Impaired bone healing upon neutrophil-specific adrenoreceptor beta 2 knockout in non-osteoporotic and osteoporotic mice

Abstract After a bone fracture, osteoporotic mice show delayed healing associated with elevated systemic inflammation and increased neutrophil numbers in the early fracture hematoma. Because short-term treatment with the beta-adrenoreceptor-blocker propranolol reduced neutrophil recruitment, we hypothesized that deletion of β 2 -adrenoreceptor (Adrb2) signaling in neutrophils would normalize neutrophil recruitment and accelerate bone healing in osteoporotic mice. A conditional Adrb2 knockout in Ly6G⁺ neutrophils was generated using Ly6G-Cre Adrb2-flox mice. Bone and immune phenotypes were analyzed via µCT and histology under non-fracture conditions and during bone healing in ovariectomized postmenopausal mice. Both non-osteoporotic and osteoporotic female Ly6G-Adrb2-KO mice showed impaired bone healing vs. controls, while only minor bone alterations were observed under non-fracture conditions. Pathway analysis of isolated neutrophils, characterized by RNA-sequencing, suggested reduced neutrophil activation and disturbed neutrophil/mast cell interactions upon Ly6G-Adrb2-KO. Summarily, our data demonstrate that Adrb2 signaling is important for neutrophil recruitment and seems to be critical for proper bone healing.