Abstract
There is increasing evidence that complement may play a role in bone development. Our previous studies demonstrated that the key complement receptor C5aR was strongly expressed in the fracture callus not only by immune cells but also by bone cells and chondroblasts, indicating a function in bone repair. To further elucidate the role of complement in bone healing, this study investigated fracture healing in mice in the absence of the key complement molecules C3 and C5. C3-/- and C5-/- as well as the corresponding wildtype mice received a standardized femur osteotomy, which was stabilized using an external fixator. Fracture healing was investigated after 7 and 21 days using histological, micro-computed tomography and biomechanical measurements. In the early phase of fracture healing, reduced callus area (C3-/-: -25%, p=0.02; C5-/-: -20% p=0.052) and newly formed bone (C3-/-: -38%, p=0.01; C5-/-: -52%, p=0.009) was found in both C3- and C5-deficient mice. After 21 days, healing was successful in the absence of C3, whereas in C5-deficient mice fracture repair was significantly reduced, which was confirmed by a reduced bending stiffness (-45%; p=0.029) and a smaller callus volume (-17%; p=0.039). We further demonstrated that C5a was activated in C3-/- mice, suggesting cleavage via extrinsic pathways. Our results suggest that the activation of the terminal complement cascade in particular may be crucial for successful fracture healing.
Highlights
It is known that the immune and skeletal systems are closely linked [1], because both share crucial regulatory cytokines, the most prominent being the receptor activator of nuclear factorκB ligand (RANKL), which is released by osteoblasts and by immune cells, stimulating osteoclast formation and activity [2,3]
These results suggest that the terminal complement pathway, which was completely abolished in C5-/- mice, but not in C3-/- mice, may be important for successful fracture healing
We demonstrated that the key complement receptor C5aR was abundantly expressed in the fracture callus of rats by immune cells during the early inflammatory phase and by osteoblasts, chondroblasts and osteoclasts throughout the entire healing period [17]
Summary
It is known that the immune and skeletal systems are closely linked [1], because both share crucial regulatory cytokines, the most prominent being the receptor activator of nuclear factorκB ligand (RANKL), which is released by osteoblasts and by immune cells, stimulating osteoclast formation and activity [2,3]. There is increasing evidence that the complement system, a crucial part of innate immunity, may play an important role in bone biology [4,5]. All three pathways result in the generation of the anaphylatoxins C3a and C5a, which, via binding to their corresponding receptors C3aR and C5aR, induce important functions of immune cells, including cytokine release and cell migration [4]. Complement-independent pathways exist, such as cross-activation with other serine protease systems (e.g. the coagulation system) [6] or cellular activation by macrophages [7]. Extrinsic complement activation is regarded as an important mechanism in traumatic injuries [6]
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