gms | German Medical Science

Objectives: Traumatic brain injury (TBI) negatively affects bone metabolism in intact bone, but paradoxically stimulates the healing process of long bone fractures. The understanding of the involved pathways can result in the identification of new drug targets to treat impaired bone healing such as malunions or non-unions. The examination of our previously established mouse model combining TBI with a femoral fracture points towards an involvement of adrenergic signaling which possibly stimulates bone-forming osteoblasts within the fracture callus. Since adrenergic signaling was shown to exert an inhibitory effect on bone formation in intact bone, it was suggested to negatively influence the bone healing as well. Therefore, further molecular investigations were required in order to understand the role of adrenergic signaling in intact and in fractured bone.

Methods: Female C57BL/6J mice received a controlled cortical impact injury simulating TBI and/or a femoral osteotomy stabilized by an external fixator (Fx). The four intervention groups (Control, TBI, Fx, TBI+Fx) were compared regarding the expression profiles of specific target genes in the fracture callus, the hypothalamus and secondary organs. The amount of stress metabolites was evaluated in the serum. To analyze the underlying molecular pathways in vitro, mineralization and gene expression assays were conducted in murine bone marrow-derived osteoblasts following stimulation with adrenergic metabolites.

Results and conclusion: Mice with TBI showed an enriched serum level of adrenergic metabolites, resulting in the activation and browning of adipose tissue. In vitro experiments proved a stimulatory effect of adrenergic reagents on osteoblastogenesis and osteoblast activity. This was mediated by the activation of a specific adrenergic receptor that is highly expressed in differentiating osteoblasts. The expression of this receptor was significantly higher in the fracture callus compared to the intact bone, explaining the controversial effect of TBI on these two tissue types. On the molecular level, the stimulatory effect of adrenergic substances was mediated via Calcitonin gene-related peptide alpha (αCGRP) and Wnt signaling. In conclusion, the increased callus size after TBI appears to be induced through increased adrenergic signaling and mediated through subsequent activation of αCGRP and Wnt modulators. Further research is necessary to analyze the suitability of these molecular mediators for therapeutic applications.