title: Female mice lacking estrogen receptor-alpha in osteoblasts have compromised bone mass and strength.
abstract: Reduced bioavailability of estrogen increases skeletal fracture risk in postmenopausal women, but the mechanisms by which estrogen regulates bone mass are incompletely understood. Because estrogen signaling in bone acts, in part, through estrogen receptor alpha (ERα), mice with global deletion of ERα (ERαKO) have been used to determine the role of estrogen signaling in bone biology. These animals, however, have confounding systemic effects arising from other organs, such as increased estrogen and decreased insulin-like growth factor 1 (IGF-1) serum levels, which may independently affect bone. Mice with tissue-specific ERα deletion in chondrocytes, osteoblasts, osteocytes, or osteoclasts lack the systemic effects seen in the global knockout, but show that presence of the receptor is important for the function of each cell type. Although bone mass is reduced when ERα is deleted from osteoblasts, no study has determined if this approach reduces whole bone strength. To address this issue, we generated female osteoblast-specific ERαKO mice (pOC-ERαKO) by crossing mice expressing a floxed ERα gene (ERα(fl/fl)) with mice transgenic for the osteocalcin-Cre promoter (OC-Cre). Having confirmed that serum levels of estrogen and IGF-1 were unaltered, we focused on relating bone mechanics to skeletal phenotype using whole bone mechanical testing, microcomputed tomography, histology, and dynamic histomorphometry. At 12 and 18 weeks of age, pOC-ERαKO mice had decreased cancellous bone mass in the proximal tibia, vertebra, and distal femur, and decreased cortical bone mass in the tibial midshaft, distal femoral cortex, and L5 vertebral cortex. Osteoblast activity was reduced in cancellous bone of the proximal tibia, but osteoclast number was unaffected. Both femora and vertebrae had decreased whole bone strength in mechanical tests to failure, indicating that ERα in osteoblasts is required for appropriate bone mass and strength accrual in female mice. This pOC-ERαKO mouse is an important animal model that could enhance our understanding of estrogen signaling in bone cells in vivo.
authors.affiliation: Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, USA; Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Melville
authors.forename: Natalie H
authors.initials: NH
authors.lastname: Kelly
authors.forename: Sohaib A
authors.initials: SA
authors.lastname: Khan
authors.forename: John C
authors.initials: JC
authors.lastname: Schimenti
authors.forename: F Patrick
authors.initials: FP
authors.lastname: Ross
authors.forename: Russell P
authors.initials: RP
authors.lastname: Main
authors.forename: Marjolein C H
authors.initials: MC
authors.lastname: van der Meulen
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D050723:Fractures, Bone / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D015663:Osteoporosis, Postmenopausal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D047628:Estrogen Receptor alpha; C519530:insulin-like growth factor-1, mouse; D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I
keywords: BIOMECHANICS; GENETIC ANIMAL MODELS; OSTEOBLASTS; OSTEOPOROSIS; SEX STEROIDS