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 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 Osteocyte- and late Osteoblast-derived NOTUM Reduces Cortical Bone Mass in Mice

2021 ◽  
Author(s):  
Karin H. Nilsson ◽  
Petra Henning ◽  
Maha El Shahawy ◽  
Jianyao Wu ◽  
Antti Koskela ◽  
...  
Keyword(s):  
Bone Mass ◽  
Trabecular Bone ◽  
Cortical Bone ◽  
Vertebral Fractures ◽  
Volume Fraction ◽  
Substantial Reduction ◽  
Lumbar Vertebrae ◽  
Bone Homeostasis ◽  
Increased Risk ◽  
Cortical Bone Mass

Osteoporosis is a common skeletal disease, with increased risk of fractures. Currently available osteoporosis treatments reduce the risk of vertebral fractures, mainly dependent on trabecular bone, whereas the effect on non-vertebral fractures, mainly dependent on cortical bone, is less pronounced. WNT signaling is a crucial regulator of bone homeostasis, and the activity of WNTs is inhibited by NOTUM, a secreted WNT lipase. We previously demonstrated that conditional inactivation of NOTUM in all osteoblast lineage cells increases the cortical but not the trabecular bone mass. The aim of the present study was to determine if NOTUM increasing cortical bone is derived from osteoblast precursors/early osteoblasts or from osteocytes/late osteoblasts. First, we demonstrated Notum mRNA expression in Dmp1-expressing osteocytes and late osteoblasts in cortical bone using in situ hybridization. We then developed a mouse model with inactivation of NOTUM in Dmp1 expressing osteocytes and late osteoblasts (Dmp1-creNotumflox/flox mice). We observed that the Dmp1-creNotumflox/flox mice displayed a substantial reduction of Notum mRNA in cortical bone, resulting in increased cortical bone mass and decreased cortical porosity in femur, but no change in trabecular bone volume fraction (BV/TV) in femur or in the lumbar vertebrae L5 in Dmp1-creNotumflox/flox mice as compared to control mice. In conclusion, osteocytes and late osteoblasts are the principal source of NOTUM in cortical bone, and NOTUM derived from osteocytes/late osteoblasts reduces cortical bone mass. These findings demonstrate that inhibition of osteocyte/late osteoblast-derived NOTUM might be an interesting pharmacological target to increase cortical bone mass and reduce non-vertebral fracture risk.

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.

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
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