Estrogen blocks M-CSF gene expression and osteoclast formation by regulating phosphorylation of Egr-1 and its interaction with Sp-1.

S Srivastava; M N Weitzmann; R B Kimble; M Rizzo; M Zahner; J Milbrandt; F P Ross; R Pacifici

doi:10.1172/JCI4561

Division of Bone and Mineral Diseases, Washington University School of Medicine, and Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.

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Division of Bone and Mineral Diseases, Washington University School of Medicine, and Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.

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Division of Bone and Mineral Diseases, Washington University School of Medicine, and Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.

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Division of Bone and Mineral Diseases, Washington University School of Medicine, and Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.

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Division of Bone and Mineral Diseases, Washington University School of Medicine, and Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.

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Division of Bone and Mineral Diseases, Washington University School of Medicine, and Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.

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Division of Bone and Mineral Diseases, Washington University School of Medicine, and Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.

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Division of Bone and Mineral Diseases, Washington University School of Medicine, and Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.

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Published in Volume 102, Issue 10 on November 15, 1998
J Clin Invest. 1998;102(10):1850–1859. https://doi.org/10.1172/JCI4561.
© 1998 The American Society for Clinical Investigation

Published November 15, 1998 - Version history

Central to the pathogenesis of osteoporosis is the ability of estrogen deficiency to increase osteoclast formation by enhancing stromal cell production of the osteoclastogenic cytokine macrophage colony-stimulating factor (M-CSF). We report that stromal cells from ovariectomized mice exhibit increased casein kinase II-dependent phosphorylation of the nuclear protein Egr-1. Phosphorylated Egr-1 binds less avidly to the transcriptional activator Sp-1 and the resulting higher levels of free Sp-1 stimulate transactivation of the M-CSF gene. Estrogen replacement fails to block M-CSF mRNA expression and osteoclast formation in ovariectomized mice lacking Egr-1, confirming the critical role played by this transcription factor in mediating the antiosteoclastogenic effects of estrogen. Thus, by downregulating formation of a novel Egr-1/Sp-1 complex in stromal cells, estrogen deficiency results in enhanced levels of free Sp-1 and increased M-CSF gene expression and osteoclast formation.

Version 1 (November 15, 1998): No description

Estrogen blocks M-CSF gene expression and osteoclast formation by regulating phosphorylation of Egr-1 and its interaction with Sp-1.

S Srivastava, M N Weitzmann, R B Kimble, M Rizzo, M Zahner, J Milbrandt, F P Ross, and R Pacifici

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Estrogen blocks M-CSF gene expression and osteoclast formation by regulating phosphorylation of Egr-1 and its interaction with Sp-1.

S Srivastava, M N Weitzmann, R B Kimble, M Rizzo, M Zahner, J Milbrandt, F P Ross, and R Pacifici

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