Induction of osteoblast differentiation by selective activation of kinase-mediated actions of the estrogen receptor

Stavroula Kousteni, Maria Almeida, Li Han, Teresita Bellido, Robert L. Jilka, Stavros C. Manolagas

Research output: Contribution to journalArticle

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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-3α,17β-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, 17β-estradiol (E2) suppressed BMP-2-induced osteoblast progenitor commitment and differentiation. Consistent with the in vitro findings, estren, but not E2, stimulated Wnt/β-catenin-mediated transcription in T-cell factor-lacZ transgenic mice. Moreover, E2 stimulated BMP signaling in mice in which ERα lacks DNA binding activity and classical estrogen response element-mediated transcription (ERαNERKI/-) 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.

Original languageEnglish (US)
Pages (from-to)1516-1530
Number of pages15
JournalMolecular and Cellular Biology
Volume27
Issue number4
DOIs
StatePublished - Feb 2007
Externally publishedYes

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Osteoblasts
Estrogen Receptors
Phosphotransferases
Estradiol
DNA
Estrogens
TCF Transcription Factors
Dendrimers
Catenins
Protein Conformation
Bone Morphogenetic Proteins
Estrogen Receptor alpha
Response Elements
Transgenic Mice
Ligands
Cell Line
Genes
4-estren-3,17-diol

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Induction of osteoblast differentiation by selective activation of kinase-mediated actions of the estrogen receptor. / Kousteni, Stavroula; Almeida, Maria; Han, Li; Bellido, Teresita; Jilka, Robert L.; Manolagas, Stavros C.

In: Molecular and Cellular Biology, Vol. 27, No. 4, 02.2007, p. 1516-1530.

Research output: Contribution to journalArticle

Kousteni, Stavroula ; Almeida, Maria ; Han, Li ; Bellido, Teresita ; Jilka, Robert L. ; Manolagas, Stavros C. / Induction of osteoblast differentiation by selective activation of kinase-mediated actions of the estrogen receptor. In: Molecular and Cellular Biology. 2007 ; Vol. 27, No. 4. pp. 1516-1530.
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