Improvement of bone regeneration in posttraumatic osteomyelitis through modulation of sphingosine-1-phosphate signaling

• Applicants: Professor Dr. Björn Behr; Professor Dr. Bodo Levkau
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2016 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320411856

Posttraumatic osteomyelitis (pom) represents a major complication in open fractures and can lead to multiple surgical interventions and even limb amputation. The treatment of pom includes surgical measures as well as antibiotic therapy. However, a typical consequence after severe bone infections is a reduced bone healing capacity. In previous studies, we could already demonstrate a prolonged inflammatory reaction contributing to this reduced healing capacity. Moreover, local application of adipose-derived mesenchymal stem cells (ASCs) could enhance osteogenesis, decrease osteoclast activity and modulate B-cell activity in infected animals. However, further optimization of treatment to enhance the anti-inflammatory potential of ASCs is needed. Sphingosin-1-Phosphate (S1P) is a bioactive molecule with an important anti-inflammatory role, enhancing the transition of lymphocytes from lymphatic tissue to the blood stream. Moreover, it was recently identified as an important mediator in bone regeneration: S1P increases the activity of osteoblasts and inhibits osteoclasts and has thus an osteoanabolic effect. However, the immunomodulatory role of S1P in bone regeneration in terms of bone infections has not been investigated in great detail yet. Our proposed project aims to examine the anti-inflammatory effect of S1P in a pom model, while simultaneously taking into account the added benefit of its osteoanabolic component. We intend to identify and analyze cell types, signaling pathways and receptors involved in the S1P transduction pathway in order to outline potential pharmacological treatment approaches. Furthermore, we aim to further enhance osteogenesis by pretreating ASCs with S1P-Lyase-inhibitors.In a first step, we intend to examine the exact biological mechanisms of S1P in an already established murine model of pom by inhibiting the degradation of S1P systemically. By means of immunohistochemistry, gene expression, protein analysis and micro CT, we aim to analyse the bone physiology as well as inflammatory and apoptotic processes. In order to identify signaling receptors and to outline possible pharmacological treatment approaches, we will then examine global and tissue specific S1PR knockout mice with and without previous S1PR-lyase inhibition. Moreover, we plan to further improve the osteoregenerative potential of ASCs by altering S1P levels or utilizing ASCs from S1P-Lyase deficient KO-mice respectively. We hypothesize that induction of the S1P-signaling pathway will enhance bone regeneration in posttraumatic osteomyelitis by stimulating osteoblastogenesis, modulating osteoclast activity and promoting anti-inflammatory effects. Moreover, we aim to identify and test possible pharmacological approaches through S1P-receptor agonists or antagonists or indirectly through modulation of pretreated ASCs.

• DFG Programme: Research Grants