Abstract
The anaphylatoxin receptor C5aR1 plays an important role not only in innate immune responses, but also in bone metabolism and fracture healing, being highly expressed on immune and bone cells, including osteoblasts and osteoclasts. C5aR1 induces osteoblast migration, cytokine generation and osteoclastogenesis, however, the exact role of C5aR1-mediated signaling in osteoblasts is not entirely known. Therefore, we hypothesized that osteoblasts are essential target cells for C5a and that fracture healing should be disturbed in mice with an osteoblast-specific C5aR1 overexpression (Col1a1-C5aR1). Osteoblast activity in vitro, bone phenotype and fracture healing after isolated osteotomy and after combined osteotomy with additional thoracic trauma were analyzed. The systemic and local inflammatory reactions were analyzed by determining C5a and IL-6 concentrations in blood, bronchoalveolar lavage fluid and fracture callus and the recruitment of immune cells. In vitro, osteoblast proliferation and differentiation were similar to wildtype cells, and phosphorylation of p38 and expression of IL-6 and RANKL were increased in osteoblasts derived from Col1a1-C5aR1 mice. Bone phenotype and the inflammatory reaction were unaffected in Col1a1-C5aR1 mice. Fracture healing was significantly impaired as demonstrated by significantly reduced bone content, bone mineral density and flexural rigidity, possibly due to significantly increased osteoclast numbers. C5aR1 signaling in osteoblasts might possibly affect RANKL/OPG balance, leading to increased bone resorption. Additional trauma significantly impaired fracture healing, particularly in Col1a1-C5aR1 mice. In conclusion, the data indicate that C5aR1 signaling in osteoblasts plays a detrimental role in bone regeneration after fracture.
Highlights
The objective of the present study was to unravel the role of the C5aR1 in osteoblasts regarding inflammation and bone formation post fracture using mice with an osteoblast-specific overexpression of C5aR1
Transgenic Col1a1-C5aR1 mice displayed normal bone development and turnover. Fracture healing both in a model of uncomplicated fracture and in a model after severe additional trauma was considerably impaired in transgenic mice, indicating that C5aR1 signaling in osteoblasts may be crucially involved in bone formation under pathological conditions
These results demonstrated that osteoblast-specific C5aR1 overexpression did not alter bone development or turnover
Summary
We and others have demonstrated that C5aR1 is strongly upregulated during osteogenic differentiation of mesenchymal stem cells (MSCs) and induced osteoblast migration and the production of pro-inflammatory cytokines, including interleukin (IL) and IL-8 in vitro [1,10,11]. We demonstrated that C5aR1 was strongly upregulated in the periosteum, where precursor cells already start to proliferate and undergo osteogenic differentiation during the early phase after bone fracture [1]. These osteoblasts may modulate the local immune response after stimulation with C5a, which is locally and, depending on trauma severity, systemically generated as a response to damage-associated molecular patterns. The specific role of the C5aC5aR1-interaction in osteoblasts during bone healing is currently poorly understood
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