Effects of forskolin on bone

Martz, A; Thomas, Mary L.

doi:10.1016/0006-2952(83)90372-6

Cited by 11 publications

(6 citation statements)

References 10 publications

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“…When cyclic AMP has declined to basal levels (after 24 h) the bones start to resorb. In the study by Martz & Thomas (1983), the cyclic AMP response was of much shorter duration than in our system. The divergent results on Ca2+ mobilization in short-term cultures (< 24 h) is not easily explained.…”

Section: Discussioncontrasting

confidence: 48%

“…However, the effect was not sustained, and the magnitude was less than the effect by PTH at a dose giving the same cyclic AMP response. In a study by Martz & Thomas (1983) it was demonstrated that, in 2-8 h incubations, forskolin, at a concentration of 1 ,tmol/l, stimulated Ca2+ efflux from a chick-embryo system. However, in our system the forskolin-induced inhibition of bone resorption is transient (Lerner et al, 1984; the present study), and forskolin produces a dose-dependent stimulation of 45Ca and 3H release in long-term cultures (120 h; the present study).…”

Section: Discussionmentioning

confidence: 99%

“…The divergent results on Ca2+ mobilization in short-term cultures (< 24 h) is not easily explained. However, the two studies showing an initial stimulatory effect by forskolin (Martz & Thomas, 1983;Lowik et al, 1985) use the release of stable Ca2+, which is the net effect of accretion and resorption processes, as a parameter of bone resorption, whereas we and Lorenzo & Nishimoto (1982) use 45Ca release to quantify the rate of resorption processes.…”

Section: Discussionmentioning

confidence: 99%

“…At lower concentrations forskolin stimulated bone resorption in long-term experiments. Martz & Thomas (1983) have found that forskolin can stimulate cyclic AMP accumulation in chick-embryo tibiae in vitro and that forskolin causes a biphasic stimulatory effect on Ca2+ efflux from these bones. Recently, Lowik et al (1985) reported that forskolin is a weak transient stimulator of Ca2+ release from fetalmouse calvaria, although it induced a cyclic AMP response comparable with that induced by PTH.…”

Section: Introductionmentioning

confidence: 94%

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Use of forskolin to study the relationship between cyclic AMP formation and bone resorption in vitro

Lerner¹,

Fredholm²,

Ransjö³

1986

Biochemical Journal

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The effect of the adenylate cyclase activator forskolin on bone resorption and cyclic AMP accumulation was studied in an organ-culture system by using calvarial bones from 6-7-day-old mice. Forskolin caused a rapid and fully reversible increase of cyclic AMP, which was maximal after 20-30 min. The phosphodiesterase inhibitor rolipram (30 mumol/l), enhanced the cyclic AMP response to forskolin (50 mumol/l) from a net cyclic AMP response of 1234 +/- 154 pmol/bone to 2854 +/- 193 pmol/bone (mean +/- S.E.M., n = 4). The cyclic AMP level in bones treated with forskolin (30 mumol/l) was significantly increased after 24 h of culture. Forskolin, at and above 0.3 mumol/l, in the absence and the presence of rolipram (30 mumol/l), caused a dose-dependent cyclic AMP accumulation with an calculated EC50 (concentration producing half-maximal stimulation) value at 8.3 mumol/l. In 24 h cultures forskolin inhibited spontaneous and PTH (parathyroid hormone)-stimulated 45Ca release with calculated IC50 (concentration producing half-maximal inhibition) values at 1.6 and 0.6 mumol/l respectively. Forskolin significantly inhibited the release of 3H from [3H]proline-labelled bones stimulated by PTH (10 nmol/l). The inhibitory effect by forskolin on PTH-stimulated 45Ca release was significant already after 3 h of culture. In 24 h cultures forskolin (3 mumol/l) significantly inhibited 45Ca release also from bones stimulated by prostaglandin E2 (1 mumol/l) and 1 alpha-hydroxycholecalciferol (0.1 mumol/l). The inhibitory effect of forskolin on spontaneous and PTH-stimulated 45Ca release was transient. A dose-dependent stimulation of basal 45Ca release was seen in 120 h cultures, at and above 3 nmol of forskolin/l, with a calculated EC50 value at 16 nmol/l. The stimulatory effect of forskolin (1 mumol/l) could be inhibited by calcitonin (0.1 unit/ml), but was insensitive to indomethacin (1 mumol/l). Forskolin increased the release of 3H from [3H]proline-labelled bones cultured for 120 h and decreased the amount of hydroxyproline in bones after culture. Forskolin inhibited PTH-stimulated release of Ca2+, Pi, beta-glucuronidase and beta-N-acetylglucosaminidase in 24 h cultures. In 120 h cultures forskolin stimulated the basal release of minerals and lysosomal enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Discussioncontrasting

