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

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

doi:10.1038/srep29473

K L Gustafsson, V Lionikaite + Show 11 more

Open Access

https://doi.org/10.1038/srep29473

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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.

Highlights

Estrogen receptor α (ERα) signaling leads to cellular responses in several tissues and in addition to nuclear ERα-mediated effects, membrane ERα signaling may be of importance
The ERαmRNA expression was slightly lower in the axial trabecular bone compared to the appendicular cortical bone, but this was observed both in WT (−29 ± 3%, p < 0.01) and in Nuclear-Only Estrogen Receptor (NOER) mice (−25 ± 4%, p < 0.001). 12-week-old NOER mice displayed no differences in bone mass parameters, body weight, total body fat mass, or weights of liver, uterus or thymus compared to WT littermates
Ovariectomy resulted in an expected decrease in total body areal bone mineral density (aBMD) (WT: −9 ± 1%, p < 0.001; NOER: −5 ± 1%, p < 0.01), lumbar spine aBMD (WT: −14 ± 2%, p < 0.001; NOER: −9 ± 3%, p < 0.05), trabecular bone volume/tissue volume (BV/TV) (WT: −3 3 ± 3%, p < 0.001; NOER: −2 7 ± 4%, p < 0.01), and cortical thickness (WT: −9 ± 1%, p < 0.001; NOER: −7 ± 2%, p < 0.01) while no change by ovx was found on body weight

Summary

Introduction

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. The genomic effects involve translocation of the estrogen-ERαcomplex into the nucleus and either direct binding to estrogen response elements in regulatory sequences of target genes (classical pathway), or binding to other transcription factors (non-classical pathway) and subsequent regulation of gene transcription In addition to these genomic effects, it is well established that estrogen exerts non-genomic effects, which are rapid effects that do not involve nuclear localization of the ERs12,13. Neuroprotective effects[16] and prevent cortical, but not trabecular, bone loss after estrogen deprivation in female mice[17]

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