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Molecular and Cellular Biology, February 2007, p. 1516-1530, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.01550-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Induction of Osteoblast Differentiation by Selective Activation of Kinase-Mediated Actions of the Estrogen Receptor{triangledown}

Stavroula Kousteni,{dagger} Maria Almeida, Li Han, Teresita Bellido, Robert L. Jilka, and Stavros C. Manolagas*

Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, and Central Arkansas Veterans Health Care System, Little Rock, Arkansas 72205

Received 18 August 2006/ Returned for modification 15 November 2006/ Accepted 30 November 2006

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

* Corresponding author. Mailing address: Division of Endocrinology and Metabolism, Slot 587, University of Arkansas for Medical Sciences, 4301 West Markham, Little Rock, AR 72205. Phone: (501) 686-5130. Fax: (501) 686-8148. E-mail: manolagasstavros{at}uams.edu.

{triangledown} Published ahead of print on 11 December 2006.

{dagger} Present address: Department of Medicine, Division of Endocrinology, Columbia University, Russ Berrie Medical Sciences Pavilion, 1150 St. Nicholas Avenue, New York, NY 10032.

Molecular and Cellular Biology, February 2007, p. 1516-1530, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.01550-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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