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Estrogens are important mediators of bone homeostasis, and postmenopausal estrogen replacement therapy is extensively used to prevent osteoporosis. The biological effects of estrogen are mediated by receptors belonging to the superfamily of steroid/thyroid nuclear receptors, estrogen receptor (ER)α and ERβ. ERα, not only trans-activates target genes in a hormone-specific fashion, but it can also neutralize other transcriptional activators, such as nuclear factor (NF)-κB, causing repression of their target genes. A major mechanism by which estrogens prevent osteoporosis seems to be repression of transcription of NF-κB target genes, such as the osteoclast-activating cytokines interleukin-6 and interleukin-1. To study the capacity of both ERs in repression of NF-κB signaling in bone cells, we first carried out transient transfections with ERα or ERβ of the human osteoblastic U2-OS cell line, in which endogenous NF-κB was stimulated by tumor necrosis factor α. Repression by ERα was already observed without 17β-estradiol, whereas addition of the ligand increased repression to 90%. ERβ, however, was able to repress NF-κB activity only in the presence of ligand. Because it is known that some antiestrogens can also display tissue-specific agonistic properties, 4-hydroxytamoxifen was tested for its capacity in repressing NF-κB activity and was found to be active (albeit less efficient than 17β-estradiol) and, interestingly, only with ERα. The pure antagonist ICI 164,384 was incapable of repressing through any ER subtypes. Deletion analysis and the use of receptor ERα/ERβ-chimeras showed that the A/B domain, containing activation function-1, is essential for this suppressive action. Next, we developed stable transfectants of the human osteoblastic U2-OS cell line containing ERα or ERβ in combination with an NF-κB luciferase reporter construct. In these cell lines, repression of NF-κB activity was only mediated through ERα and not through ERβ. These findings offer new insights into the specific role of both ER subtypes in bone homeostasis and could eventually help in developing more specific medical intervention strategies for osteoporosis.

4-Hydroxytamoxifen Trans-Represses Nuclear Factor-κB Activity in Human Osteoblastic U2-OS Cells through Estrogen Receptor (ER)α, and Not through ERβ*