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. 2016 Jul 8:6:29473.
doi: 10.1038/srep29473.

The role of membrane ERα signaling in bone and other major estrogen responsive tissues

K L Gustafsson  1 , H Farman  1 , P Henning  1 , V Lionikaite  1 , S Movérare-Skrtic  1 , J Wu  1 , H Ryberg  1 , A Koskela  2 , J-Å Gustafsson  3 , J Tuukkanen  2 , E R Levin  4   5 , C Ohlsson  1 , M K Lagerquist  1
Affiliations

The role of membrane ERα signaling in bone and other major estrogen responsive tissues

K L Gustafsson et al. Sci Rep. .

Abstract

Estrogen receptor α (ERα) signaling leads to cellular responses in several tissues and in addition to nuclear ERα-mediated effects, membrane ERα (mERα) signaling may be of importance. To elucidate the significance, in vivo, of mERα signaling in multiple estrogen-responsive tissues, we have used female mice lacking the ability to localize ERα to the membrane due to a point mutation in the palmitoylation site (C451A), so called Nuclear-Only-ER (NOER) mice. Interestingly, the role of mERα signaling for the estrogen response was highly tissue-dependent, with trabecular bone in the axial skeleton being strongly dependent (>80% reduction in estrogen response in NOER mice), cortical and trabecular bone in long bones, as well as uterus and thymus being partly dependent (40-70% reduction in estrogen response in NOER mice) and effects on liver weight and total body fat mass being essentially independent of mERα (<35% reduction in estrogen response in NOER mice). In conclusion, mERα signaling is important for the estrogenic response in female mice in a tissue-dependent manner. Increased knowledge regarding membrane initiated ERα actions may provide means to develop new selective estrogen receptor modulators with improved profiles.

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Figures

Figure 1
Figure 1. Loss of membrane ERα signaling leads to disturbed hormonal feedback regulation.
ERα mRNA expression in uterus and bone from 16-week-old gonad intact female NOER and wild type (WT) mice (a). Western blot showing ERα protein expression in uterus and bone from NOER and WT mice (b) (blot images are cropped and full-length blots are presented in suppl. Fig. 1). Serum levels of 17β-estradiol (c) and testosterone (d), measured by GC-MS/MS in 12-week-old gonad intact female mice. Values are given as mean ± sem. [n = 10–14]. *p < 0.05, **p < 0.01, student’s t-test, NOER vs WT.
Figure 2
Figure 2. The estrogen response on trabecular bone mass in the axial skeleton is strongly dependent on membrane ERα signaling.
12-week-old NOER and wild type (WT) mice were ovariectomized and treated with 17β-estradiol (E2, 16,7 ng·mouse−1·day−1) or placebo (P) for four weeks. Total body (a) and lumbar spine (b) areal bone mineral density (aBMD) was measured by DXA. Trabecular bone volume per total volume (BV/TV) (c), trabecular number (Tb.N.) (d) and trabecular thickness (Tb.Th.) (e) were analyzed in vertebrae L5. The role of membrane ERα signaling for different tissues/parameters (f). The estrogenic response in WT mice, for each parameter, is set to 100%. The bars represent the estrogenic response in percent for the E2 treated ovx NOER mice compared to the estrogenic response in ovx WT mice, where 0% means no E2 response whereas 100% means normal E2 response. White bars; parameters with high (>80% reduction in E2 response) dependency on membrane ERα signaling, with no significant E2 effect in NOER mice. Grey bars; parameters with medium (40–70% reduction in E2 response) dependency on membrane ERα signaling, with significant E2 effects in NOER mice, but the E2 response is significantly attenuated when compared to the response in WT mice. Black bars; parameters with low or no dependency (<35% reduction in E2 response) on membrane initiated ERα signaling, with significant E2 effects in NOER mice that do not statistically differ from E2 effects in WT mice. Tb. N; trabecular number, BV/TV; bone volume per total volume, Ct; cortical, Th; thickness, Ar; Area, aBMD; areal bone mineral density. Values are given as mean ± sem. [n = 10–12]. **p < 0.01, ***p < 0.001, student’s t-test, E2 vs placebo treatment. ##p < 0.01, ###p < 0.001, interaction P value from two-way-ANOVA analysis, E2 effect in NOER vs E2 effect in WT.
Figure 3
Figure 3. The estrogen response in the appendicular skeleton is partly dependent on membrane ERα signaling.
12-week-old NOER and wild type (WT) mice were ovariectomized and treated with 17β-estradiol (E2, 16,7 ng·mouse−1·day−1) or placebo (P) for four weeks. Trabecular bone volume per total volume (BV/TV) (a), trabecular number (Tb.N.) (b) and trabecular thickness (Tb.Th.) (c) were analyzed in the metaphyseal part of the distal femur. Cortical thickness (Ct.Th.) (d) and cortical area (Ct.Ar.) (e) were analyzed in the mid-diaphyseal part of the femur. Maximal load at failure (Fmax) (f) was analyzed by 3-point bending of humerus. Representative images of trabecular (left) and cortical (right) bone in femur (g). Values are given as mean ± sem. [n = 10–12]. *p < 0.05, **p < 0.01, ***p < 0.001, student’s t-test, E2 vs placebo treatment. ###p < 0.001, interaction P value from two-way-ANOVA analysis, E2 effect in NOER vs E2 effect in WT.
Figure 4
Figure 4. The importance of membrane ERα signaling is tissue-dependent.
12-week-old NOER and wild type (WT) mice were ovariectomized (ovx) and treated with 17β-estradiol (E2, 16,7 ng·mouse−1·day−1) or placebo (P) for four weeks. Estrogen effects on organ weights are given as weight per body weight (BW). Uterus weight (a), thymus weight (b), % total body fat measured by DXA (c), retroperitoneal fat weight (d), gonadal fat weight (e), serum leptin levels (f) and liver weight (g). Values are given as mean ± sem. [n = 10–12]. *p < 0.05, **p < 0.01, ***p < 0.001, student’s t-test, E2 vs placebo treatment. ###p < 0.001, interaction P value from two-way-ANOVA analysis, E2 effect in NOER vs E2 effect in WT.
Figure 5
Figure 5
Proposed tissue-dependent role of membrane ERα (mERα) in multiple estrogen responsive tissues based on the findings in the present study and in a previous study regarding vascular estrogenic effects, including (a) estrogen responsive tissues strongly dependent on membrane ERα, (b) tissues which are partly dependent on membrane ERα, suggesting cross-talk between membrane and nuclear ERα signaling and (c) tissues independent on membrane ERα signaling. ↑ = estrogen increases, ↓ estrogen decreases, nERα = nuclear ERα.
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