title: Bone marrow oxytocin mediates the anabolic action of estrogen on the skeleton.
abstract: Estrogen uses two mechanisms to exert its effect on the skeleton: it inhibits bone resorption by osteoclasts and, at higher doses, can stimulate bone formation. Although the antiresorptive action of estrogen arises from the inhibition of the MAPK JNK, the mechanism of its effect on the osteoblast remains unclear. Here, we report that the anabolic action of estrogen in mice occurs, at least in part, through oxytocin (OT) produced by osteoblasts in bone marrow. We show that the absence of OT receptors (OTRs) in OTR(-/-) osteoblasts or attenuation of OTR expression in silenced cells inhibits estrogen-induced osteoblast differentiation, transcription factor up-regulation, and/or OT production in vitro. In vivo, OTR(-/-) mice, known to have a bone formation defect, fail to display increases in trabecular bone volume, cortical thickness, and bone formation in response to estrogen. Furthermore, osteoblast-specific Col2.3-Cre(+)/OTR(fl/fl) mice, but not TRAP-Cre(+)/OTR(fl/fl) mice, mimic the OTR(-/-) phenotype and also fail to respond to estrogen. These data attribute the phenotype of OTR deficiency to an osteoblastic rather than an osteoclastic defect. Physiologically, feed-forward OT release in bone marrow by a rising estrogen concentration may facilitate rapid skeletal recovery during the latter phases of lactation.
authors: Mount Sinai Bone Program, Mount Sinai School of Medicine, New York 10029, USA.
authors: Graziana
authors: G
authors: Colaianni
authors: Li
authors: L
authors: Sun
authors: Adriana
authors: A
authors: Di Benedetto
authors: Roberto
authors: R
authors: Tamma
authors: Ling-Ling
authors: LL
authors: Zhu
authors: Jay
authors: J
authors: Cao
authors: Maria
authors: M
authors: Grano
authors: Tony
authors: T
authors: Yuen
authors: Sylvia
authors: S
authors: Colucci
authors: Concetta
authors: C
authors: Cuscito
authors: Lucia
authors: L
authors: Mancini
authors: Jianhua
authors: J
authors: Li
authors: Katsuhiko
authors: K
authors: Nishimori
authors: Itai
authors: I
authors: Bab
authors: Heon-Jin
authors: HJ
authors: Lee
authors: Jameel
authors: J
authors: Iqbal
authors: W Scott
authors: WS
authors: Young
authors: Clifford
authors: C
authors: Rosen
authors: Alberta
authors: A
authors: Zallone
authors: Mone
authors: M
authors: Zaidi
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D007774:Lactation / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology*; D010121:Oxytocin / Q000235:genetics / Q000378:metabolism*; D018045:Receptors, Oxytocin / Q000235:genetics / Q000378:metabolism*
chemical_list: D004967:Estrogens; D018045:Receptors, Oxytocin; D010121:Oxytocin; D048031:JNK Mitogen-Activated Protein Kinases