamaguchi et al (1987) have demonstrated that PTH can elevate [Ca]l by cyclic AMP-dependent and -independent pathways.…”

On the role of cyclic AMP as a mediator of bone resorption: γ-Interferon completely inhibits cholera toxin- and forskolin-induced but only partially inhibits parathyroid hormone-stimulated 45Ca release from mouse calvarial bones

“…(11.34.35) Based on the observations that stimulation of the adenylate cyclase-cyclic AMP system by dibutyrylcyclic AMP,(4.5) phosphodiesterase inhibitor^,'^.^^) forsko-1in,(8. [37][38][39] and cholera is substantially delayed compared to the effect of PTH, we have suggested that the rapid activation of osteoclasts is not mediated by cyclic AMP. However, the late bone resorptive response to nonreceptor-mediated cyclic AMP stimulation may very well be related to the capacity of PTH to enhance the formation of new osteoclasts, although this interpretation needs to be confirmed by morphologic data.…”