scholarly journals Non-Nuclear–Initiated Actions of the Estrogen Receptor Protect Cortical Bone Mass

2013 ◽  
Vol 27 (4) ◽  
pp. 649-656 ◽  
Author(s):  
Shoshana M. Bartell ◽  
Li Han ◽  
Ha-neui Kim ◽  
Sung Hoon Kim ◽  
John A. Katzenellenbogen ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Bone Mass ◽  
Cortical Bone ◽  
Estrogen Receptor Α ◽  
Reproductive Organs ◽  
Protective Effects ◽  
Bone Maintenance ◽  
17Β Estradiol ◽  
Cortical Bone Mass ◽  
And Oxidative Stress

Abstract Extensive evidence has suggested that at least some of the effects of estrogens on bone are mediated via extranuclear estrogen receptor α signaling. However, definitive proof for this contention and the extent to which such effects may contribute to the overall protective effects of estrogens on bone maintenance have remained elusive. Here, we investigated the ability of a 17β-estradiol (E2) dendrimer conjugate (EDC), incapable of stimulating nuclear-initiated actions of estrogen receptor α, to prevent the effects of ovariectomy (OVX) on the murine skeleton. We report that EDC was as potent as an equimolar dose of E2 in preventing bone loss in the cortical compartment that represents 80% of the entire skeleton, but was ineffective on cancellous bone. In contrast, E2 was effective in both compartments. Consistent with its effect on cortical bone mass, EDC partially prevented the loss of both vertebral and femoral strength. In addition, EDC, as did E2, prevented the OVX-induced increase in osteoclastogenesis, osteoblastogenesis, and oxidative stress. Nonetheless, the OVX-induced decrease in uterine weight was unaltered by EDC but was restored by E2. These results demonstrate that the protection of cortical bone mass by estrogens is mediated, at least in part, via a mechanism that is distinct from the classic mechanism of estrogen action on reproductive organs.

scholarly journals The Estrogen Receptor-α in Osteoclasts Mediates the Protective Effects of Estrogens on Cancellous But Not Cortical Bone

2010 ◽  
Vol 24 (2) ◽  
pp. 323-334 ◽  
Author(s):  
Marta Martin-Millan ◽  
Maria Almeida ◽  
Elena Ambrogini ◽  
Li Han ◽  
Haibo Zhao ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Cortical Bone ◽  
Cancellous Bone ◽  
Cell Lineage ◽  
Fold Increase ◽  
Estrogen Receptor Α ◽  
Protective Effects ◽  
Polymeric Form ◽  
17Β Estradiol ◽  
Osteoclast Apoptosis

Abstract Estrogens attenuate osteoclastogenesis and stimulate osteoclast apoptosis, but the molecular mechanism and contribution of these effects to the overall antiosteoporotic efficacy of estrogens remain controversial. We selectively deleted the estrogen receptor (ER)α from the monocyte/macrophage cell lineage in mice (ERαLysM−/−) and found a 2-fold increase in osteoclast progenitors in the marrow and the number of osteoclasts in cancellous bone, along with a decrease in cancellous bone mass. After loss of estrogens these mice failed to exhibit the expected increase in osteoclast progenitors, the number of osteoclasts in bone, and further loss of cancellous bone. However, they lost cortical bone indistinguishably from their littermate controls. Mature osteoclasts from ERαLysM−/− were resistant to the proapoptotic effect of 17β-estradiol. Nonetheless, the effects of estrogens on osteoclasts were unhindered in mice bearing an ERα knock-in mutation that prevented binding to DNA. Moreover, a polymeric form of estrogen that is not capable of stimulating the nuclear-initiated actions of ERα was as effective as 17β-estradiol in inducing osteoclast apoptosis in cells with the wild-type ERα. We conclude that estrogens attenuate osteoclast generation and life span via cell autonomous effects mediated by DNA-binding-independent actions of ERα. Elimination of these effects is sufficient for loss of bone in the cancellous compartment in which complete perforation of trabeculae by osteoclastic resorption precludes subsequent refilling of the cavities by the bone-forming osteoblasts. However, additional effects of estrogens on osteoblasts, osteocytes, and perhaps other cell types are required for their protective effects on the cortical compartment, which constitutes 80% of the skeleton.

scholarly journals Female Mice Lacking Estrogen Receptor-α in Hypothalamic Proopiomelanocortin (POMC) Neurons Display Enhanced Estrogenic Response on Cortical Bone Mass

Endocrinology ◽  
2016 ◽  
Vol 157 (8) ◽  
pp. 3242-3252 ◽  
Author(s):  
H. H. Farman ◽  
S. H. Windahl ◽  
L. Westberg ◽  
H. Isaksson ◽  
E. Egecioglu ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Bone Mass ◽  
Mechanical Strength ◽  
Cortical Bone ◽  
Volume Fraction ◽  
Bone Thickness ◽  
Female Mice ◽  
Cortical Bone Thickness ◽  
Cortical Bone Mass ◽  
Estrogenic Responses

