Role of ERαMISS in the Effect of Estradiol on Cancellous and Cortical Femoral Bone in Growing Female Mice
Estrogen receptor-α (ERα) acts primarily in the nucleus as a transcription factor involving two activation functions, AF1 and AF2, but it can also induce membrane-initiated steroid signaling (MISS) through the modulation of various kinase activities and/or secondary messenger levels. Previous work has demonstrated that nuclear ERα is required for the protective effect of the estrogen 17β-estradiol (E2), whereas the selective activation of ERαMISS is sufficient to confer protection in cortical but not cancellous bone. The aim of this study was to define whether ERαMISS is necessary for the beneficial actions of chronic E2 exposure on bone. We used a mouse model in which ERα membrane localization had been abrogated due to a point mutation of the palmitoylation site of ERα (ERα-C451A). Alterations of the sex hormones in ERα-C451A precluded the interpretation of bone parameters that were thus analyzed on ovariectomized and supplemented or not with E2 (8 μg/kg/d) to circumvent this bias. We found the beneficial action of E2 on femoral bone mineral density as well as in both cortical and cancellous bone was decreased in ERα-C451A mice compared with their wild-type littermates. Histological and biochemical approaches concurred with the results from bone marrow chimeras to demonstrate that ERαMISS signaling affects the osteoblast but not the osteoclast lineage in response to E2. Thus, in contrast to the uterine and endothelial effects of E2 that are specifically mediated by nuclear ERα and ERαMISS effects, respectively, bone protection is dependent on both, underlining the exquisite tissue-specific actions and interactions of membrane and nuclear ERα.
INSERM Unité 1048 (A.V., M.C.V., M.B., M.A., M.G., F.L., J.F.A., C.F.), I2MC, University of Toulouse 3, F-31432 Toulouse, France; Unité Mixte de Recherche 1132 (E.H., M.C.-S.), Bone and Cartilage Biology, University of Paris 7, F-75006 Paris, France; and Centre for Bone and Arthritis Research (C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Alexia
A
Vinel
INSERM Unité 1048 (A.V., M.C.V., M.B., M.A., M.G., F.L., J.F.A., C.F.), I2MC, University of Toulouse 3, F-31432 Toulouse, France; Unité Mixte de Recherche 1132 (E.H., M.C.-S.), Bone and Cartilage Biology, University of Paris 7, F-75006 Paris, France; and Centre for Bone and Arthritis Research (C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Eric
E
Hay
INSERM Unité 1048 (A.V., M.C.V., M.B., M.A., M.G., F.L., J.F.A., C.F.), I2MC, University of Toulouse 3, F-31432 Toulouse, France; Unité Mixte de Recherche 1132 (E.H., M.C.-S.), Bone and Cartilage Biology, University of Paris 7, F-75006 Paris, France; and Centre for Bone and Arthritis Research (C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Marie-Cécile
MC
Valera
INSERM Unité 1048 (A.V., M.C.V., M.B., M.A., M.G., F.L., J.F.A., C.F.), I2MC, University of Toulouse 3, F-31432 Toulouse, France; Unité Mixte de Recherche 1132 (E.H., M.C.-S.), Bone and Cartilage Biology, University of Paris 7, F-75006 Paris, France; and Centre for Bone and Arthritis Research (C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Mélissa
M
Buscato
INSERM Unité 1048 (A.V., M.C.V., M.B., M.A., M.G., F.L., J.F.A., C.F.), I2MC, University of Toulouse 3, F-31432 Toulouse, France; Unité Mixte de Recherche 1132 (E.H., M.C.-S.), Bone and Cartilage Biology, University of Paris 7, F-75006 Paris, France; and Centre for Bone and Arthritis Research (C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Marine
M
Adlanmerini
INSERM Unité 1048 (A.V., M.C.V., M.B., M.A., M.G., F.L., J.F.A., C.F.), I2MC, University of Toulouse 3, F-31432 Toulouse, France; Unité Mixte de Recherche 1132 (E.H., M.C.-S.), Bone and Cartilage Biology, University of Paris 7, F-75006 Paris, France; and Centre for Bone and Arthritis Research (C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Maeva
M
Guillaume
INSERM Unité 1048 (A.V., M.C.V., M.B., M.A., M.G., F.L., J.F.A., C.F.), I2MC, University of Toulouse 3, F-31432 Toulouse, France; Unité Mixte de Recherche 1132 (E.H., M.C.-S.), Bone and Cartilage Biology, University of Paris 7, F-75006 Paris, France; and Centre for Bone and Arthritis Research (C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Martine
M
Cohen-Solal
INSERM Unité 1048 (A.V., M.C.V., M.B., M.A., M.G., F.L., J.F.A., C.F.), I2MC, University of Toulouse 3, F-31432 Toulouse, France; Unité Mixte de Recherche 1132 (E.H., M.C.-S.), Bone and Cartilage Biology, University of Paris 7, F-75006 Paris, France; and Centre for Bone and Arthritis Research (C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Claes
C
Ohlsson
INSERM Unité 1048 (A.V., M.C.V., M.B., M.A., M.G., F.L., J.F.A., C.F.), I2MC, University of Toulouse 3, F-31432 Toulouse, France; Unité Mixte de Recherche 1132 (E.H., M.C.-S.), Bone and Cartilage Biology, University of Paris 7, F-75006 Paris, France; and Centre for Bone and Arthritis Research (C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Françoise
F
Lenfant
INSERM Unité 1048 (A.V., M.C.V., M.B., M.A., M.G., F.L., J.F.A., C.F.), I2MC, University of Toulouse 3, F-31432 Toulouse, France; Unité Mixte de Recherche 1132 (E.H., M.C.-S.), Bone and Cartilage Biology, University of Paris 7, F-75006 Paris, France; and Centre for Bone and Arthritis Research (C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Jean-François
JF
Arnal
INSERM Unité 1048 (A.V., M.C.V., M.B., M.A., M.G., F.L., J.F.A., C.F.), I2MC, University of Toulouse 3, F-31432 Toulouse, France; Unité Mixte de Recherche 1132 (E.H., M.C.-S.), Bone and Cartilage Biology, University of Paris 7, F-75006 Paris, France; and Centre for Bone and Arthritis Research (C.O.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-413 45 Gothenburg, Sweden.
Coralie
C
Fontaine
D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects*; D000071556:Cancellous Bone / Q000166:cytology / Q000187:drug effects*; D000071538:Cortical Bone / Q000166:cytology / Q000187:drug effects*; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D005269:Femur / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010052:Ovariectomy; D015398:Signal Transduction / Q000187:drug effects
D004967:Estrogens; D004958:Estradiol