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

Sunil Srivastava, M. Neale Weitzmann, Robert B. Kimble, Monica Rizzo, Michael Zahner, Jeffrey Milbrandt, F. Patrick Ross, Roberto Pacifici

Research output: Contribution to journalArticlepeer-review

168 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1850-1859
Number of pages10
JournalJournal of Clinical Investigation
Volume102
Issue number10
DOIs
StatePublished - Nov 15 1998

Keywords

  • Egr-1
  • Estrogen
  • Macrophage colony-stimulating factor
  • Osteoclasts
  • Sp-1

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