Estrogens are important regulators of bone mass and their effects are mainly mediated via estrogen receptor (ER)α. Central ERα exerts an inhibitory role on bone mass. ERα is highly expressed in the arcuate (ARC) and the ventromedial (VMN) nuclei in the hypothalamus. To test whether ERα in proopiomelanocortin (POMC) neurons, located in ARC, is involved in the regulation of bone mass, we used mice lacking ERα expression specifically in POMC neurons (POMC-ERα−/−). Female POMC-ERα−/− and control mice were ovariectomized (OVX) and treated with vehicle or estradiol (0.5 μg/d) for 6 weeks. As expected, estradiol treatment increased the cortical bone thickness in femur, the cortical bone mechanical strength in tibia and the trabecular bone volume fraction in both femur and vertebrae in OVX control mice. Importantly, the estrogenic responses were substantially increased in OVX POMC-ERα−/− mice compared with the estrogenic responses in OVX control mice for cortical bone thickness (+126 ± 34%, P < .01) and mechanical strength (+193 ± 38%, P < .01). To test whether ERα in VMN is involved in the regulation of bone mass, ERα was silenced using an adeno-associated viral vector. Silencing of ERα in hypothalamic VMN resulted in unchanged bone mass. In conclusion, mice lacking ERα in POMC neurons display enhanced estrogenic response on cortical bone mass and mechanical strength. We propose that the balance between inhibitory effects of central ERα activity in hypothalamic POMC neurons in ARC and stimulatory peripheral ERα-mediated effects in bone determines cortical bone mass in female mice.

scholarly journals The Nutritional Flavanone Naringenin Triggers Antiestrogenic Effects by Regulating Estrogen Receptor α-Palmitoylation

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2567-2575 ◽  
Author(s):  
Paola Galluzzo ◽  
Paolo Ascenzi ◽  
Pamela Bulzomi ◽  
Maria Marino
Keyword(s):  
Estrogen Receptor ◽  
Fruits And Vegetables ◽  
Estrogen Receptor Α ◽  
Transcriptional Level ◽  
Protective Effects ◽  
Antiproliferative Effects ◽  
Caveolin 1 ◽  
17Β Estradiol ◽  
Phosphoinositide 3 Kinase ◽  
Antiestrogenic Effects

Naringenin (Nar) is a component of fruits and vegetables associated with healthful benefits, such as in osteoporosis, cancer, and cardiovascular diseases. These protective effects have been linked with Nar antiestrogenic as well as estrogenic activities. Previous studies indicate that Nar impaired estrogen receptor (ER) α signaling by interfering with ERα-mediated activation of ERK and phosphoinositide 3-kinase signaling pathways in the absence of effects at the transcriptional level. The present studies evaluated the hypothesis that these Nar antagonistic effects occur at the level of the plasma membrane. Our results indicate that Nar induces ERα depalmitoylation faster than 17β-estradiol, which results in receptor rapid dissociation from caveolin-1. Furthermore, Nar impedes ERα to bind adaptor (modulator of nongenomic actions of the ER) and signaling (c-Src) proteins involved in the activation of the mitogenic signaling cascades (i.e. ERK and phosphoinositide 3-kinase). On the other hand, Nar induces the ER-dependent, but palmitoylation-independent, activation of p38 kinase, which in turn is responsible for Nar-mediated antiproliferative effects in cancer cells. Altogether, these data highlight new ER-dependent mechanisms on the root of antiproliferative and antiestrogenic effects of Nar. Moreover, the different modulation of ERα palmitoylation exerted by different ligands represents a pivotal mechanism that drives cancer cell to proliferation or apoptosis.

scholarly journals Deletion of Estrogen Receptor Beta in Osteoprogenitor Cells Increases Trabecular but Not Cortical Bone Mass in Female Mice

2015 ◽  
Vol 31 (3) ◽  
pp. 606-614 ◽  
Author(s):  
Kristy M Nicks ◽  
Koji Fujita ◽  
Daniel Fraser ◽  
Ulrike McGregor ◽  
Matthew T Drake ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Bone Mass ◽  
Cortical Bone ◽  
Estrogen Receptor Beta ◽  
Osteoprogenitor Cells ◽  
Female Mice ◽  
Cortical Bone Mass ◽  
Receptor Beta

scholarly journals The Estrogen Receptor-α in Osteoclasts Mediates the Protective Effects of Estrogens on Cancellous But Not Cortical Bone

2010 ◽  
Vol 95 (2) ◽  
pp. 981-981
Author(s):  
Marta Martin-Millan ◽  
Maria Almeida ◽  
Elena Ambrogini ◽  
Li Han ◽  
Haibo Zhao ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Cortical Bone ◽  
Estrogen Receptor Α ◽  
Protective Effects

Effects of long-term sedentary behaviour on the cortical bone mass and distribution during growth: The HAPPY bone study

2017 ◽  
Author(s):  
Rachel L Duckham ◽  
Timo Rantalainen ◽  
Christine Rodda ◽  
Anna Timperio ◽  
Nicola Hawley ◽  
...  
Keyword(s):  
Bone Mass ◽  
Cortical Bone ◽  
Sedentary Behaviour ◽  
Cortical Bone Mass

scholarly journals PARP7 and Mono-ADP-Ribosylation Negatively Regulate Estrogen Receptor α Signaling in Human Breast Cancer Cells

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 623
Author(s):  
Marit Rasmussen ◽  
Susanna Tan ◽  
Venkata S. Somisetty ◽  
David Hutin ◽  
Ninni Elise Olafsen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Protein Modification ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Transactivation Domain ◽  
Adp Ribosylation ◽  
Protein Levels ◽  
17Β Estradiol ◽  
Mcf 7

ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor’s ligand-independent transactivation domain. Co-immunoprecipitation with truncated estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in estrogen receptor positive breast cancer.

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