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Suppression of Ligand-Dependent Estrogen Receptor Activity by Bone-Resorbing Cytokines in Human Osteoblasts

Women’s Health Research Institute, Wyeth-Ayerst Research, Inc., Radnor, Pennsylvania 19087

Address all correspondence and requests for reprints to: Dr. Peter V. N. Bodine, Women’s Health Research Institute, Wyeth-Ayerst Research, Inc., 145 King of Prussia Road, Radnor, Pennsylvania 19087. E-mail: bodinep{at}war.wyeth.com

Estrogens are important for bone homeostasis and are classified as antiresorptive agents. One of the mechanisms for this effect is the inhibition of cytokine-induced bone resorption, which is mediated in part through an interaction between the estrogen receptor (ER) and nuclear factor (NF)-B in osteoblasts. We present evidence that bone-resorbing cytokines that activate NF-B conversely inhibit ligand-dependent ER activity in the conditionally immortalized human osteoblast cell line, HOB-03-CE6. Treatment of HOB-03-CE6 cells with 17ß-estradiol (17ß-E₂) up-regulated reporter gene activity [ERE-thymidine kinase (tk)-luciferase] 3- to 5-fold in a dose-dependent manner (EC₅₀ = 1.0 pM). However, cotreatment of the cells with 17ß-E₂ and increasing concentrations of either tumor necrosis factor- (TNF), interleukin-1 (IL-1), or IL-1ß completely suppressed ERE-tk-luciferase activity in a dose-dependent manner (IC₅₀ = 0.05–5.0 pM). On the other hand, treatment of the cells with growth factors either up-regulated or had no effect on ERE-tk-luciferase expression. Neither TNF, IL-1, nor IL-1ß treatment affected basal reporter gene activity in the cells, and the TNF effect was reversed by a neutralizing antibody to the cytokine. TNF treatment also suppressed ligand-dependent ER activity in MCF-7 human breast cancer cells, but not in Chinese hamster ovary cells that overexpressed human ER, even though both cell lines responded to the cytokine as measured by the up-regulation of NFB-tk-luciferase activity. TNF treatment did not affect the steady state levels of either ER or ERß messenger RNA expression by the HOB-03-CE6 cells, nor did it reduce [¹²⁵I]17ß-E₂ binding. Moreover, TNF treatment only weakly inhibited ligand-dependent glucocorticoid receptor activity in the HOB-03-CE6 cells. Bone-resorbing cytokines, which do not signal through the NF-B pathway, did not suppress ERE-tk-luciferase activity in HOB-03-CE6 cells. Treatment of the cells with 17ß-E₂ partially suppressed the activation of NF-B by TNF, but did not block cytokine-induced IL-6 secretion. Finally, cotreatment of HOB-03-CE6 cells with an antisense oligonucleotide to NF-B p50 partially reversed the suppression of ERE-tk-luciferase activity by TNF. In summary, these data provide evidence for a potent feedback inhibition of estrogen action in human osteoblasts that is at least partly mediated by the activation of NF-B.

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