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Increased β2-adrenergic signaling promotes fracture healing through callus neovascularization in mice

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Increased β2-adrenergic signaling promotes fracture healing through callus neovascularization in mice. / Jahn, Denise; Knapstein, Paul Richard; Otto, Ellen; Köhli, Paul; Sevecke, Jan; Graef, Frank; Graffmann, Christine; Fuchs, Melanie; Jiang, Shan; Rickert, Mayla; Erdmann, Cordula; Appelt, Jessika; Revend, Lawik; Küttner, Quin; Witte, Jason; Rahmani, Adibeh; Duda, Georg; Xie, Weixin; Donat, Antonia; Schinke, Thorsten; Ivanov, Andranik; Tchouto, Mireille Ngokingha; Beule, Dieter; Frosch, Karl-Heinz; Baranowsky, Anke; Tsitsilonis, Serafeim; Keller, Johannes.

In: SCI TRANSL MED, Vol. 16, No. 743, 17.04.2024, p. eadk9129.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Jahn, D, Knapstein, PR, 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, MN, Beule, D, Frosch, K-H, Baranowsky, A, Tsitsilonis, S & Keller, J 2024, 'Increased β2-adrenergic signaling promotes fracture healing through callus neovascularization in mice', SCI TRANSL MED, vol. 16, no. 743, pp. eadk9129. https://doi.org/10.1126/scitranslmed.adk9129

APA

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., ... Keller, J. (2024). Increased β2-adrenergic signaling promotes fracture healing through callus neovascularization in mice. SCI TRANSL MED, 16(743), eadk9129. https://doi.org/10.1126/scitranslmed.adk9129

Vancouver

Jahn D, Knapstein PR, Otto E, Köhli P, Sevecke J, Graef F et al. Increased β2-adrenergic signaling promotes fracture healing through callus neovascularization in mice. SCI TRANSL MED. 2024 Apr 17;16(743):eadk9129. https://doi.org/10.1126/scitranslmed.adk9129

Bibtex

@article{bdb2ef77e1734ed4acec218c50d68944,
title = "Increased β2-adrenergic signaling promotes fracture healing through callus neovascularization in mice",
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 β2-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.",
author = "Denise Jahn and Knapstein, {Paul Richard} and Ellen Otto and Paul K{\"o}hli and Jan Sevecke and Frank Graef and Christine Graffmann and Melanie Fuchs and Shan Jiang and Mayla Rickert and Cordula Erdmann and Jessika Appelt and Lawik Revend and Quin K{\"u}ttner and Jason Witte and Adibeh Rahmani and Georg Duda and Weixin Xie and Antonia Donat and Thorsten Schinke and Andranik Ivanov and Tchouto, {Mireille Ngokingha} and Dieter Beule and Karl-Heinz Frosch and Anke Baranowsky and Serafeim Tsitsilonis and Johannes Keller",
year = "2024",
month = apr,
day = "17",
doi = "10.1126/scitranslmed.adk9129",
language = "English",
volume = "16",
pages = "eadk9129",
journal = "SCI TRANSL MED",
issn = "1946-6234",
publisher = "AMER ASSOC ADVANCEMENT SCIENCE",
number = "743",

}

RIS

TY - JOUR

T1 - Increased β2-adrenergic signaling promotes fracture healing through callus neovascularization in mice

AU - Jahn, Denise

AU - Knapstein, Paul Richard

AU - Otto, Ellen

AU - Köhli, Paul

AU - Sevecke, Jan

AU - Graef, Frank

AU - Graffmann, Christine

AU - Fuchs, Melanie

AU - Jiang, Shan

AU - Rickert, Mayla

AU - Erdmann, Cordula

AU - Appelt, Jessika

AU - Revend, Lawik

AU - Küttner, Quin

AU - Witte, Jason

AU - Rahmani, Adibeh

AU - Duda, Georg

AU - Xie, Weixin

AU - Donat, Antonia

AU - Schinke, Thorsten

AU - Ivanov, Andranik

AU - Tchouto, Mireille Ngokingha

AU - Beule, Dieter

AU - Frosch, Karl-Heinz

AU - Baranowsky, Anke

AU - Tsitsilonis, Serafeim

AU - Keller, Johannes

PY - 2024/4/17

Y1 - 2024/4/17

N2 - 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 β2-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.

AB - 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 β2-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.

U2 - 10.1126/scitranslmed.adk9129

DO - 10.1126/scitranslmed.adk9129

M3 - SCORING: Journal article

C2 - 38630849

VL - 16

SP - eadk9129

JO - SCI TRANSL MED

JF - SCI TRANSL MED

SN - 1946-6234

IS - 743

ER -