PMID- 10342828
OWN - NLM
STAT- MEDLINE
DCOM- 19990603
LR  - 20131121
IS  - 0013-7227 (Print)
IS  - 0013-7227 (Linking)
VI  - 140
IP  - 6
DP  - 1999 Jun
TI  - Suppression of ligand-dependent estrogen receptor activity by bone-resorbing 
      cytokines in human osteoblasts.
PG  - 2439-51
AB  - 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)-kappaB in 
      osteoblasts. We present evidence that bone-resorbing cytokines that activate 
      NF-kappaB conversely inhibit ligand-dependent ER activity in the conditionally 
      immortalized human osteoblast cell line, HOB-03-CE6. Treatment of HOB-03-CE6 
      cells with 17beta-estradiol (17beta-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 17beta-E2 and increasing 
      concentrations of either tumor necrosis factor-alpha (TNF alpha), 
      interleukin-1alpha (IL-1alpha), or IL-1beta 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 alpha, IL-1alpha, nor 
      IL-1beta treatment affected basal reporter gene activity in the cells, and the 
      TNF alpha effect was reversed by a neutralizing antibody to the cytokine. TNF 
      alpha 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 alpha, even though both cell lines responded to the cytokine as measured 
      by the up-regulation of NFkappaB-tk-luciferase activity. TNF alpha treatment did 
      not affect the steady state levels of either ER alpha or ER beta messenger RNA 
      expression by the HOB-03-CE6 cells, nor did it reduce [125I]17beta-E2 binding. 
      Moreover, TNF alpha 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-kappaB pathway, did not suppress 
      ERE-tk-luciferase activity in HOB-03-CE6 cells. Treatment of the cells with 
      17beta-E2 partially suppressed the activation of NF-kappaB by TNF alpha, but did 
      not block cytokine-induced IL-6 secretion. Finally, cotreatment of HOB-03-CE6 
      cells with an antisense oligonucleotide to NF-kappaB p50 partially reversed the 
      suppression of ERE-tk-luciferase activity by TNF alpha. 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-kappaB.
FAU - Bodine, P V
AU  - Bodine PV
AD  - Women's Health Research Institute, Wyeth-Ayerst Research, Inc., Radnor, 
      Pennsylvania 19087, USA. bodinep@war.wyeth.com
FAU - Harris, H A
AU  - Harris HA
FAU - Komm, B S
AU  - Komm BS
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Cytokines)
RN  - 0 (NF-kappa B)
RN  - 0 (NF-kappa B p50 Subunit)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Estrogen)
RN  - 0 (Receptors, Glucocorticoid)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 4TI98Z838E (Estradiol)
SB  - IM
MH  - Animals
MH  - Bone Resorption/*etiology
MH  - CHO Cells
MH  - Cells, Cultured
MH  - Cricetinae
MH  - Cytokines/*pharmacology
MH  - Estradiol/*pharmacology
MH  - Humans
MH  - NF-kappa B/physiology
MH  - NF-kappa B p50 Subunit
MH  - Osteoblasts/*drug effects
MH  - RNA, Messenger/analysis
MH  - Receptors, Estrogen/analysis/*drug effects/genetics
MH  - Receptors, Glucocorticoid/analysis
MH  - Tumor Necrosis Factor-alpha/pharmacology
EDAT- 1999/05/26 00:00
MHDA- 1999/05/26 00:01
CRDT- 1999/05/26 00:00
PHST- 1999/05/26 00:00 [pubmed]
PHST- 1999/05/26 00:01 [medline]
PHST- 1999/05/26 00:00 [entrez]
AID - 10.1210/endo.140.6.6612 [doi]
PST - ppublish
SO  - Endocrinology. 1999 Jun;140(6):2439-51. doi: 10.1210/endo.140.6.6612.