M-CSF neutralization and Egr-1 deficiency prevent ovariectomy-induced boneloss

Increased stromal cell production of M-CSF, an event caused by enhanced pho sphorylation of the nuclear protein Egr-1, is central to the mechanism by w hich estrogen (E2) deficiency upregulates osteoclast (OC) formation. Howeve r, the contribution of enhanced M-CSF production to the bone loss induced b y E2 deficiency remains to be determined. We found that treatment with an A b 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 ov ariectomy (ovx). We also found that adult, intact Egr-1-deficient mice, a s train characterized by maximally stimulated stromal cell production of M-CS F, exhibit: increased bone resorption and decreased bone mass. In these mic e, 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 i ncreased 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 bon e sparing effects of E2 in vivo.