Reflections on the Discovery and Significance of Estrogen Receptor β

Koehler, Konrad F.; Helguero, Luísa A.; Haldosén, Lars Arne; Warner, Margaret; Gustafsson, Jan‐Åke

doi:10.1210/er.2004-0027

Cited by 340 publications

(264 citation statements)

References 110 publications

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“…2F). CM also enhanced gene expression in 7-day-old cultures through ER␤ (31), which may function independently of ER␣ in bone remodeling in females (32). Whereas basal activity was Ϸ10-fold higher with ER␤ relative to ER␣, the relative stimulatory effect of CM or 17␤E was significantly less, and no activity through ER␤ was evident in 21-day-old cultures ( Fig.…”

Section: Resultsmentioning

confidence: 86%

Expression of an estrogen receptor agonist in differentiating osteoblast cultures

McCarthy

Clough²,

Gundberg³

et al. 2008

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

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Osteoblasts respond in direct and indirect ways to estrogens, and age-dependent changes in hormone levels and bone health can be limited by focused hormone replacement therapy. In this study, we report the release and isolation of an estrogen receptor agonist from osteoblast cultures. This entity reprises many aspects of estradiol activity in isolated osteoblasts, but differs from authentic estradiol by several biochemical and physical criteria. At levels that occur in conditioned medium from differentiating osteoblast cultures, the agonist directly drives gene expression through estrogen-sensitive response elements, activates the obligate osteoblast transcription factor Runx2, and potently enhances Smad-dependent gene expression in response to TGF-␤, but exhibits relatively lesser suppressive effects on gene expression through C/EBP and AP-1-binding protein transcription factors. Estrogen receptor agonist activity is resistant to heating at 100°C and separable from the bulk of the remaining alcohol-and hexane-soluble molecules by C18 chromatography. MS and molecular fragmentation analyses predict a Mr of 415.2 to 437.2. Therefore, in addition to earlier studies showing that osteoblasts readily respond to and metabolize various sex steroid-like substrates, we find that they also generate a potent estrogen receptor agonist during differentiation in vitro. Changes in the availability of a molecule like this within bone may relate to differences in skeletal integrity with aging or metabolic disease.intracrine ͉ selective estrogen receptor modulator ͉ steroid S ex steroids cause direct genomic transcriptional effects through specific receptors that contain ligand binding, dimerization, DNA binding, and gene transactivation domains. They also cause indirect stimulatory or inhibitory effects through complexes composed of activated hormone receptor and other transcription factors or through variations in the activation potential of other transcriptional components (1-6) The skeleton is a well recognized target for sex steroids. Bone fragility is notable when sex steroid levels fall in women after menopause, in elderly males, or after sex organ ablation (7-11). In such cases, bone loss follows a release from native constraints on bone resorption that largely result from changes in growth regulators expressed by osteoblasts and from opposing effects on osteoblast and osteoclast activation and apoptosis, leading to an overall increase in bone remodeling (12-16). Importantly, imbalances in bone remodeling are restored by sex hormone replacement therapy. Regardless of a clear benefit for bone, use of native sex steroids risks inappropriate gene activation in other tissues. The possibility of breast, cardiovascular, and prostate disease that can occur in this context (17-19) has driven the search for sex hormone receptor modulators with tissue-or function-restricted effects. However, the value of agents like these may be complicated by steroid and precursor metabolizing enzymes expressed by osteoblasts (3,20,21).Many cells u...

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Section: Resultsmentioning

confidence: 86%

Expression of an estrogen receptor agonist in differentiating osteoblast cultures

McCarthy

Clough²,

Gundberg³

et al. 2008

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

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“…Oestradiol receptor (ER) β is present in GCs (Hall et al 2001;Jacob et al 2006;Juengel et al 2006;Deroo et al 2009). Not only does ERβ interact with ERα, but it also regulates cell signalling cascades associated with E2 (Pettersson et al 1997;Koehler et al 2005;Galluzzo et al 2007;Zhao et al 2008). …”

Section: Discussionmentioning

confidence: 99%

Localisation and endocrine control of hyaluronan synthase (HAS) 2, HAS3 and CD44 expression in sheep granulosa cells

Chavoshinejad

Marei

Hartshorne

et al. 2016

Reprod. Fertil. Dev.

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The aim of the present study was to investigate the hormonal regulation of hyaluronan (HA) components in sheep granulosa cells. HA components are present in the reproductive tract and have a range of physical and signalling properties related to reproductive function in several species. First, abattoir-derived ovaries of sheep were used to determine the localisation of HA synthase (HAS) 1–3 and CD44 proteins in antral follicles. Staining for HAS1–3 and CD44 proteins was most intense in the granulosa layer. Accordingly, the expression of HAS2, HAS3 and CD44 mRNA was measured in cultured granulosa cells exposed to 0–50 ng mL–1 of 17β-oestradiol and different combinations of oestradiol, gonadotropins, insulin-like growth factor (IGF)-1 and insulin for 48–96 h (1 ng mL–1 FSH, 10 ng mL–1 insulin, 10 ng mL–1 IGF-1, 40 ng mL–1 E2 and 25 ng mL–1 LH.). mRNA expression was quantified by real-time polymerase chain reaction using a fold induction method. The results revealed that the hormones tested generally stimulated mRNA expression of the genes of interest in cultured granulosa cells. Specifically, oestradiol, when combined with IGF-1, insulin and FSH, stimulated HAS2 mRNA expression. Oestradiol and LH had synergistic effects in increasing HAS3 mRNA expression. In conclusion, we suggest that the hormones studied differentially regulate HAS2, HAS3 and CD44 in ovine granulosa cells in vitro. Further work is needed to address the signalling pathways involved.

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“…Though highly homologous overall, the relative lack of homology between ERβ and ERα in the transcriptional activation domain and differences in the tissue distribution of the two receptors (Dechering et al, 2000;Kuiper et al, 1997) suggested functional differences, a conclusion supported by characterization of ERα and ERβ knockout mice (Hewitt and Korach, 2003). As the functional characterization of the two classical estrogen receptors continued, it became largely accepted that the diverse physiological functions of estrogen could be entirely ascribed to the combined effects of ERα and ERβ (Koehler et al, 2005). However, over the same time period, reports also described estrogen binding properties and cellular/physiological effects of estrogen that were not easily explained by transcriptional activation mediated by soluble estrogen receptors (Ho and Liao, 2002).…”

Section: Introductionmentioning

confidence: 99%

GPR30: A G protein-coupled receptor for estrogen

Prossnitz

Arterburn

Sklar

2007

Molecular and Cellular Endocrinology

273

186

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Estrogen is a critical steroid in human physiology exerting its effect both at the transcriptional level as well as at the level of rapid intracellular signaling through second messengers. Many of estrogen's transcriptional effects have long been known to be mediated through classical nuclear steroid receptors but recent studies also demonstrate the existence of a 7-transmembrane G protein-coupled receptor, GPR30 that responds to estrogen with rapid cellular signaling. There is currently controversy over the ability of classical estrogen receptors to recapitulate GPR30-mediated signaling mechanisms and vice versa. This article will summarize recent literature and address the relationship between GPR30 and conventional estrogen receptor signaling.

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Reflections on the Discovery and Significance of Estrogen Receptor β

Cited by 340 publications

References 110 publications

Expression of an estrogen receptor agonist in differentiating osteoblast cultures

Expression of an estrogen receptor agonist in differentiating osteoblast cultures

Localisation and endocrine control of hyaluronan synthase (HAS) 2, HAS3 and CD44 expression in sheep granulosa cells

GPR30: A G protein-coupled receptor for estrogen

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