Increased β ₂ -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 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.

Brain–Bone Crosstalk in a Murine Polytrauma Model Promotes Bone Remodeling but Impairs Neuromotor Recovery and Anxiety-Related Behavior

“…Histological analysis of bone tissue at 42 dpi revealed increased bone formation in CCI+FF mice as compared to FF mice. This observation is consistent with previous findings from clinical and experimental studies [11,12,23,26,42]. We further observed fractureinduced up-regulation of gene markers associated with bone mineralization, metabolism and remodeling, i.e., Alpl, Ibsp, and Spp1, encoding for alkaline phosphatase, BSP, and osteopontin, respectively.…”

“…Both clinical observations and experimental data from animal studies indicated reciprocal brain-bone interactions [6][7][8][9]. However, most studies focused on either brain injury [40] or bone fracture [23,41] and consider the other merely a necessary co-factor.…”

“…Animal studies expanded the clinical observations of bone healing and remodeling after fractures and provided evidence for central regulation of bone remodeling [18]. Among the potential factors associated with these processes are circulating growth factors, chemokines, and hormones [19][20][21] including leptin [22] and norepinephrine [23] as well as amino acids and lipid metabolites including leucine and arachidonic acid, respectively [24,25]. Moreover, small extracellular vesicles released by injured neurons have been shown to promote osteoblastic differentiation after tibial fracture via specific micro RNAs [26] suggesting direct brain-tobone signaling after TBI.…”