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

J Clin Invest. 1998 Nov 15;102(10):1850-9. doi: 10.1172/JCI4561.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Casein Kinase II
  • Chloramphenicol O-Acetyltransferase
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Early Growth Response Protein 1
  • Estrogens / pharmacology*
  • Gene Expression Regulation*
  • Immediate-Early Proteins*
  • Macrophage Colony-Stimulating Factor / genetics
  • Macrophage Colony-Stimulating Factor / metabolism*
  • Mice
  • Mice, Inbred C3H
  • Mice, Knockout
  • Osteoclasts / drug effects
  • Osteoclasts / physiology*
  • Ovariectomy
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein-Serine-Threonine Kinases / metabolism
  • Sp1 Transcription Factor / metabolism*
  • Sp3 Transcription Factor
  • Stromal Cells / physiology
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection

Substances

  • DNA-Binding Proteins
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Estrogens
  • Immediate-Early Proteins
  • Sp1 Transcription Factor
  • Transcription Factors
  • Sp3 Transcription Factor
  • Macrophage Colony-Stimulating Factor
  • Chloramphenicol O-Acetyltransferase
  • Casein Kinase II
  • Protein-Serine-Threonine Kinases