In vivo characterization of estrogen receptor modulators with reduced genomic versus nongenomic activity in vitro

Otto, Christiane; Fuchs, Iris; Altmann, Helga; Klewer, Mario; Schwarz, Gilda; Bohlmann, Rolf; Nguyen, Duy Duc; Zorn, Ludwig; Vonk, Richardus; Prelle, Katja; Österman, T.; Mälmström, Chira; Fritzemeier, Karl-Heinrich

doi:10.1016/j.jsbmb.2008.05.003

Cited by 21 publications

(16 citation statements)

References 19 publications

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“…The clear distinctions we observed between responses in endothelium, uterus, and breast cancer in mice indicate that non-nuclear ER signaling is indeed a means of differential tissue responsiveness to estrogen in vivo, as has been suggested in previous in vivo studies of the impact on bone mineralization of ER ligands with reduced nuclear activity in vitro (43).…”

Section: Figuresupporting

confidence: 76%

Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice

et al. 2010

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Steroid hormone receptors function classically in the nucleus as transcription factors. However, recent data indicate that there are also non-nuclear subpopulations of steroid hormone receptors, including estrogen receptors (ERs), that mediate membrane-initiated signaling of unclear basis and significance. Here we have shown that an estrogen-dendrimer conjugate (EDC) that is excluded from the nucleus stimulates endothelial cell proliferation and migration via ERα, direct ERα-Gαi interaction, and endothelial NOS (eNOS) activation. Analysis of mice carrying an estrogen response element luciferase reporter, ER-regulated genes in the mouse uterus, and eNOS enzyme activation further indicated that EDC specifically targets non-nuclear processes in vivo. In mice, estradiol and EDC equally stimulated carotid artery reendothelialization in an ERα-and G protein-dependent manner, and both agents attenuated the development of neointimal hyperplasia following endothelial injury. In contrast, endometrial carcinoma cell growth in vitro and uterine enlargement and MCF-7 cell breast cancer xenograft growth in vivo were stimulated by estradiol but not EDC. Thus, EDC is a non-nuclear selective ER modulator (SERM) in vivo, and in mice, non-nuclear ER signaling promotes cardiovascular protection. These processes potentially could be harnessed to provide vascular benefit without increasing the risk of uterine or breast cancer.

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Section: Figuresupporting

confidence: 76%

Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice

et al. 2010

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“…91 Similarly, synthetic estrogen-like compounds, which selectively activate kinases but have weak genomic effects, have far more potent effects on bone than on the uterus and breast, and also reproduce the vasodilatory effect of estradiol. 92,93 …”

Section: Molecular Mechanisms Of Erα Actionmentioning

confidence: 99%

The role of estrogen and androgen receptors in bone health and disease

2013

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Mouse models with cell-specific deletion of the estrogen receptor (ER) α, the androgen receptor (AR) or the receptor activator of nuclear factor κB ligand (RANKL), as well as cascade-selective estrogenic compounds have provided novel insights into the function and signalling of ERα and AR. The studies reveal that the effects of estrogens on trabecular versus cortical bone mass are mediated by direct effects on osteoclasts and osteoblasts, respectively. The protection of cortical bone mass by estrogens is mediated via ERα, using a non-nucleus-initiated mechanism. By contrast, the AR of mature osteoblasts is indispensable for the maintenance of trabecular bone mass in male mammals, but not required for the anabolic effects of androgens on cortical bone. Most unexpectedly, and independently of estrogens, ERα in osteoblast progenitors stimulates Wnt signalling and periosteal bone accrual in response to mechanical strain. RANKL expression in B lymphocytes, but not T lymphocytes, contributes to the loss of trabecular bone caused by estrogen deficiency. In this Review, we summarize this evidence and discuss its implications for understanding the regulation of trabecular and cortical bone mass; the integration of hormonal and mechanical signals; the relative importance of estrogens versus androgens in the male skeleton; and, finally, the pathogenesis and treatment of osteoporosis.

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“…Selective activation of non-nuclear initiated actions of the ER dissociates the beneficial effects of estrogens on bone from their effects on reproductive organs [53-59]. This contention has been recently tested using an estrogen-dendrimer conjugate (EDC) that cannot enter the cell nucleus but it is very effective in stimulating non-nuclear signaling [60].…”

Section: Cellular and Molecular Mechanisms Of Sex Steroid Action Imentioning

confidence: 99%

Effects of sex steroids on bones and muscles: Similarities, parallels, and putative interactions in health and disease

Carson

Manolagas

2015

Bone

129

100

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Estrogens and androgens influence the growth and maintenance of bones and muscles and are responsible for their sexual dimorphism. A decline in their circulating levels leads to loss of mass and functional integrity in both tissues. In the article, we highlight the similarities of the molecular and cellular mechanisms of action of sex steroids in the two tissues; the commonality of a critical role of mechanical forces on tissue mass and function; emerging evidence for an interplay between mechanical forces and hormonal and growth factor signals in both bones and muscles; as well as the current state of evidence for or against a cross-talk between muscles and bone. In addition, we review evidence for the parallels in the development of osteoporosis and sarcopenia with advancing age and the potential common mechanisms responsible for the age-dependent involution of these two tissues. Lastly, we discuss the striking difference in the availability of several drug therapies for the prevention and treatment of osteoporosis, as compared to none for sarcopenia.

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In vivo characterization of estrogen receptor modulators with reduced genomic versus nongenomic activity in vitro

Cited by 21 publications

References 19 publications

Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice

Non-nuclear estrogen receptor α signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice

The role of estrogen and androgen receptors in bone health and disease

Effects of sex steroids on bones and muscles: Similarities, parallels, and putative interactions in health and disease

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