Estrogen directly acts on osteoclasts via inhibition of inward rectifier K+ channels

Using the whole-cell patch-clamp technique in freshly isolated rat osteoclasts we examined the effects of estrogen on ionic channels. The predominant current was an inward rectifier K+ current (IKir). In the absence of non-osteoclastic cells, extracellularly applied 17beta-estradiol (>0.1 microM) inhibited IKir, indicating that estrogen acts directly on osteoclasts. Application of 17beta-estradiol (10 microM) for 10 min reduced IKir at the membrane potential of -120 mV to 70 +/- 15% of control. Removal of 17beta-estradiol partially restored the inhibition. The inhibition of IKir was dependent on concentration and application time. Intracellularly applied 17beta-estradiol had no effect on IKir. 17alpha-estradiol also inhibited the IKir, whereas progesterone and testosterone had no effect. The inhibitory action of 17beta-estradiol was not affected by guanosine 5'-O-(2-thiodiphosphate) (GDPbetaS), adenosine 3',5'-cyclic monophosphothioate Rp diastereomer (Rp-cAMPS), okadaic acid, staurosporine and phorbol ester, and was independent of intracellular Ca2+ concentration ([Ca2+]i). With no influence from soluble factors secreted from non-osteoclastic cells, preincubation of the osteoclasts for more than 60 min with much lower concentrations of 17beta-estradiol (1 and 10 nM) caused a reduction of IKir. In current-clamp configuration, application of 17beta-estradiol (10 microM) depolarized the membrane associated with a decrease in a membrane conductance, indicating that 17beta-estradiol inhibits IKir and depolarizes the membrane of osteoclasts. These results suggest that the 17beta-estradiol-induced inhibition of IKir might be mediated via non-genomic mechanisms. This direct action of 17beta-estradiol on osteoclasts may contribute to the regulation of [Ca2+]i and partially account for the protective effects of estrogen against bone loss.