Macrophage plasticity deployed for efficient bone (re-) generation

• Applicant: Professor Dr. Lorenz Meinel
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 270576131

• Final Report Year: 2019

Final Report Abstract

The aim of the Sino-German consortium was to develop an experimental system, consisting of an index and supply compartment, which is decorated with the anti-inflammatory cytokine interleukin 4 (IL4) to investigate its therapeutic potential in tibia bone defects. IL4 variants suitable for site-specific decoration of the supply compartment were successfully developed by recombinant expression following amber codon expansion. Unnatural amino acids at position K42 of IL-4 were used to perform copper-catalyzed click reaction (CuAAC) connecting IL4 with a peptide encoding for a protease-sensitive linker sequence (PSL) and a transglutaminase (TG) peptide sequence. All IL-4 muteins maintained wild-type like bioactivity and were covalently immobilized on decellularized extracellular matrices (ECM) by transglutaminase. Release of IL-4 from the depot was studied in the presences of matrix metalloproteinases (MMPs). Anti-inflammatory effects of IL-4 variants were finally investigated in an osteoarthritic rabbit destabilization of the medial meniscus (DMM) model. IL-4 variants with a PSL were found to reduce sub-synovial inflammation in contrast to controls (IL-4 without cleavable PSL, soluble IL-4 and PBS). The bio-responsive release of anti-inflammatory cytokines from the depot in the joint may be a useful therapeutic strategy in osteoarthritis (OA) because it expands the administration intervals, which are limited due to systemic toxicity and restricted number of articular visits per year.

Publications

• (2016). Interleukin‐4‐clicked surfaces drive M2 macrophage polarization. Chembiochem, 17(22), 2123-2128
  Lühmann, T., Spieler, V., Werner, V., Ludwig, M. G., Fiebig, J., Mueller, T. D., & Meinel, L.
  
• (2017). Matrix metalloproteinase responsive delivery of myostatin inhibitors. Pharm. Res. 34(1) 58–72
  Braun A., Gutmann, M., Ebert R., Jakob F., Lühmann, T., and Meinel L.
  
• (2017). Site-specific POxylation of interleukin-4. ACS Biomaterials Science & Engineering, 3(3), 304-312
  Lühmann, T., Schmidt, M., Leiske, M. N., Spieler, V., Majdanski, T. C., Grube, M., ... & Meinel, L.