M-CSF neutralization and egr-1 deficiency prevent ovariectomy-induced bone loss.
Increased stromal cell production of M-CSF, an event caused by enhanced phosphorylation of the nuclear protein Egr-1, is central to the mechanism by which estrogen (E2) deficiency upregulates osteoclast (OC) formation. However, the contribution of enhanced M-CSF production to the bone loss induced by E2 deficiency remains to be determined. We found that treatment with an Ab that neutralizes M-CSF in vivo completely prevents the rise in OC number, the increase in bone resorption, and the resulting bone loss induced by ovariectomy (ovx). We also found that adult, intact Egr-1-deficient mice, a strain characterized by maximally stimulated stromal cell production of M-CSF, exhibit increased bone resorption and decreased bone mass. In these mice, treatment with anti-M-CSF Ab restored normal levels of bone resorption, thus confirming that increased M-CSF production accounts for the remodeling abnormalities of Egr-1-deficient mice. Consistent with the failure of ovx to further increase M-CSF production in Egr-1-deficient mice, ovx neither increased bone resorption further, nor caused bone loss in these animals. In summary, the data demonstrate that E2 deficiency induces M-CSF production via an Egr-1-dependent mechanism that is central to the pathogenesis of ovx-induced bone loss. Thus, Egr-1 and M-CSF are critical mediators of the bone sparing effects of E2 in vivo.
Cenci
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Division of Bone and Mineral Diseases, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.
Weitzmann
M N
MN
Gentile
M A
MA
Aisa
M C
MC
Pacifici
R
R
D000596:Amino Acids / Q000652:urine; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015519:Bone Density; D001862:Bone Resorption / Q000517:prevention & control*; D002452:Cell Count; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins / Q000172:deficiency*; D003720:Densitometry / Q000379:methods; D051766:Early Growth Response Protein 1; D004958:Estradiol / Q000172:deficiency*; D015914:Estrogen Replacement Therapy; D005260:Female; D017874:Immediate-Early Proteins; D016173:Macrophage Colony-Stimulating Factor / Q000172:deficiency* / Q000276:immunology; D051379:Mice; D009500:Neutralization Tests; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000166:cytology; D010052:Ovariectomy; D014157:Transcription Factors / Q000172:deficiency*; D014965:X-Rays
D000596:Amino Acids; D000906:Antibodies; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D017874:Immediate-Early Proteins; D014157:Transcription Factors; D015675:Osteocalcin; D004958:Estradiol; D016173:Macrophage Colony-Stimulating Factor; C036020:deoxypyridinoline