Sex steroids, ANGELS and osteoporosis

Moggs, Jonathan G.; Deavall, Damian G.; Orphanides, George M.

doi:10.1002/bies.10249

Cited by 18 publications

(16 citation statements)

References 32 publications

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“…Furthermore, this work demonstrates that comparison of temporal changes in gene expression and conventional toxicology parameters (uterine weight and histologic changes) can provide an understanding of the relationships between gene expression patterns and phenotypic change. E 2 can regulate transcription through a combination of at least two distinct signaling pathways: a) via activation of the nuclear transcription factors ER-α and ER-β (Hall et al 2001;McKenna and O'Malley 2002;Moggs and Orphanides 2001;Tremblay and Giguere 2002) and b) via extranuclear or "nongenomic" signaling events (Falkenstein et al 2000;Hammes 2003;Moggs et al 2003). The transcriptional responses to E 2 that we have defined here are likely to involve a combination of direct gene regulation by nuclear ERs and indirect gene regulation via extranuclear signaling pathways.…”

Section: Discussionmentioning

confidence: 92%

“…Although the events described above have been characterized at the physiologic level, little is known about how E 2 , acting through the estrogen receptors ER-α and ER-β, coordinates at the molecular level the myriad cellular processes involved, despite significant progress in elucidating the molecular mechanisms by which ERs regulate gene expression in vitro (Hall et al 2001;McKenna and O'Malley 2002;Metivier et al 2003;Moggs and Orphanides 2001;Moggs et al 2003;Tremblay and Giguere 2002). Our data reveal the transcriptional program associated with E 2 -induced uterine growth.…”

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confidence: 83%

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Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth

Moggs¹,

Tinwell²,

Spurway³

et al. 2004

Environ Health Perspect

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A major challenge in the emerging field of toxicogenomics is to define the relationships between chemically induced changes in gene expression and alterations in conventional toxicologic parameters such as clinical chemistry and histopathology. We have explored these relationships in detail using the rodent uterotrophic assay as a model system. Gene expression levels, uterine weights, and histologic parameters were analyzed 1, 2, 4, 8, 24, 48, and 72 hr after exposure to the reference physiologic estrogen 17β-estradiol (E 2 ). A multistep analysis method, involving unsupervised hierarchical clustering followed by supervised gene ontology-driven clustering, was used to define the transcriptional program associated with E 2 -induced uterine growth and to identify groups of genes that may drive specific histologic changes in the uterus. This revealed that uterine growth and maturation are preceded and accompanied by a complex, multistage molecular program. The program begins with the induction of genes involved in transcriptional regulation and signal transduction and is followed, sequentially, by the regulation of genes involved in protein biosynthesis, cell proliferation, and epithelial cell differentiation. Furthermore, we have identified genes with common molecular functions that may drive fluid uptake, coordinated cell division, and remodeling of luminal epithelial cells. These data define the mechanism by which an estrogen induces organ growth and tissue maturation, and demonstrate that comparison of temporal changes in gene expression and conventional toxicology end points can facilitate the phenotypic anchoring of toxicogenomic data.

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Section: Discussionmentioning

confidence: 92%

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confidence: 83%

Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth

Moggs¹,

Tinwell²,

Spurway³

et al. 2004

Environ Health Perspect

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“…The cellular effects of estrens have been attributed to activation of membrane signaling through the MAPK cascade and not to direct activation of gene regulation, in contrast to estrogens, androgens, or SERMs. Hence the use of the term ANGELS (activators of non-genomic estrogen-like signaling) to describe this family of compounds (12,13).…”

Section: Introductionmentioning

confidence: 99%

Bone protection by estrens occurs through non–tissue-selective activation of the androgen receptor

Windahl

Galien²,

Chiusaroli³

et al. 2006

J. Clin. Invest.

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The use of estrogens and androgens to prevent bone loss is limited by their unwanted side effects, especially in reproductive organs and breast. Selective estrogen receptor modulators (SERMs) partially avoid such unwanted effects, but their efficacy on bone is only moderate compared with that of estradiol or androgens. Estrens have been suggested to not only prevent bone loss but also exert anabolic effects on bone while avoiding unwanted effects on reproductive organs. In this study, we compared the effects of a SERM (PSK3471) and 2 estrens (estren-α and estren-β) on bone and reproductive organs to determine whether estrens are safe and act via the estrogen receptors and/or the androgen receptor (AR). Estrens and PSK3471 prevented gonadectomy-induced bone loss in male and female mice, but none showed true anabolic effects. Unlike SERMs, the estrens induced reproductive organ hypertrophy in both male and female mice and enhanced MCF-7 cell proliferation in vitro. Estrens directly activated transcription in several cell lines, albeit at much higher concentrations than estradiol or the SERM, and acted for the most part through the AR. We conclude that the estrens act mostly through the AR and, in mice, do not fulfill the preclinical efficacy or safety criteria required for the treatment or prevention of osteoporosis.

