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

Autor: Jahn D; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany.; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany., Knapstein PR; University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany., Otto E; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany.; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany., Köhli P; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany.; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany.; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, 13353 Berlin, Germany., Sevecke J; University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany., Graef F; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany.; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, 13353 Berlin, Germany., Graffmann C; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany., Fuchs M; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany.; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany., Jiang S; University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany., Rickert M; University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany., Erdmann C; University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany., Appelt J; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany.; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany., Revend L; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany., Küttner Q; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany., Witte J; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany., Rahmani A; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany.; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany., Duda G; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany., Xie W; University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany., Donat A; University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany., Schinke T; University Medical Center Hamburg-Eppendorf, Department of Osteology and Biomechanics, 20251 Hamburg, Germany., Ivanov A; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, 10117 Berlin, Germany.; Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany., Tchouto MN; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, 10117 Berlin, Germany., Beule D; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Core Unit Bioinformatics, 10117 Berlin, Germany.; Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany., Frosch KH; University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany., Baranowsky A; University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany., Tsitsilonis S; Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Center for Musculoskeletal Surgery, 13353 Berlin, Germany.; Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Julius Wolff Institute, 13353 Berlin, Germany., Keller J; University Medical Center Hamburg-Eppendorf, Department of Trauma and Orthopedic Surgery, 20251 Hamburg, Germany.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2024 Apr 17; Vol. 16 (743), pp. eadk9129. Date of Electronic Publication: 2024 Apr 17.
DOI: 10.1126/scitranslmed.adk9129
Abstrakt: 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.
Databáze: MEDLINE