Membrane estrogen receptor α is essential for estrogen signaling in the male skeleton

2018 ◽  
Vol 239 (3) ◽  
pp. 303-312 ◽  
Author(s):  
H H Farman ◽  
K L Gustafsson ◽  
P Henning ◽  
L Grahnemo ◽  
V Lionikaite ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Estrogen Signaling ◽  
Areal Bone Mineral Density ◽  
Male Mice ◽  
Mineral Density ◽  
Intact Male ◽  
Trabecular Thickness ◽  
Total Body

The importance of estrogen receptor α (ERα) for the regulation of bone mass in males is well established. ERα mediates estrogenic effects both via nuclear and membrane-initiated ERα (mERα) signaling. The role of mERα signaling for the effects of estrogen on bone in male mice is unknown. To investigate the role of mERα signaling, we have used mice (Nuclear-Only-ER; NOER) with a point mutation (C451A), which results in inhibited trafficking of ERα to the plasma membrane. Gonadal-intact male NOER mice had a significantly decreased total body areal bone mineral density (aBMD) compared to WT littermates at 3, 6 and 9 months of age as measured by dual-energy X-ray absorptiometry (DEXA). High-resolution microcomputed tomography (µCT) analysis of tibia in 3-month-old males demonstrated a decrease in cortical and trabecular thickness in NOER mice compared to WT littermates. As expected, estradiol (E2) treatment of orchidectomized (ORX) WT mice increased total body aBMD, trabecular BV/TV and cortical thickness in tibia compared to placebo treatment. E2 treatment increased these skeletal parameters also in ORX NOER mice. However, the estrogenic responses were significantly decreased in ORX NOER mice compared with ORX WT mice. In conclusion, mERα is essential for normal estrogen signaling in both trabecular and cortical bone in male mice. Increased knowledge of estrogen signaling mechanisms in the regulation of the male skeleton may aid in the development of new treatment options for male osteoporosis.

scholarly journals Sclerostin Levels and Changes in Bone Metabolism After Bariatric Surgery

2015 ◽  
Vol 100 (3) ◽  
pp. 891-901 ◽  
Author(s):  
Christian Muschitz ◽  
Roland Kocijan ◽  
Christina Marterer ◽  
Arastoo Rahbar Nia ◽  
Gabriela Katharina Muschitz ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Premenopausal Women ◽  
Serum Levels ◽  
Areal Bone Mineral Density ◽  
Mineral Density ◽  
Entire Study ◽  
Turnover Markers ◽  
Total Body ◽  
Dickkopf 1

Context: The role of sclerostin as a key regulator of bone formation remains unknown after Roux-en-Y gastric bypass (RYGB) or laparoscopic sleeve gastrectomy (SG). Objectives: The study objectives were evaluation of sclerostin and Dickkopf-1 (DKK-1) serum levels after surgery and correlations with bone turnover markers (P1NP, CTX), parathyroid hormone (iPTH) and areal bone mineral density (BMD), changes at total body, lumbar spine and total hip. Design and Setting: This was a prospective observational single-center two-arm study in premenopausal women with acute adipositas over 24 months. Participants: Participants were 52 premenopausal women (40 ± 8 years, BMI 43.4) after RYGB and 38 premenopausal women (41 ± 7 years, BMI 45.7) after SG. Main Outcome Measures: Prior to surgery and 1, 3, 6, 9, 12, 18, and 24 months after surgery sclerostin, DKK-1, CTX, P1NP levels and BMD were measured. Results: Sclerostin, CTX and (to a lesser extent) P1NP increased after surgery and remained elevated during the entire study period (P < 0.001). DKK-1 declined during months 3–9 (P < 0.005) and then remained unchanged, serum phosphate continuously increased (P < 0.001), iPTH remained within the upper normal limit. Sclerostin increases were significantly positively correlated with CTX and P1NP increases and negatively correlated with BMD loss. BMD independently declined regardless of RYGB and SG. Elevations of sclerostin, CTX, P1NP, and phosphate, but not DKK-1 and iPTH, were significant discriminating factors for BMD loss (AUC 0.920). Conclusion: Rapid and sustained increases of sclerostin, CTX, and to a lesser extent, P1NP cause an increase in bone metabolism and result in BMD loss at all skeletal sites.

scholarly journals miR-22 Inhibits Estrogen Signaling by Directly Targeting the Estrogen Receptor α mRNA

2009 ◽  
Vol 29 (13) ◽  
pp. 3783-3790 ◽  
Author(s):  
Deo Prakash Pandey ◽  
Didier Picard
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Breast Cancer Cells ◽  
Estrogen Receptor Α ◽  
Estrogen Signaling ◽  
Systematic Assessment ◽  
Small Noncoding Rnas ◽  
Evolutionarily Conserved ◽  
Target Sites

