title: Extracellular norepinephrine clearance by the norepinephrine transporter is required for skeletal homeostasis.
abstract: Changes in bone remodeling induced by pharmacological and genetic manipulation of β-adrenergic receptor (βAR) signaling in osteoblasts support a role of sympathetic nerves in the regulation of bone remodeling. However, the contribution of endogenous sympathetic outflow and nerve-derived norepinephrine (NE) to bone remodeling under pathophysiological conditions remains unclear. We show here that differentiated osteoblasts, like neurons, express the norepinephrine transporter (NET), exhibit specific NE uptake activity via NET and can catabolize, but not generate, NE. Pharmacological blockade of NE transport by reboxetine induced bone loss in WT mice. Similarly, lack of NE reuptake in norepinephrine transporter (Net)-deficient mice led to reduced bone formation and increased bone resorption, resulting in suboptimal peak bone mass and mechanical properties associated with low sympathetic outflow and high plasma NE levels. Last, daily sympathetic activation induced by mild chronic stress was unable to induce bone loss, unless NET activity was blocked. These findings indicate that the control of endogenous NE release and reuptake by presynaptic neurons and osteoblasts is an important component of the complex homeostatic machinery by which the sympathetic nervous system controls bone remodeling. These findings also suggest that drugs antagonizing NET activity, used for the treatment of hyperactivity disorders, may have deleterious effects on bone accrual.
authors.affiliation: From the Department of Medicine, Division of Clinical Pharmacology,; Vanderbilt Center for Bone Biology.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Medicine, Division of Genetic Medicine.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Krueger
authors.affiliation: Department of Medicine, Division of Genetic Medicine.
authors.forename: Sara N
authors.initials: SN
authors.lastname: Redmon
authors.affiliation: Vanderbilt Center for Bone Biology,; the Department of Orthopaedic, Surgery and Rehabilitation.
authors.forename: Sasidhar
authors.initials: S
authors.lastname: Uppuganti
authors.affiliation: Vanderbilt Center for Bone Biology,; the Department of Orthopaedic, Surgery and Rehabilitation,; Tennessee Valley Healthcare System, Department of Veterans Affairs, Nashville, Tennessee 37232.
authors.forename: Jeffry S
authors.initials: JS
authors.lastname: Nyman
authors.affiliation: Department of Medicine, Division of Genetic Medicine,; Department of Pharmacology,; Vanderbilt Kennedy Center for Research on Human Development, and.
authors.forename: Maureen K
authors.initials: MK
authors.lastname: Hahn
authors.affiliation: From the Department of Medicine, Division of Clinical Pharmacology,; Vanderbilt Center for Bone Biology,; Department of Pharmacology,; Department of Cancer Biology,. Electronic address: florent.elefteriou@vanderbilt.edu.
authors.forename: Florent
authors.initials: F
authors.lastname: Elefteriou
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000009:adverse effects / Q000494:pharmacology; D001693:Biological Transport, Active / Q000502:physiology; D016723:Bone Remodeling / Q000502:physiology*; D001862:Bone Resorption / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009025:Morpholines / Q000009:adverse effects / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009638:Norepinephrine / Q000235:genetics / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D011596:Psychomotor Disorders / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000077593:Reboxetine; D013564:Sympathetic Nervous System / Q000166:cytology / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; D000077593:Reboxetine; D009638:Norepinephrine
keywords: ADHD; Bone Remodeling; Gene Knockout; Mouse; Nerve; Neurotransmitter Transport; Norepinephrine Transporter; Osteoblasts; Sympathetic Nervous System