Experimental Physiology



Forskolin has a bimodal cAMP-independent effect on superoxide anion generation in isolated osteoclasts


Christine E. M.  Berger a1 and Harish K.  Datta a1
a1 Department of Clinical Biochemistry, The Medical School, Framlington Place, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK

Abstract

The mode of action of forskolin is of clinical and scientific interest since forskolin has been shown to have potentially therapeutic bone anti-resorptive and anti-hypertensive properties. Forskolin is thought to inhibit the bone resorptive activity of osteoclasts by elevating cytosolic cAMP and to mimic as well as augment the anti-resorptive effect of calcitonin (CT). Other studies have found that forskolin has a dose-dependent dual effect in mouse calavaria, stimulating bone resorption at low doses and having an inhibitory effect at high doses. However, the acute effect of forskolin on osteoclast functional modality has never been studied. The present investigation examined the effect of low (1 mM) and high doses (10 mM) of forskolin on superoxide anion (O2Σ-) generation in isolated bone-resorbing rat osteoclasts. Forskolin was found to have a bimodal cAMP-independent effect on O2Σ- generation, being stimulatory at a low dose and having an inhibitory effect at a higher dose. These findings also suggest that CT-induced inhibition of O2Σ- generation in the osteoclasts is likely to be mediated by cAMP-independent pathways, perhaps involving [Ca2+]i modulation.

(Received July 28 1999)
(Accepted October 19 1999)