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Roles of transactivating functions 1 and 2 of estrogen receptor-alpha in bone.

ABSTRACT: The bone-sparing effect of estrogen is primarily mediated via estrogen receptor-? (ER?), which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand binding domain. To evaluate the role of ER? AF-1 and ER? AF-2 for the effects of estrogen in bone in vivo, we analyzed mouse models lacking the entire ER? protein (ER?(-/-)), ER? AF-1 (ER?AF-1(0)), or ER? AF-2 (ER?AF-2(0)). Estradiol (E2) treatment increased the amount of both trabecular and cortical bone in ovariectomized (OVX) WT mice. Neither the trabecular nor the cortical bone responded to E2 treatment in OVX ER?(-/-) or OVX ER?AF-2(0) mice. OVX ER?AF-1(0) mice displayed a normal E2 response in cortical bone but no E2 response in trabecular bone. Although E2 treatment increased the uterine and liver weights and reduced the thymus weight in OVX WT mice, no effect was seen on these parameters in OVX ER?(-/-) or OVX ER?AF-2(0) mice. The effect of E2 in OVX ER?AF-1(0) mice was tissue-dependent, with no or weak E2 response on thymus and uterine weights but a normal response on liver weight. In conclusion, ER? AF-2 is required for the estrogenic effects on all parameters evaluated, whereas the role of ER? AF-1 is tissue-specific, with a crucial role in trabecular bone and uterus but not cortical bone. Selective ER modulators stimulating ER? with minimal activation of ER? AF-1 could retain beneficial actions in cortical bone, constituting 80% of the skeleton, while minimizing effects on reproductive organs.

SUBMITTER: Borjesson AE

PROVIDER: S-EPMC3076831 | biostudies-other | 2011 Apr

REPOSITORIES: biostudies-other

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Roles of transactivating functions 1 and 2 of estrogen receptor-alpha in bone.

Börjesson A E AE Windahl S H SH Lagerquist M K MK Engdahl C C Frenkel B B Movérare-Skrtic S S Sjögren K K Kindblom J M JM Stubelius A A Islander U U Antal M C MC Krust A A Chambon P P Ohlsson C C

Proceedings of the National Academy of Sciences of the United States of America 20110328 15

The bone-sparing effect of estrogen is primarily mediated via estrogen receptor-α (ERα), which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand binding domain. To evaluate the role of ERα AF-1 and ERα AF-2 for the effects of estrogen in bone in vivo, we analyzed mouse models lacking the entire ERα protein (ERα(-/-)), ERα AF-1 (ERαAF-1(0)), or ERα AF-2 (ERαAF-2(0)). Estradiol (E2) treatment increased the amount of both trab ...[more]

PMID: 21444817

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Project description:Loading-related changes in gene expression in resident cells in the tibia of female mice in the contexts of normality (WT), estrogen deficiency (WT-OVX), absence of estrogen receptor alpha (ERalpha(-/-)) and disuse due to sciatic neurectomy (WT-SN) were established by microarray. Total RNA was extracted from loaded and contra-lateral non-loaded tibiae at selected time points after a single, short period of dynamic loading sufficient to engender an osteogenic response. There were marked changes in the expression of many genes according to context as well as in response to loading within those contexts. In WT mice at 3, 8, 12 and 24 h after loading the expression of 642, 341, 171 and 24 genes, respectively, were differentially regulated compared with contra-lateral bones which were not loaded. Only a few of the genes differentially regulated by loading in the tibiae of WT mice have recognized roles in bone metabolism or have been linked previously to osteogenesis (Opn, Sost, Esr1, Tgfb1, Lrp1, Ostn, Timp, Mmp, Ctgf, Postn and Irs1, BMP and DLX5). The canonical pathways showing the greatest loading-related regulation were those involving pyruvate metabolism, mitochondrial dysfunction, calcium-induced apoptosis, glycolysis/gluconeogenesis, aryl hydrocarbon receptor and oxidative phosphorylation. In the tibiae from WT-OVX, ERalpha(-/-) and WT-SN mice, 440, 439 and 987 genes respectively were differentially regulated by context alone compared to WT. The early response to loading in tibiae of WT-OVX mice involved differential regulation compared to their contra-lateral non-loaded pair of fewer genes than in WT, more down-regulation than up-regulation and a later response. This was shared by WT-SN. In tibiae of ERalpha(-/-) mice, the number of genes differentially regulated by loading was markedly reduced at all time points. These data indicate that in resident bone cells, both basal and loading-related gene expression is substantially modified by context. Many of the genes differentially regulated by the earliest loading-related response were primarily involved in energy metabolism and were not specific to bone.

Dataset Information

Roles of transactivating functions 1 and 2 of estrogen receptor-alpha in bone.

Publications

Roles of transactivating functions 1 and 2 of estrogen receptor-alpha in bone.

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