Extracellular norepinephrine clearance by the norepinephrine transporter is required for skeletal homeostasis

J Biol Chem. 2013 Oct 18;288(42):30105-30113. doi: 10.1074/jbc.M113.481309. Epub 2013 Sep 4.


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.

Keywords: ADHD; Bone Remodeling; Gene Knockout; Mouse; Nerve; Neurotransmitter Transport; Norepinephrine Transporter; Osteoblasts; Sympathetic Nervous System.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antidepressive Agents / adverse effects
  • Antidepressive Agents / pharmacology
  • Biological Transport, Active / physiology
  • Bone Remodeling / physiology*
  • Bone Resorption / chemically induced
  • Bone Resorption / genetics
  • Bone Resorption / metabolism
  • Bone Resorption / pathology
  • Humans
  • Mice
  • Mice, Mutant Strains
  • Morpholines / adverse effects
  • Morpholines / pharmacology
  • Neurons / cytology
  • Neurons / metabolism
  • Norepinephrine / genetics
  • Norepinephrine / metabolism*
  • Norepinephrine Plasma Membrane Transport Proteins / antagonists & inhibitors
  • Norepinephrine Plasma Membrane Transport Proteins / genetics
  • Norepinephrine Plasma Membrane Transport Proteins / metabolism*
  • Osteoclasts / cytology
  • Osteoclasts / metabolism*
  • Psychomotor Disorders / drug therapy
  • Psychomotor Disorders / genetics
  • Psychomotor Disorders / metabolism
  • Psychomotor Disorders / pathology
  • Reboxetine
  • Sympathetic Nervous System / cytology
  • Sympathetic Nervous System / metabolism


  • Antidepressive Agents
  • Morpholines
  • Norepinephrine Plasma Membrane Transport Proteins
  • Slc6a2 protein, mouse
  • Reboxetine
  • Norepinephrine