ECE2015 Guided Posters Calcium, Vitamin D and Bone (10 abstracts)
Roles of membrane oestrogen receptor alpha in bone sparing effects of oestrogens
Alexia Vinel 1 , Coralie Fontaine 1 , Eric Hay 2 , Marie Valera 1 , Françoise Lenfant 1 , Martine Cohen-Solal 2 & Jean-François Arnal 1
1INSERM U1048, Université Paul Sabatier, Toulouse, France; 2INSERM UMR‐1132, Université Paris Diderot, Sorbonne, Paris, France.
Introduction: The bone-sparing effect of oestrogen is mediated via oestrogen receptor alpha (ERα), which stimulates transcriptional action through its two activation functions (AF1 and AF2). In addition to these nuclear effects, a fraction of this receptor is targeted to the plasma membrane and triggers membrane initiated steroid signaling (MISS). Whereas, ERα AF1 plays a crucial role in trabecular bone, but not cortical bone, ERα AF2 is necessary for the oestrogen effect in both types of bone. A pharmacological approach using an oestrogen dendrimer conjugate suggested that the selective activation of membrane ERα is sufficient to elicit a sparing effect in cortical but not in trabecular bone.
Methods: The aim of this study was to define the role of ERαMISS on the beneficial actions of oestrogens on bone in vivo, using a mouse model in which ERα membrane localisation is abrogated due to a point mutation of the palmitoylation site of ERα (C451A-ERα).
Results: Intact (unovariectomised) C451A-ERα mice showed an accelerated loss of both trabecular and cortical bone compared to littermate WT controls. Furthermore, chronic 17β-oestradiol administration (8 μg/kg per day) elicited a strong bone protection in ovariectomised mice, whereas, these actions were significantly reduced in C451A-ERα mice.
Conclusion: We show here that in bone tissues, membrane ERα is necessary for oestrogen protection and thus that nuclear and membrane actions cooperate to the bone sparing effects of oestrogens. This contrasts with the absence of ERαMISS role for the uterotrophic action of oestrogens. Our work underlines the exquisite tissue-specific actions of ERα subfunctions, and should help to understand the mechanisms by which selective ER modulators can act in vivo.
Volume 37
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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