Artikel
Evidence for a molecular crosstalk linking traumatic brain injury and fracture healing
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Veröffentlicht: | 6. November 2018 |
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Gliederung
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Objectives: More than fifty years ago, clinicians observed a faster union and increased callus size in long bone fractures of patients with additional traumatic brain injury (TBI). Unfortunately, the current knowledge about the interaction between brain, bone and secondary organs following isolated or combined injury is insufficient to explain this observation. As treatment options for impaired fracture healing remain limited, the molecular understanding of this phenomenon exhibits a large potential to develop novel therapeutic approaches for affected patients. Previously, we established an in vivo mouse model combining a femoral fracture with TBI, and were able to reproduce the positive effect of TBI on callus formation and fracture healing. In order to gain insights into the molecular processes underlying this effect, we have now performed systemic and local expression analyses on mRNA and protein level in this model.
Methods: The in vivo mouse model uses a femoral osteotomy stabilized by an external fixator in combination with a controlled cortical impact injury (CCII/TBI). Female C57BL/6J mice were divided into four groups including controls, isolated TBI or fracture, or the combination of both. Eleven different organs and blood samples were collected 3, 7 and 14 days after trauma. Expression analyses representative for a large variety of different signaling pathways were evaluated by qPCR, protein profiling, and histology.
Results and conclusion: In bone tissue, TBI caused a dramatic decrease in the expression of osteoblast and osteoclast marker genes in intact bone, in line with a reduced biomechanical strength after isolated TBI. In contrast, TBI resulted in a modified expression of extracellular matrix components in the early fracture callus accompanied by a reduced expression of osteoclast marker genes, potentially explaining increased callus formation. Most importantly, while the majority of the selected signaling pathways did not reveal major differences during combined injury, key components of the Wnt pathway were found to be significantly modulated in several organs, including the hypothalamus and the fracture site. Together with distinct alterations in local metabolic processes, these observations point towards a central role of Wnt signaling in mediating the posttraumatic crosstalk between brain and bone, and provide a potential molecular explanation for accelerated fracture healing following TBI. Although further in vitro and in vivo studies are required, these results may ultimately aid in developing novel therapeutic strategies to treat impaired fracture healing.