Srivastava S, Weitzmann M N, Kimble R B, Rizzo M, Zahner M, Milbrandt J, Ross F P, Pacifici R
Division of Bone and Mineral Diseases, Washington University School of Medicine, and Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA.
J Clin Invest. 1998 Nov 15;102(10):1850-9. doi: 10.1172/JCI4561.
Central to the pathogenesis of osteoporosis is the ability of estrogen deficiency to increase osteoclast formation by enhancing stromal cell production of the osteoclastogenic cytokine macrophage colony-stimulating factor (M-CSF). We report that stromal cells from ovariectomized mice exhibit increased casein kinase II-dependent phosphorylation of the nuclear protein Egr-1. Phosphorylated Egr-1 binds less avidly to the transcriptional activator Sp-1 and the resulting higher levels of free Sp-1 stimulate transactivation of the M-CSF gene. Estrogen replacement fails to block M-CSF mRNA expression and osteoclast formation in ovariectomized mice lacking Egr-1, confirming the critical role played by this transcription factor in mediating the antiosteoclastogenic effects of estrogen. Thus, by downregulating formation of a novel Egr-1/Sp-1 complex in stromal cells, estrogen deficiency results in enhanced levels of free Sp-1 and increased M-CSF gene expression and osteoclast formation.
雌激素缺乏通过增强破骨细胞生成细胞因子巨噬细胞集落刺激因子（M-CSF）的基质细胞产生来增加破骨细胞形成，这是骨质疏松症发病机制的核心。我们报道，来自去卵巢小鼠的基质细胞表现出核蛋白Egr-1的酪蛋白激酶II依赖性磷酸化增加。磷酸化的Egr-1与转录激活因子Sp-1的结合亲和力降低，导致游离Sp-1水平升高，从而刺激M-CSF基因的反式激活。在缺乏Egr-1的去卵巢小鼠中，雌激素替代不能阻止M-CSF mRNA表达和破骨细胞形成，证实了该转录因子在介导雌激素的抗破骨细胞生成作用中所起的关键作用。因此，通过下调基质细胞中新型Egr-1/Sp-1复合物的形成，雌激素缺乏导致游离Sp-1水平升高、M-CSF基因表达增加和破骨细胞形成增加。
