title: C5aR inhibition in the early inflammatory phase does not affect bone regeneration in a model of uneventful fracture healing.
abstract: BACKGROUND
  Recent studies were able to demonstrate involvement of the complement cascade in bone biology. Further studies analyzed the role of complement in traumatic injuries and demonstrated negative effects after excessive systemic activation of the inflammatory response with early abrogation of complement activation after application of a C5aR-antagonist exerting beneficial effects upon bone regeneration. In contrast, own fracture healing experiments with complement-deficient animals implied a crucial role of the complement cascade for sufficient fracture healing.
  
  
  METHODS
  To analyze the effect of a short abrogation of the complement system in the local process of fracture healing, a fracture healing experiment with wild-type mice (C57BL6), femoral osteotomy, consecutive external fixation for 21 days and blockade of the early complement activation (C5aRA) directly after trauma and after 12 h was performed. Control animals received a peptide without any biological effects. After 1-3 days, the inflammatory response was monitored with IL-6 immunostaining, serum analyses of C5a and after 3 days with histological evaluation of PMN. Fracture healing was examined with biomechanical, radiological and histological methods after 21 days.
  
  
  RESULTS
  While a decrease of the early inflammatory response was seen on day 1 of the C5aRA-treated group regarding immunostaining for IL-6 and after 3 days in the histological evaluation of PMN, no significant differences were demonstrated between both experimental groups after 21 days in the biomechanical, radiological and histological evaluation.
  
  
  CONCLUSIONS
  The present results demonstrate that the short-term inhibition of complement activation immediately after fracture does not significantly affect bone regeneration in an experimental model of regular fracture healing. Whereas other studies demonstrated that the early posttraumatic blockade of the C5aR improves fracture healing in a scenario of combined trauma, the present findings implicate that the same treatment has no effect in uneventful bone healing.
authors: Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm, Albert-Einstein Allee 23, 89081, Ulm, Germany. christian.ehrnthaller@uniklinik-ulm.de.
authors: Christian
authors: C
authors: Ehrnthaller
authors: Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm, Albert-Einstein Allee 23, 89081, Ulm, Germany.
authors: Markus
authors: M
authors: Huber-Lang
authors: Institute of Orthopedic Research and Biomechanics, Center of Musculoskeletal Research, University of Ulm, Ulm, Germany.
authors: Anna
authors: A
authors: Kovtun
authors: Institute of Orthopedic Research and Biomechanics, Center of Musculoskeletal Research, University of Ulm, Ulm, Germany.
authors: Anna Elise
authors: AE
authors: Rapp
authors: Institute of Orthopedic Research and Biomechanics, Center of Musculoskeletal Research, University of Ulm, Ulm, Germany.
authors: Julia
authors: J
authors: Kemmler
authors: Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm, Albert-Einstein Allee 23, 89081, Ulm, Germany.
authors: Florian
authors: F
authors: Gebhard
authors: Institute of Orthopedic Research and Biomechanics, Center of Musculoskeletal Research, University of Ulm, Ulm, Germany.
authors: Anita
authors: A
authors: Ignatius
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001861:Bone Regeneration / Q000187:drug effects* / Q000502:physiology; D015936:Complement C5a / Q000032:analysis; D004195:Disease Models, Animal; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy; D005269:Femur / Q000601:surgery; D017102:Fracture Healing / Q000187:drug effects*; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D010027:Osteotomy; D010456:Peptides, Cyclic / Q000494:pharmacology*; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D055114:X-Ray Microtomography
chemical_list: C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D015850:Interleukin-6; D010456:Peptides, Cyclic; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a
keywords: Antagonist; C5aR; C5aRA; Complement; Fracture healing