Increased β(2)-adrenergic signaling promotes fracture healing through callus neovascularization in mice

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Item Type:	Article
Title:	Increased β(2)-adrenergic signaling promotes fracture healing through callus neovascularization in mice
Creators Name:	Jahn, D., Knapstein, P.R., Otto, E., Köhli, P., Sevecke, J., Graef, F., Graffmann, C., Fuchs, M., Jiang, S., Rickert, M., Erdmann, C., Appelt, J., Revend, L., Küttner, Q., Witte, J., Rahmani, A., Duda, G., Xie, W., Donat, A., Schinke, T., Ivanov, A., Tchouto, M.N., Beule, D., Frosch, K.H., Baranowsky, A., Tsitsilonis, S. and Keller, J.
Abstract:	Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the β(2)-adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene–related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.
Keywords:	Adrenergic Agents, Bone Fractures, Fracture Healing, Norepinephrine, Pathologic Neovascularization, Retrospective Studies, Traumatic Brain Injuries, Vascular Endothelial Growth Factor A, Animals, Mice
Source:	Science Translational Medicine
ISSN:	1946-6234
Publisher:	American Association for the Advancement of Science
Volume:	16
Number:	743
Page Range:	eadk9129
Date:	17 April 2024
Official Publication:	https://doi.org/10.1126/scitranslmed.adk9129
PubMed:	View item in PubMed

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