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

PI: A. Ignatius

Confirming clinical evidence, we recently demonstrated that a severe trauma, inducing an acute systemic inflammation, considerably impairs fracture healing. However, the underlying molecular mechanisms are poorly understood. Here, we focus on the role of interleukin-6 (IL-6), a key cytokine in posttraumatic inflammation. IL-6 is pivotal for acute phase inflammatory responses and lymphocyte stimulation. It also mediates anti-inflammatory effects, thus promoting regenerative proliferation and angiogenesis. Importantly, IL-6 plays a crucial role in bone metabolism and regulates fracture healing in a presently unknown process. IL-6 signals are transmitted via the transmembrane glycoprotein 130 (gp130) by two distinct mechanisms: Firstly, classic signalling via the membrane-anchored IL-6 receptor and, secondly, trans-signalling using the soluble IL-6 receptor. Whereas IL-6 trans-signalling is considered as a danger signal driving inflammation, classic signalling may rather mediate anti-inflammatory, pro-regenerative processes. The role of these distinct pathways in posttraumatic inflammation and fracture healing is currently unclear. Here, we will study, firstly, the impact of IL-6 classic and trans-signalling on the inflammatory, repair and remodelling phases of fracture healing and, secondly, the function of IL-6 in the pathophysiology of compromised bone healing induced by severe trauma. The results of our study will help to develop novel therapeutic approaches to improve bone healing in severely injured patients. The project has a strong translational character, because modulators of IL-6 pathways are already in clinical trials for other inflammatory diseases.



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

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.