title: Estrogen directly acts on osteoclasts via inhibition of inward rectifier K+ channels.
abstract: 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.
authors.affiliation: Department of Oral Physiology, Fukuoka Dental College, Japan. okapi@college.fdcnet.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Okabe
authors.forename: F
authors.initials: F
authors.lastname: Okamoto
authors.forename: H
authors.initials: H
authors.lastname: Kajiya
authors.forename: K
authors.initials: K
authors.lastname: Takada
authors.forename: H
authors.initials: H
authors.lastname: Soeda
mesh_terms: D000818:Animals; D001464:Barium / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology*; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D019319:Okadaic Acid / Q000494:pharmacology; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D011374:Progesterone / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019311:Staurosporine / Q000494:pharmacology; D013739:Testosterone / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors
chemical_list: D002614:Chelating Agents; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D013873:Thionucleotides; D006153:Guanosine Diphosphate; D019319:Okadaic Acid; C016957:adenosine-3',5'-cyclic phosphorothioate; D001464:Barium; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol; C023427:guanosine 5'-O-(2-thiodiphosphate); D000242:Cyclic AMP; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium