Enhanced osetoclast (OC) formation is a key mechanism by which estrogen (E2) deficiency induces bone loss. E2 deficiency stimulates OC formation by altering the phenotypic characteristics of mature stromal cells (CS). As a result, mature SC from ovariectomized (ovx) mice produce increased levels of macrophage colony-stimulating factor (M-CSF), a cytokine essential for the proliferation and differentiation of OC precursors. SC from ovx mice produce high M-CSF levels because of decreased binding of the transcriptional initiator Sp-1 to an overlapping Egr/Sp site in the M-CSF promoter. We have recently discovered that the transcription factor Egr-1 inhibits Sp-1 induced M-SCF gene expression without itself binding to DNA. We have also found that Egr-1 interacts directly with Sp-1 forming a novel association of Egr-1 with Sp-1, and increased availability of unbound Sp-1, capable of transactivating the M-CSF gene. Thus, E2 deficiency, by increasing Egr-1 phosphoryl ati on, decreases association between Egr-1 and Sp-1. Mass spectrometry is being developed to follow the extent and site of phosphorylation in this protein.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR000954-24
Application #
6336828
Study Section
Project Start
2000-08-01
Project End
2001-07-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
24
Fiscal Year
2000
Total Cost
$7,430
Indirect Cost
Name
Washington University
Department
Type
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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