C1: Mechanisms of interleukin-6 action in trauma-induced impairment of bone regeneration

PI: A. Ignatius

In the first funding period we investigated the role of interleukin-6 (IL-6), a key mediator in posttraumatic inflammation, in compromised bone fracture healing after severe injury. IL-6 signals are transmitted by two different mechanisms: classic signaling via the membrane bound receptor and trans-signaling via its soluble form. We demonstrated that IL-6 classic signaling, but not IL-6 trans-signaling, is crucial for a balanced immune response, endochondral bone formation and callus remodeling in regular bone healing after isolated fracture. In contrast, after severe trauma, IL-6 trans-signaling contributes to compromised fracture healing, as its selective inhibition improves bone repair under these conditions. We will now further unravel the role of IL-6 effector and target cells in bone fracture healing with a focus on neutrophils and mast cells, because, being the first line of cellular defense after injury, they may regulate essential initial steps in the bone healing cascade. Based on our findings that neutrophil recruitment and/or survival in the fracture hematoma is regulated through IL-6 classic signaling and that a tight regulation of neutrophil activity might be essential for the bone healing process, we will decipher neutrophil functions in regular and in trauma-induced compromised fracture healing. We will investigate how they affect or are regulated by IL-6 signaling. Furthermore, as we found that mast cells crucially trigger inflammatory responses after isolated fracture, we aim to decipher their function in trauma- induced compromised bone repair. The results of this project will contribute to a better understanding of the influence of the early immune response on subsequent bone regeneration and will help to develop novel therapies to improve bone healing in fracture patients with concomitant injuries.

Projektleiterin

Prof. Dr. med. vet. Anita Ignatius
Institut für Unfallchirurgische Forschung und Biomechanik
Zentrum für Tramaforschung Ulm (ZTF)
Universitätsklinikum Ulm
Helmholtzstr. 14
89081 Ulm 
Tel.: +49 731 500 55301
Fax: +49 731 500 55302
anita.ignatius(at)uni-ulm.de
www.biomechanics.de

The fracture haematoma is characterised by hypoxia, low pH, pro- and anti-inflammatory mediators and inflammatory cells. The inflammation must be properly terminated to allow bone regeneration. We showed that systemic inflammation induced by a severe trauma (first hit) influences the inflammatory phase of fracture healing, thus disturbing bone regeneration. We could also demonstrate that the accumulation of second hits, such as second surgical interventions (e.g. conversion of the fixation device) could lead to a further aggravation of fracture healing.