Abstract
Severely injured patients frequently suffer compromised fracture healing because of systemic post-traumatic inflammation. An important trigger of the posttraumatic immune response is the complement anaphylatoxin C5a, which acts via two receptors, C5aR1 and C5aR2, expressed on immune and bone cells. The blockade of C5a-mediated inflammation during the early inflammatory phase was demonstrated to improve fracture healing after severe injury. However, the distinct roles of the two complement receptors C5aR1 and C5aR2 in bone has to date not been studied. Here, we investigated bone turnover and regeneration in mice lacking either C5aR1 or C5aR2 in a model of isolated fracture and after severe injury, combining the fracture with an additional thoracic trauma. Both C5aR1−/− and C5aR2−/− mice displayed an increased bone mass compared to wild-type controls due to reduced osteoclast formation and increased osteoblast numbers, respectively. Following fracture, the inflammatory response was differently affected in these strains: It was decreased in C5aR1−/− mice but enhanced in C5aR2−/− mice. Both strains exhibited impaired fracture healing, disturbed osteoclastogenesis and delayed cartilage-to-bone transformation. Thus, our data suggest that C5aR1 and C5aR2 differentially regulate the immune response after fracture and are required for effective cartilage-to-bone transformation in the fracture callus and for undisturbed bone healing.
Highlights
The complement system is an important part of the innate immune system
Our group demonstrated strong C5aR1 up-regulation by osteoblasts in response to bone injury and that bone healing is severely disturbed in mice with osteoblast-specific C5aR1 overexpression, suggesting that osteoblasts are effector cells for C5a in bone repair[14,18]
The present study addressed the role of C5aR1 and C5aR2 in fracture healing using respective knockout mouse models
Summary
The complement system is an important part of the innate immune system. It includes more than 40 proteases, which are sequentially activated after inflammatory stimuli. Bone tissue is continuously rebuilt during bone remodelling, a dynamic balance between bone-forming osteoblasts and resorbing osteoclasts, which is essential for maintaining bone mass Complement might regulate this process, because it was demonstrated that complement protein www.nature.com/scientificreports/. C3aR and C5aR1 are strongly up-regulated during osteoblastogenesis and mediate the production of pro-inflammatory cytokines, including interleukin (IL)-6 and IL-8 in osteoblasts[13,14,15]. These data indicate that the activation of the C3aR- and C5aR1-axis induces an immune response in these cells. We used an isolated fracture model and model of severe trauma, where the fracture was combined with an additional thoracic trauma to induce a more pronounced inflammation[21]
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