M-CSF neutralization and Egr-1 deficiency prevent ovariectomy-induced bone loss
Simone Cenci, … , M.C. Aisa, Roberto Pacifici
Simone Cenci, … , M.C. Aisa, Roberto Pacifici
Published May 1, 2000
Citation Information: J Clin Invest. 2000;105(9):1279-1287. https://doi.org/10.1172/JCI8672.
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Article

M-CSF neutralization and Egr-1 deficiency prevent ovariectomy-induced bone loss

Abstract

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.

Authors

Simone Cenci, M. Neale Weitzmann, M.A. Gentile, M.C. Aisa, Roberto Pacifici

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Figure 1

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Effect of serum from 5A1 Ab–treated mice on M-CSF–induced monocyte proli...
Effect of serum from 5A1 Ab–treated mice on M-CSF–induced monocyte proliferation. Results (mean + SEM) are expressed as percent of M-CSF–induced proliferation. Sera (100 μL) obtained at the end of the treatment period from ovx mice treated with either 5A1 Ab or irrelevant Ab and fresh 5A1 Ab (200 ng in 100 μL) were serially diluted (1:2) and added to CD11b+ cells seeded in triplicate in 96-well plates (final volume 200 μL per well). Recombinant murine M-CSF (25 ng/mL) was then added to each well. Cell proliferation was measured after a 3-day incubation, as described in Methods. AP < 0.05, compared with the other groups.