M-CSF neutralization and Egr-1 deficiency prevent ovariectomy-induced bone loss
M-CSF neutralization and Egr-1 deficiency prevent ovariectomy-induced bone loss
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DOI：
10.1172/jci8672
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发表时间：
2000-05-01
影响因子：
15.9
通讯作者：
Pacifici, R
中科院分区：
文献类型：
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作者：
Cenci, S;Weitzmann, MN;Pacifici, R
由核蛋白Egr-1的磷酸化增强引起的M-CSF的基质细胞产生增加是雌激素（E2）缺乏上调破骨细胞（OC）形成的机制的核心。然而，M-CSF产生的增加对E2缺乏引起的骨丢失的贡献仍有待确定。我们发现，治疗与抗体，中和M-CSF在体内完全防止OC数量的上升，骨吸收的增加，并导致骨质疏松引起的卵巢切除术（OVX）。我们还发现，成年的，完整的Egr-1缺陷小鼠，一个菌株的特点是最大限度地刺激基质细胞产生的M-CSF，表现出：骨吸收增加和骨量减少。在这些小鼠中，用抗M-CSF Ab治疗恢复了骨吸收的正常水平，从而证实M-CSF产生的增加解释了Egr-1缺陷小鼠的重塑异常。与ovx未能进一步增加Egr-1缺陷小鼠中M-CSF产生一致，ovx既不进一步增加骨吸收，也不引起这些动物的骨丢失。总之，数据表明E2缺乏通过Egr-1依赖性机制诱导M-CSF产生，该机制是OVX诱导的骨丢失的发病机制的核心。因此，Egr-1和M-CSF是E2体内骨保护作用的关键介质。
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.