Estrogen receptor specificity for the effects of estrogen in ovariectomized mice

Lindberg, Mattias F.; Zhang, Weihua; Andersson, Niklas; Movérare, Sofia; Gao, Hui; Vidal, Olle; Erlandsson, Malin C.; Windahl, Sara H; Andersson, Göran; Lubahn, Dennis B.; Carlsten, Hans; Dahlman-Wright, Karin; Gustafsson, Jan‐Åke; Ohlsson, Claes

doi:10.1677/joe.0.1740167

Cited by 161 publications

(126 citation statements)

References 40 publications

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“…These data are in agreement with studies performed in knockout mice: application of E 2 did not prevent the development of osteoporosis in ERKO female (Lindberg et al 2001a, Lindberg et al 2002a) and male mice (Lindberg et al 2002b), indicating that the bone-protective effects of E 2 are primarily mediated by ER. Further, ERα gene polymorphisms are associated with osteoporosis in human populations (Gómez et al 2007).…”

Section: Discussionsupporting

confidence: 84%

Estrogen receptor subtype-specific effects on markers of bone homeostasis

Hertrampf

Schleipen

Velders

et al. 2008

Molecular and Cellular Endocrinology

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Please cite this article as: Hertrampf, T., Schleipen, B., Velders, M., Laudenbach, U., Fritzemeier, K.H., Diel, P., Estrogen receptor subtype-specific effects on markers of bone homeostasis, Molecular and Cellular Endocrinology (2007), doi:10.1016/j.mce.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractTo further elucidate the processes involved in the physiology of bone-protection by estrogens, ovariectomized (OVX) rats were treated subcutaneously with 17-estradiol, the ER-specific agonist (16-LE2) and the ER-specific agonist (8-VE2).OVX and intact animals served as controls. Biomarkers of bone-formation (osteocalcin (OC), osteopontin (OPN)) and bone-resorption (telopeptides of collagen type I (CTx), pyridinoline cross-links (Pyd)) were quantified. Bone mineral density was measured by computed tomography.OVX-induced bone loss could be antagonized by subcutaneous administration of 17-estradiol and 16-LE2. Serum levels of CTx, OC and OPN were significantly elevated in OVX compared to intact animals and reduced by 17-estradiol and 16-LE2. Treatment of OVX rats with 8-VE2 did not affect BMD or bone-marker serum levels.Taken together, the complex expression pattern of bone-markers in OVX rats following subcutaneous administration of ER subtype-specific agonists indicates that 17-estradiol exerts its bone-protective effects by modulating the activity of osteoclasts and osteoblasts via ERα.

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Section: Discussionsupporting

confidence: 84%

Estrogen receptor subtype-specific effects on markers of bone homeostasis

Hertrampf

Schleipen

Velders

et al. 2008

Molecular and Cellular Endocrinology

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“…The functional significance of ER␣ in ameloblasts remains unclear to date, though estrogen has been known to have a diverse function, including cell proliferation and differentiation, motility, and apoptosis (Evans, 1988;Katzenellenbogen, 1996;Lindberg et al, 2002). The expression pattern of ER␣ immunolabeling in ameloblasts as shown in this study was similar to that of epidermal growth factor (EGF) and EGF receptor (EGFr), which is part of the tyrosine kinase receptor family.…”

Section: Discussionsupporting

confidence: 56%

Characteristic distribution of immunoreaction for estrogen receptor alpha in rat ameloblasts

2005

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Estrogen has a diverse function, including cell proliferation and differentiation via estrogen receptors (ER), which have been reported to be the case in various tissues in addition to female reproductive organs. A recent immunocytochemical study has reported the expression of ER␣, a subtype of ER, in rat odontoblasts, suggesting an involvement of estrogen in the differentiation of tooth-forming cells. However, there is no information on the ER␣ immunoexpression in ameloblasts. The present study was therefore undertaken to examine the localization of ER␣ immunoreaction in rat ameloblasts during amelogenesis. A computer-assisted quantitative analysis under a confocal laser scanning microscope was employed to demonstrate the stage-specific localization pattern of ER␣ immunoreaction. Immunohistochemistry of the rat enamel organ revealed ER␣ expression as nuclear localization in ameloblasts, stratum intermedium, stellate reticulum, and papillary layer, in addition to mature and immature odontoblasts. The ratio of immunopositive nuclei to total nuclei (immunopositive ratio) in ameloblasts was high at the apical loop region and gradually declined at the presecretory stage to zero at the secretory stage with statistically significant difference. The ER␣ immunolabeling pattern exhibited a periodic change at the maturation stage proper with constant higher labeling in ruffle-ended ameloblasts than in smooth-ended ameloblasts. The positive ratio was then followed by a statistically significant increase in immunolabeling thereafter. This stage-specific immunolabeling pattern during amelogenesis suggests a possible role of ER␣ in ameloblast proliferation and differentiation.

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“…ERα is essential for the negative feedback regulation of serum sex steroids as reflected by elevated levels of testosterone, E2, and LH in female ERα −/− mice (27,28). In the present study, we made the observation that not only female ERα −/− but also female ERαAF-2 0 and ERαAF-1 0 mice had elevated serum levels of testosterone, E2, and LH compared with their corresponding WT mice, demonstrating that a normal negative feedback regulation of serum sex steroids requires an intact AF-1 and an intact AF-2 in ERα.…”

Section: Discussionmentioning

confidence: 99%

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

Börjesson

Windahl

Lagerquist

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

113

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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. 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 ERα −/− or OVX ERαAF-2 0 mice. OVX ERαAF-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 ERα −/− or OVX ERαAF-2 0 mice. The effect of E2 in OVX ERαAF-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, ERα AF-2 is required for the estrogenic effects on all parameters evaluated, whereas the role of ERα AF-1 is tissue-specific, with a crucial role in trabecular bone and uterus but not cortical bone. Selective ER modulators stimulating ERα with minimal activation of ERα AF-1 could retain beneficial actions in cortical bone, constituting 80% of the skeleton, while minimizing effects on reproductive organs.

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Estrogen receptor specificity for the effects of estrogen in ovariectomized mice

Cited by 161 publications

References 40 publications

Estrogen receptor subtype-specific effects on markers of bone homeostasis

Estrogen receptor subtype-specific effects on markers of bone homeostasis

Characteristic distribution of immunoreaction for estrogen receptor alpha in rat ameloblasts

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

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