title: Induction of osteoblast differentiation by selective activation of kinase-mediated actions of the estrogen receptor.
abstract: Estrogens control gene transcription by cis or trans interactions of the estrogen receptor (ER) with target DNA or via the activation of cytoplasmic kinases. We report that selective activation of kinase-mediated actions of the ER with 4-estren-3alpha,17beta-diol (estren) or an estradiol-dendrimer conjugate, each a synthetic compound that stimulates kinase-mediated ER actions 1,000 to 10,000 times more potently than direct DNA interactions, induced osteoblastic differentiation in established cell lines of uncommitted osteoblast precursors and primary cultures of osteoblast progenitors by stimulating Wnt and BMP-2 signaling in a kinase-dependent manner. In sharp contrast, 17beta-estradiol (E(2)) suppressed BMP-2-induced osteoblast progenitor commitment and differentiation. Consistent with the in vitro findings, estren, but not E(2), stimulated Wnt/beta-catenin-mediated transcription in T-cell factor-lacZ transgenic mice. Moreover, E(2) stimulated BMP signaling in mice in which ERalpha lacks DNA binding activity and classical estrogen response element-mediated transcription (ERalpha(NERKI/-)) but not in wild-type controls. This evidence reveals for the first time the existence of a large signalosome in which inputs from the ER, kinases, bone morphogenetic proteins, and Wnt signaling converge to induce differentiation of osteoblast precursors. ER can either induce it or repress it, depending on whether the activating ligand (and presumably the resulting conformation of the receptor protein) precludes or accommodates ERE-mediated transcription.
authors.affiliation: Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205, USA.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Kousteni
authors.forename: Maria
authors.initials: M
authors.lastname: Almeida
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.forename: Teresita
authors.initials: T
authors.lastname: Bellido
authors.forename: Robert L
authors.initials: RL
authors.lastname: Jilka
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D010766:Phosphorylation / Q000187:drug effects; D011944:Receptors, Androgen / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C468666:4-estren-3,17-diol; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D004963:Estrenes; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D013196:Dihydrotestosterone; D004958:Estradiol; D048049:Extracellular Signal-Regulated MAP Kinases