Role of neutrophil extracellular traps (NETs) in impaired Fracture in type 2 diabetics

• Applicant: Privatdozentin Dr. Sabrina Ehnert
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 499304393

Diabetes mellitus is the metabolic disorder with the highest prevalence and incidence worldwide. The disease is associated with numerous complications, which, despite complex and cost-intensive treatment, often cause serious damage to health. Not only diabetics but already prediabetics show an altered bone structure. As a result, pre-/diabetics suffer more often from fractures than those with healthy metabolism. It is therefore assumed that the rate of prediabetics and previously unrecognized diabetics (estimated number of unreported cases in Germany approx. 4.5 million) is particularly high in trauma surgery. In the case of a fracture, the fixation of the bone pieces, the handling of the surrounding soft tissue and the following mobilization of the patient represent great challenges. The healing process is often prolonged and rich in complications, among which the amputation of the affected limbs is not an isolated case. Treating these complications accounts for a large proportion of the direct diabetes-associated costs in Germany.In order to improve the treatment of fractures in pre-/diabetics, we aim to establish a screening during this project that enables pre-/diabetics to be identified at an early stage so that they can be treated in a targeted manner. The risk of complications can already be reduced through optimized blood sugar control (medication). However, in order to develop targeted therapies in the future, a fundamental understanding of the underlying mechanisms is required. After a fracture, neutrophils are the first cells arriving in the fracture hematoma. In a mouse model it was shown that diabetes stimulates neutrophils to form NETs (neutrophil extracellular traps). In the process of NETosis, neutrophils release their DNA from the cell with citrullinated histones and antimicrobial peptides in order to bind pathogens and render them harmless. We suspect that an excessive formation of NETs in diabetics damages the surrounding tissue and thus delays or prevents wound and fracture healing. The enzyme PADI4 (peptidyl arginine deiminase 4) plays a special role in this process. We expect increased levels of PADI4 in neutrophils from diabetics, sensitizing the cells for NETosis stimuli. After a fracture, diabetics experience increased oxidative and nitrosative stress. We suspect that this is a critical trigger for the NETosis. In addition, our preliminary work suggests that the genetic variants of PADI4 influence how strongly the neutrophils respond to the NETosis stimuli. This in turn determines the susceptibility of pre-/diabetics to complications such as tissue and implant-associated infections. Aim of this proposal is to prove these assumptions and hypotheses and to identify possible underlying mechanisms. The knowledge gained within this project will be used in the future to develop new therapeutic approaches to support wound and fracture healing in pre-/diabetics.

• DFG Programme: Research Grants