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“…Moreover, the use of selective activators of kinases, as well as compounds that dissociate the classical genomic actions of the estrogen receptor from cross talk with other transcription factors (8,56), has provided extensive proof of the general concept that it is possible to eliminate the uterotropic activity of estrogens while retaining other nonreproductive actions. Together with cell and murine models expressing mutant receptors that cannot enter the nucleus and interact with DNA directly, these tools have become increasingly important for our understanding of nuclear receptor pharmacology (25,37,47,48,64). Heretofore, however, it has remained unknown whether kinase-mediated actions of the ER or androgen receptor (AR), in the absence of classical genotropic actions, could result in unique biologic outcomes that cannot be elicited by the natural sex steroids.…”

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confidence: 99%

Induction of Osteoblast Differentiation by Selective Activation of Kinase-Mediated Actions of the Estrogen Receptor

Kousteni

Almeida

Han

et al. 2007

Molecular and Cellular Biology

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Estrogens control gene transcription by cis or trans interactions of the estrogen receptor (ER) with target DNA or via the activation of cytoplasmic kinases. We report that selective activation of kinase-mediated actions of the ER with 4-estren-3␣,17␤-diol (estren) or an estradiol-dendrimer conjugate, each a synthetic compound that stimulates kinase-mediated ER actions 1,000 to 10,000 times more potently than direct DNA interactions, induced osteoblastic differentiation in established cell lines of uncommitted osteoblast precursors and primary cultures of osteoblast progenitors by stimulating Wnt and BMP-2 signaling in a kinase-dependent manner. In sharp contrast, 17␤-estradiol (E 2 ) suppressed BMP-2-induced osteoblast progenitor commitment and differentiation. Consistent with the in vitro findings, estren, but not E 2 , stimulated Wnt/␤-catenin-mediated transcription in T-cell factor-lacZ transgenic mice. Moreover, E 2 stimulated BMP signaling in mice in which ER␣ lacks DNA binding activity and classical estrogen response element-mediated transcription (ER␣ NERKI/؊ ) but not in wild-type controls. This evidence reveals for the first time the existence of a large signalosome in which inputs from the ER, kinases, bone morphogenetic proteins, and Wnt signaling converge to induce differentiation of osteoblast precursors. ER can either induce it or repress it, depending on whether the activating ligand (and presumably the resulting conformation of the receptor protein) precludes or accommodates EREmediated transcription.Steroid hormones, including estrogens and androgens, can induce cellular responses not only through direct activation of gene transcription resulting from cis or trans interactions of their receptors with DNA binding sequences on target gene promoters but also indirectly. The latter responses result from extranuclear actions of the same hormone receptors, causing activation of various cytoplasmic protein kinase cascades, which in turn alter the activities of other transcription factors or coactivators of the receptors themselves (5,6,27,40,43,46,53,67). During the last few years, we and others have identified several synthetic compounds that, unlike estradiol, can selectively activate kinase-initiated routes by which the estrogen receptor (ER) controls gene transcription (28,38,60). By use of these compounds, substantial evidence that kinase-mediated effects on gene transcription are dissociable from direct cis or trans effects on transcription has been obtained (28,38,39,54). Moreover, the use of selective activators of kinases, as well as compounds that dissociate the classical genomic actions of the estrogen receptor from cross talk with other transcription factors (8, 56), has provided extensive proof of the general concept that it is possible to eliminate the uterotropic activity of estrogens while retaining other nonreproductive actions. Together with cell and murine models expressing mutant receptors that cannot enter the nucleus and interact with DNA directly, these tools have become increas...

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Sex steroids, ANGELS and osteoporosis

Cited by 18 publications

References 32 publications

Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth

Phenotypic Anchoring of Gene Expression Changes during Estrogen-Induced Uterine Growth

Bone protection by estrens occurs through non–tissue-selective activation of the androgen receptor

Induction of Osteoblast Differentiation by Selective Activation of Kinase-Mediated Actions of the Estrogen Receptor

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