confidence: 48%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

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Use of forskolin to study the relationship between cyclic AMP formation and bone resorption in vitro

Lerner¹,

Fredholm²,

Ransjö³

1986

Biochemical Journal

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“…Our results with PTH(1-34) showed a time-and dose-dependent induction of calcium mobilization and inhibition of ALP activity. It is well known that the effect of inducing calcium mobilization as well as reducing alkaline phosphatase activity correlates with cAMP formation induced by PTH in osteoblast-like cells (12,13). Salmon calcitonin and the bisphosphonate BM 21.0955 (16) substances known to inhibit osteoclast activity slightly decreased the level of calcium in the medium and decreased bone resorption and repression of ALP activity by PTH .…”

Section: Discussionmentioning

confidence: 98%

Individual and combined effects of calciotropic hormones and growth factors on mineral metabolism in embryonic chick tibiae

Duvos¹,

Scutt

Mayer

1997

In Vitro Cell.Dev.Biol.-Animal

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We have investigated single and combined effects of calciotropic hormones and growth factors on the regulation of alkaline phosphatase (ALP) activity and calcium metabolism in an optimized serum-free bone organ culture system of embryonic chick tibiae. Parathyroid hormone PTH(1-34) alone mobilized calcium from bone tissue time- and dose-dependently and inhibited ALP activity. Both the bisphosphonate (BM 21.0955) and to a lesser extent salmon calcitonin alone slightly increased calcium uptake and inhibited the stimulation of bone resorption by PTH(1-34). 1,25(OH)2D3 mobilized calcium and inhibited ALP activity in contrast to 24,25(OH)2D3 which inhibited ALP activity but had no significant effect on calcium metabolism. Interestingly the combination of PTH(1-34) with 1,25(OH)2D3 but not 24,25(OH)2D3 reduced calcium mobilization. The combination of the midregional fragment PTH(28-48), which by itself has no effect on calcium metabolism, with 1,25(OH)2D3 reduced calcium mobilization more efficiently. Several PTH-regulated mediators have been assayed in this system. Of the tested growth factors, IGF-I at high concentrations caused bone resorption with no effect on ALP activity. TGF-beta 1 (transforming growth factor beta) and BMP-2 had no significant effect on calcium metabolism; however, ALP activity was inhibited by TGF-beta 1 and induced dose dependently by BMP-2. Of the other factors known to be present in bone, platelet-derived growth factor (PDGFA/B) and epidermal growth factor (EGF) had a small effect on calcium mobilization but had no effect on ALP activity. bFGF reduced ALP activity slightly without an effect on calcium metabolism. Our results show that this in vitro system can mimic some interactions of calciotropic hormones in vivo and allows the assaying of mediators in terms of regulation of ALP activity and of calcium metabolism.

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

1987

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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.

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Effects of forskolin on bone

Cited by 11 publications

References 10 publications

Use of forskolin to study the relationship between cyclic AMP formation and bone resorption in vitro

Use of forskolin to study the relationship between cyclic AMP formation and bone resorption in vitro

Individual and combined effects of calciotropic hormones and growth factors on mineral metabolism in embryonic chick tibiae

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

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