Traumatic brain injury and fracture healing

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Osteoanabol

Denise Jahn, Paul Köhli, Ellen Otto, Dilara Kaya, Serafeim Tsitsilonis, Johannes Keller

Traumatic brain injury (TBI) has a tremendous effect on the cells of intact and broken bones. Whereas the isolated TBI weakens the bone, it shows opposite consequences in the fracture. There it leads to an increased volume of the callus and earlier bridging. The composition of the early extracellular matrix as well as the regulation of major signaling pathways yield an environment that promotes bone healing. This project identifies molecules that mediate the interaction between TBI and fracture. Evaluating the osteogenic effect of these targets will reveal their suitability for pharmacological applications.

Inflammatory response

Ellen Otto, Serafeim Tsitsilonis, Johannes Keller

Recently, increasing evidence points towards an important role of the immune system in bone regeneration. As both fracture and traumatic brain injury (TBI) trigger powerful immune responses, understanding the interplay of respective signaling cascades may help to explain the phenomenon of the accelerated fracture healing following TBI. This will directly aid in developing therapeutics and treatment options not only for delayed or impaired fracture healing, but also for immunodysregulations following multitrauma. In summary, this project aims to characterize the injury-dependent immune responses following isolated and combined trauma.

Metabolics

Paul Köhli, Serafeim Tsitsilonis, Johannes Keller

Alterations in energy utilization may provide an explanation for the phenomenon of enhanced bone healing following traumatic brain injury, as metabolic changes after TBI are potentially explained by the selfish brain hypothesis: During times of increased stress, the brain increases energy demands and alters metabolic processes and energy flow in the whole organism including bone tissue. Furthermore, high-energy demand in the first days after polytrauma is a clinical challenge not yet succeeded. Therefore, this subproject aims to characterize alterations in metabolic processes during isolated or combined injury.

Neurotransmitters

Dilara Kaya, Johannes Keller, Serafeim Tsitsilonis

In addition to the peripheral regulation of the bone metabolism, a central effect through hypothalamic neurotransmitters is observed as well. These neurotransmitters are primarily regulated through Leptin and influence the sympathetic nervous system, thus regulating bone formation. Using our novel animal experimental model combining traumatic brain injury with fracture healing, we want to show that alterations of these neurotransmitters is associated with bone metabolism in an injury-dependent manner. Currently we are preparing histological slices of the hypothalamic brain region and stain them immunohistochemically with antibodies against the neurotransmitters Neuropeptide Y (NPY), Neuromedin U (NMU), Agouti-related protein (AgRP), Cocain and amphetamine regulated transcript (CART) and Proopiomelanocortin (POMC). Analyzing the signal intensity, we compare their expression between the different groups of mice (fracture, traumatic brain injury, and combined trauma). Our goal is to identify the altered pathways involved in the regulation of bone metabolism and regeneration during TBI.

Clinical study: morphologic and molecular response

Frank Graef, Tobias Lindner, Johannes Keller, Serafeim Tsitsilonis

The phenomenon of increased callus formation in fracture healing after traumatic brain injury (TBI) was first described in the 19th century - more than 130 years ago. Although it has been known for a long time, the molecular mechanisms could not be identified yet. From a clinical point of view, it poses an interesting approach in finding pharmaceutical agents to improve bone healing. In our clinical part on the research of this topic we conduct a prospective clinical study in which we include patients who demonstrate with a) an isolated shaft fracture of long bones, b) an isolated TBI or c) the combination of a shaft fracture and TBI. Starting from the results of our screening study in mice we perform ELISA and FACS analyses in order to understand the impact of TBI on metabolic, immunological and hormonal signaling pathways and ultimately its effect on fracture healing.