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 (I Kir). In the absence of non-osteoclastic cells, extracellularly applied 17β-estradiol (>0.1 µM) inhibited I Kir, indicating that estrogen acts directly on osteoclasts. Application of 17β-estradiol (10 µM) for 10 min reduced I Kir at the membrane potential of –120 mV to 70±15% of control. Removal of 17β-estradiol partially restored the inhibition. The inhibition of I Kir was dependent on concentration and application time. Intracellularly applied 17β-estradiol had no effect on I Kir. 17α-Estradiol also inhibited the I Kir, whereas progesterone and testosterone had no effect. The inhibitory action of 17β-estradiol was not affected by guanosine 5′-O-(2-thiodiphosphate) (GDPβS), 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 17β-estradiol (1 and 10 nM) caused a reduction of I Kir. In current-clamp configuration, application of 17β-estradiol (10 µM) depolarized the membrane associated with a decrease in a membrane conductance, indicating that 17β-estradiol inhibits I Kir and depolarizes the membrane of osteoclasts. These results suggest that the 17β-estradiol-induced inhibition of I Kir might be mediated via non-genomic mechanisms. This direct action of 17β-estradiol on osteoclasts may contribute to the regulation of [Ca2+]i and partially account for the protective effects of estrogen against bone loss.