ABSTRACT Estrogen receptor α (ERα) is a ligand-regulated transcription factor with a broad range of physiological functions and one of the most important classifiers in breast cancer. MicroRNAs (miRNAs) are small noncoding RNAs that have emerged as important regulators of gene expression in a plethora of physiological and pathological processes. Upon binding the 3′ untranslated region (UTR) of target mRNAs, miRNAs typically reduce their stability and/or translation. The ERα mRNA has a long 3′ UTR of about 4.3 kb which has been reported to reduce mRNA stability and which bears evolutionarily conserved miRNA target sites, suggesting that it might be regulated by miRNAs. We have performed a comprehensive and systematic assessment of the regulatory role of all miRNAs that are predicted to target the 3′ UTR of the ERα mRNA. We found that miR-22 represses ERα expression most strongly and by directly targeting the ERα mRNA 3′ UTR. Of the three predicted miR-22 target sites in the 3′ UTR, the evolutionarily conserved one is the primary target. miR-22 overexpression leads to a reduction of ERα levels, at least in part by inducing mRNA degradation, and compromises estrogen signaling, as exemplified by its inhibitory impact on the ERα-dependent proliferation of breast cancer cells.

Implications of estrogen receptor alpha and estrogen receptor beta for adipose tissue functions and cardiometabolic complications

2013 ◽  
Vol 15 (3) ◽  
Author(s):  
Hui Gao ◽  
Karin Dahlman-Wright
Keyword(s):  
Estrogen Receptor ◽  
Adipose Tissue ◽  
Estrogen Receptor Alpha ◽  
Molecular Mechanisms ◽  
Estrogen Receptor Beta ◽  
Estrogen Receptor Α ◽  
Endocrine Function ◽  
Estrogen Signaling ◽  
Strongly Connected

AbstractThere is growing evidence that estrogen signaling regulates energy metabolism and exerts important functions in maintaining adipose tissue metabolism, including controlling the distribution of body fat. Changes in the physiological functions of adipose tissue, particularly the white adipose tissue, have been strongly connected to obesity and the development of related cardiometabolic complications. In this review, we will focus on discussing the role of estrogen signaling in regulating adipocyte differentiation, metabolism and its endocrine function with a focus on the possible underlying molecular mechanisms mediated by estrogen receptor α and estrogen receptor β.

scholarly journals Postlesion Estradiol Treatment Increases Cortical Cholinergic Innervations via Estrogen Receptor-α Dependent Nonclassical Estrogen Signaling in Vivo

Endocrinology ◽  
2011 ◽  
Vol 152 (9) ◽  
pp. 3471-3482 ◽  
Author(s):  
Zsombor Kőszegi ◽  
Éva M. Szegő ◽  
Rachel Y. Cheong ◽  
Emeline Tolod-Kemp ◽  
István M. Ábrahám
Keyword(s):  
Estrogen Receptor ◽  
Protein Kinase ◽  
Cell Loss ◽  
Estrogen Receptor Α ◽  
Estrogen Signaling ◽  
Ovariectomized Mice ◽  
Cholinergic Cell ◽  
Kinase A

17β-Estradiol (E2) treatment exerts rapid, nonclassical actions via intracellular signal transduction system in basal forebrain cholinergic (BFC) neurons in vivo. Here we examined the effect of E2 treatment on lesioned BFC neurons in ovariectomized mice and the role of E2-induced nonclassical action in this treatment. Mice given an N-methyl-d-aspartic acid (NMDA) injection into the substantia innominata-nucleus basalis magnocellularis complex (SI-NBM) exhibited cholinergic cell loss in the SI-NBM and ipsilateral cholinergic fiber loss in the cortex. A single injection of E2 after NMDA lesion did not have an effect on cholinergic cell loss in the SI-NBM, but it restored the ipsilateral cholinergic fiber density in the cortex in a time- and dose-dependent manner. The most effective cholinergic fiber restoration was observed with 33 ng/g E2 treatment at 1 h after NMDA lesion. The E2-induced cholinergic fiber restoration was absent in neuron-specific estrogen receptor-α knockout mice in vivo. Selective activation of nonclassical estrogen signaling in vivo by estren induced E2-like restorative actions. Selective blockade of the MAPK or protein kinase A pathway in vivo prevented E2's ability to restore cholinergic fiber loss. Finally, studies in intact female mice revealed an E2-induced restorative effect that was similar to that of E2-treated ovariectomized mice. These observations demonstrate that a single E2 treatment restores the BFC fiber loss in the cortex, regardless of endogenous E2 levels. They also reveal the critical role of nonclassical estrogen signaling via estrogen receptor-α and protein kinase A-MAPK pathways in E2-induced restorative action in the cholinergic system in vivo.

scholarly journals Pubertal activation of estrogen receptor α in the medial amygdala is essential for the full expression of male social behavior in mice

2016 ◽  
Vol 113 (27) ◽  
pp. 7632-7637 ◽  
Author(s):  
Kazuhiro Sano ◽  
Mariko Nakata ◽  
Sergei Musatov ◽  
Masahiro Morishita ◽  
Toshiro Sakamoto ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Sexual Behaviors ◽  
Social Behaviors ◽  
Estrogen Receptor Α ◽  
Medial Amygdala ◽  
Male Mice ◽  
Aggressive Behaviors ◽  
Intact Male ◽  
Male Type ◽  
Full Expression

