C5aR inhibition in the early inflammatory phase does not affect bone regeneration in a model of uneventful fracture healing

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.

Complement After Trauma: Suturing Innate and Adaptive Immunity

“…C5 cleavage could be inhibited ex vivo by small peptide inhibitors, which require future in vivo testing for their clinical potential ( 174 ). Whereas systemic inflammatory processes after trauma or during infection appear to significantly benefit from central complement blockades, there is no overall benefit for all injured tissues ( 22 , 175 , 176 ). For example, C5aR1 blockade failed to improve uneventful fracture healing, where femoral osteotomy was performed in mice following which immediate and post-12 h, a C5aR antagonist treatment was given ( 175 ).…”

“…Whereas systemic inflammatory processes after trauma or during infection appear to significantly benefit from central complement blockades, there is no overall benefit for all injured tissues ( 22 , 175 , 176 ). For example, C5aR1 blockade failed to improve uneventful fracture healing, where femoral osteotomy was performed in mice following which immediate and post-12 h, a C5aR antagonist treatment was given ( 175 ). Early blockade of C5aR ameliorated both, the IL-6 levels and neutrophil recruitment at the site of injury, but late blockade did not effect in the same.…”

Retracted: Downregulation of microRNA‐367 promotes osteoblasts growth and proliferation of mice during fracture by activating the PANX3‐mediated Wnt/β‐catenin pathway

“…A weight of 500 g set was released from a height of 17 cm (adjust the falling height according to the size of mice) to result a right femoral fracture. After operation, all the mice were immediately taken X-ray using the Faxitron sample radiation system (model MX-20 DC12; Dalian Lindi Imp & Exp Co Ltd, Dalian, China) on the same day to judge the modeling result, which was based on the research of Thrailkill et al 29 and Reyes et al 30 The remaining six healthy mice were used as a control.…”

C3a-C3aR signaling is a novel modulator of skeletal homeostasis

“…While global C3 −/− and C5 −/− mice displayed no differences in bone volume fraction at age 12 weeks ( Ehrnthaller et al, 2013 ), C5aR1 null mice have increased bone mass accrual ( Kovtun et al, 2017 ). Thus, prior osteoimmunology studies have focused on C5aR in fracture healing of the adult skeleton ( Kovtun et al, 2017 ; Ehrnthaller et al, 2013 ; Recknagel et al, 2012 ; Ehrnthaller et al, 2016 ; Bergdolt et al, 2017 ). However, the role of C3a/C3aR signaling in the growing skeleton is currently unknown.…”