Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization

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.; Ngokingha Tchouto, M.; Beule, D.; Frosch, K.-H.; Baranowsky, A.; Tsitsilonis, S.; Keller, J.

doi:10.1101/2023.07.14.548550

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bioRxiv · 10.1101/2023.07.14.548550

Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization

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Abstract

Traumatic brain injury (TBI) is associated with a hyperadrenergic state and paradoxically causes systemic bone loss while accelerating fracture healing. Here, we identify the beta2-adrenergic receptor (Adrb2) as a central mediator of these skeletal manifestations. While the negative effects of TBI on the unfractured skeleton can be explained by the established impact of Adrb2 signaling on bone formation, Adrb2 promotes neovascularization of the fracture callus under conditions of high sympathetic tone, including TBI and advanced age. Mechanistically, norepinephrine stimulates the expression of Vegfa and Cgrp primarily in periosteal cells via Adrb2, both of which synergistically promote the formation of osteogenic type-H vessels in the fracture callus. Accordingly, the beneficial effect of TBI on bone repair is abolished in mice lacking Adrb2 or Cgrp, and aged Adrb2-deficient mice without TBI develop fracture nonunions despite high bone formation in uninjured bone. Pharmacologically, the Adrb2 antagonist propranolol impairs, and the agonist formoterol promotes fracture healing in aged mice by regulating callus neovascularization. Clinically, intravenous beta-adrenergic sympathomimetics are associated with improved callus formation in trauma patients with long bone fractures. Thus, Adrb2 is a novel target for promoting bone healing, and widely used beta-blockers may cause fracture nonunion under conditions of increased sympathetic tone. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/548550v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@cea57corg.highwire.dtl.DTLVardef@d29642org.highwire.dtl.DTLVardef@186ea5aorg.highwire.dtl.DTLVardef@83eaae_HPS_FORMAT_FIGEXP M_FIG Artwork was created in BioRender. C_FIG

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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., Ngokingha Tchouto, M., Beule, D., Frosch, K.-H., Baranowsky, A., Tsitsilonis, S., Keller, J.. 2023-07-16. Increased beta2-adrenergic signaling is a targetable stimulus essential for bone healing by promoting callus neovascularization. https://doi.org/10.1101/2023.07.14.548550

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