Interplay between mononuclear and osteogenic cells during fracture healing in type 2 diabetics

• Applicant: Privatdozentin Dr. Sabrina Ehnert
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 388929558

With approx. 230 million patients affected and a constantly increasing prevalence, diabetes mellitus is one of the most common metabolic disorders worldwide. Alongside the classical diabetes associated comorbidities (renal insufficiency, polyneuropathies, loss of vision, etc.) diabetes-induced changes affecting the skeletal system gain more and more importance. Interestingly, bone structure is not homogeneously altered among diabetics. While type 1 diabetics often display reduced bone mineral densities, the condition is more complex for type 2 diabetics (T2DM): T2DM patients produce more bone matrix, however with a defective quality. In combination with an increased risk to tumble this increases the fracture risk in diabetics by 6- to 12-fold.In case of a fracture the osteosynthesis (fixation of the fracture and handling of the surrounding soft tissue) represents a big surgical challenge. Post-operative mobilization of the patients is difficult, which often results in a prolonged fracture healing with lots of complications. The poor convalescence limits the patients quality of life and self-dependence.In order to improve bone quality (reducing the fracture risk) as well as the fracture treatment in T2DM patients, fundamental knowledge of the underlying mechanisms is essential. Conforming to standards immediately after trauma of the bone, the fracture gap is filled with blood and a hematoma forms. In the following inflammatory phase immune cells infiltrate the hematoma in order to phagocyte and lyse the coagulated blood. While doing so, the cells secrete cytokines and growth factors, which control the following infiltration, proliferation and differentiation of bone cells. This raises the interest in systemic, blood circulating factors which might affect bone cell function. In our preliminary work we compiled a cytokine profile of T2DM patients. In comparison to healthy controls T2DM patients display significantly reduced levels of CCL and CXCL chemokines. Expression of these chemokines is typically induced by hypoxia, a condition characteristic after fracture. There the chemokines act as attractant and activator for immune cells. As these cells represent the main cellular proportion of the early fracture hematoma, they play a leading role in fracture healing. Thus it is not yet conceivable how the reduced expression of these chemokines affects fracture healing in T2DM patients.However, our preliminary work suggests that in T2DM patients based on the reduced expression of chemokines less mononuclear cells infiltrate the fracture hematoma, consequently less cytokines are secreted which in turn impairs the following fracture healing. Focus of the following grant proposal is to verify this hypothesis and to demonstrate the underlying mechanisms.

• DFG Programme: Research Grants