Testosterone plays a central role in the facilitation of male-type social behaviors, such as sexual and aggressive behaviors, and the development of their neural bases in male mice. The action of testosterone via estrogen receptor (ER) α, after being aromatized to estradiol, has been suggested to be crucial for the full expression of these behaviors. We previously reported that silencing of ERα in adult male mice with the use of a virally mediated RNAi method in the medial preoptic area (MPOA) greatly reduced sexual behaviors without affecting aggressive behaviors whereas that in the medial amygdala (MeA) had no effect on either behavior. It is well accepted that testosterone stimulation during the pubertal period is necessary for the full expression of male-type social behaviors. However, it is still not known whether, and in which brain region, ERα is involved in this developmental effect of testosterone. In this study, we knocked down ERα in the MeA or MPOA in gonadally intact male mice at the age of 21 d and examined its effects on the sexual and aggressive behaviors later in adulthood. We found that the prepubertal knockdown of ERα in the MeA reduced both sexual and aggressive behaviors whereas that in the MPOA reduced only sexual, but not aggressive, behavior. Furthermore, the number of MeA neurons was reduced by prepubertal knockdown of ERα. These results indicate that ERα activation in the MeA during the pubertal period is crucial for male mice to fully express their male-type social behaviors in adulthood.

Molecular mechanism of estrogen action in the male: insights from the estrogen receptor null mice

2001 ◽  
Vol 13 (4) ◽  
pp. 211 ◽  
Author(s):  
John F. Couse ◽  
Dipak Mahato ◽  
Edward M. Eddy ◽  
Kenneth S. Korach
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Α ◽  
Male Reproduction ◽  
Estrogen Signaling ◽  
Male Mice ◽  
Signaling System ◽  
Estrogen Action ◽  
Behavioral Deficits ◽  
Testicular Dysfunction ◽  
17Β Estradiol

Until recently, 17β-estradiol was thought to be of little importance in male fertility. However, the descriptions of testicular dysfunction and behavioral deficits leading to complete infertility in male mice lacking estrogen receptor α (ERα) have indicated the importance of estrogen action in fertility of the male rodent. In contrast, male mice lacking the newly discovered estrogen receptor β (ERβ) exhibit no compromised fertility. Recently, elaborate sperm transplantation studies have shown that the altered sperm function characteristic of the ERα knockout male are the result of the loss of ERα actions in the supporting somatic cells of the testis and epididymis rather than in the germ cell. This brief review will discuss the roles of estrogen action in male reproduction as revealed by mice lacking both known forms of the ER. A brief review of the estrogen signaling system is also included.

scholarly journals Reduced PAX2 expression in murine fallopian tube cells enhances estrogen receptor signaling

2019 ◽  
Vol 41 (5) ◽  
pp. 646-655 ◽  
Author(s):  
Jose A Colina ◽  
Peter Varughese ◽  
Subbulakshmi Karthikeyan ◽  
Amrita Salvi ◽  
Dimple A Modi ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Fallopian Tube ◽  
Messenger Rna ◽  
Estrogen Receptor Α ◽  
Estrogen Signaling ◽  
Precursor Lesions ◽  
Preneoplastic Lesions ◽  
Exogenous Estrogen ◽  
Estrogen Receptor Signaling

AbstractHigh-grade serous ovarian cancer (HGSOC) is thought to progress from a series of precursor lesions in the fallopian tube epithelium (FTE). One of the preneoplastic lesions found in the FTE is called a secretory cell outgrowth (SCOUT), which is partially defined by a loss of paired box 2 (PAX2). In the present study, we developed PAX2-deficient murine cell lines in order to model a SCOUT and to explore the role of PAX2 loss in the etiology of HGSOC. Loss of PAX2 alone in the murine oviductal epithelium (MOE) did not induce changes in proliferation, migration and survival in hypoxia or contribute to resistance to first line therapies, such as cisplatin or paclitaxel. RNA sequencing of MOE PAX2shRNA cells revealed significant alterations in the transcriptome. Silencing of PAX2 in MOE cells produced a messenger RNA expression pattern that recapitulated several aspects of the transcriptome of previously characterized human SCOUTs. RNA-seq analysis and subsequent qPCR validation of this SCOUT model revealed an enrichment of genes involved in estrogen signaling and an increase in expression of estrogen receptor α. MOE PAX2shRNA cells had higher estrogen signaling activity and higher expression of putative estrogen responsive genes both in the presence and absence of exogenous estrogen. In summary, loss of PAX2 in MOE cells is sufficient to transcriptionally recapitulate a human SCOUT, and this model revealed an enrichment of estrogen signaling as a possible route for tumor progression of precursor lesions in the fallopian tube.

1625: Role of Estrogen Receptor β in the Regulation of Sexual Behavior in Male Mice

2004 ◽  
Vol 171 (4S) ◽  
pp. 429-429
Author(s):  
Masayoshi Nomura ◽  
Naohiro Fujimoto ◽  
Donald W. Pfaff ◽  
Sonoko Ogawa ◽  
Tetsuro Matsumoto
Keyword(s):  
Estrogen Receptor ◽  
Sexual Behavior ◽  
Estrogen Receptor Β ◽  
Male Mice
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