title: Complement C3 and C5 deficiency affects fracture healing.
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.
authors.affiliation: Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, Center of Surgery, University of Ulm, Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Ehrnthaller
authors.forename: Markus
authors.initials: M
authors.lastname: Huber-Lang
authors.forename: Per
authors.initials: P
authors.lastname: Nilsson
authors.forename: Ronny
authors.initials: R
authors.lastname: Bindl
authors.forename: Simon
authors.initials: S
authors.lastname: Redeker
authors.forename: Stefan
authors.initials: S
authors.lastname: Recknagel
authors.forename: Anna
authors.initials: A
authors.lastname: Rapp
authors.forename: Tom
authors.initials: T
authors.lastname: Mollnes
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.forename: Florian
authors.initials: F
authors.lastname: Gebhard
authors.forename: Anita
authors.initials: A
authors.lastname: Ignatius
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D002146:Bony Callus / Q000000981:diagnostic imaging / Q000276:immunology* / Q000473:pathology; D003167:Complement Activation / Q000235:genetics; D015926:Complement C3a / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D015936:Complement C5a / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D004548:Elasticity; D005269:Femur / Q000000981:diagnostic imaging / Q000293:injuries; D017102:Fracture Healing / Q000235:genetics* / Q000276:immunology; D050723:Fractures, Bone / Q000000981:diagnostic imaging / Q000235:genetics* / Q000276:immunology; D017353:Gene Deletion; D015870:Gene Expression / Q000276:immunology; D006244:Hardness; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D051379:Mice; D055114:X-Ray Microtomography
chemical_list: D015850:Interleukin-6; D015926:Complement C3a; D015936:Complement C5a