Details

Autor(en) / Beteiligte

• Ma, Yun
• Krueger, Jessica J.
• Redmon, Sara N.
• Uppuganti, Sasidhar
• Nyman, Jeffry S.
• Hahn, Maureen K.
• Elefteriou, Florent

Titel

Extracellular Norepinephrine Clearance by the Norepinephrine Transporter Is Required for Skeletal Homeostasis

Ist Teil von

• The Journal of biological chemistry, 2013-10, Vol.288 (42), p.30105-30113

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2013

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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. Background: The contribution of endogenous norepinephrine (NE) to skeletal homeostasis is unclear. Results: Bone forming cells, not only neurons, express the norepinephrine transporter (NET), and blockade of extracellular NE clearance causes alterations in bone homeostasis. Conclusion: NE clearance by NET is a component of the homeostatic machinery by which sympathetic nerves and osteoblasts control bone remodeling. Significance: NET blockers may increase fracture risk.