Abstract
BackgroundRecent 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.MethodsTo 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.ResultsWhile 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.ConclusionsThe 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.
Highlights
Recent studies were able to demonstrate involvement of the complement cascade in bone biol‐ ogy
Whereas the amount of BV was equal between both experimental groups (Fig. 2a; mean bone volume for the fracture group 0.25–0.26 mm3 for Fx & C5aR antagonist (C5aRA)), the amount of tissue volume (TV) differed 66% with a mean value of 3.3 mm3 in the Fx group compared to 1.1 mm3 in the Fx & C5aRA group (p = 0.99) (Fig. 2b)
C5aRA treatment did not result in a systemic alteration of the amount of generated complement factor 5a (C5a)
Summary
Recent studies were able to demonstrate involvement of the complement cascade in bone biol‐ ogy. Huber-Lang et al were able to demonstrate cross-activation of the complement system by other serine protease systems (e.g. coagulation system) [3] and a cellular activation pathway by macrophages has been discovered [4]. Both extrinsic activation pathways have been regarded as an important mechanism in traumatic injuries [3]. Besides demonstration of complement activation in bone tissue both locally and systemically after traumatic injuries, the complement system is known to be involved in the pathophysiology of several other boneaffecting diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [8, 9]
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