ESTROGEN BLOCKS M-CSF GENE-EXPRESSION AND OSTEOCLAST FORMATION BY REGULATING PHOSPHORYLATION OF EGR-1 AND ITS INTERACTION WITH SP-1

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-stimula ting factor (M-CSF). We report that stromal cells from ovariectomized mice exhibit increased casein kinase II-dependent phosphorylation of t he nuclear protein Egr-1. Phosphorylated Egr-1 binds less avidly to he transcriptional activator Sp-1 and the resulting higher levels of fre e Sp-1 stimulate transactivation of the M-CSF gene. Estrogen replaceme nt fails to block M-CSF mRNA expression and osteoclast formation in ov ariectomized mice lacking Egr-1, confirming the critical role played b y this transcription factor in mediating the antiosteoclastogenic effe cts of estrogen. Thus, by downregulating formation of a novel Egr-1/Sp -1 complex in stromal cells, estrogen deficiency results in enhanced l evels of free Sp-1 and increased M-CSF gene expression and osteoclast formation.