Abstract
The anaphylatoxin C5a is generated upon activation of the complement system, a crucial arm of innate immunity. C5a mediates proinflammatory actions via the C5a receptor C5aR1 and thereby promotes host defence, but also modulates tissue homeostasis. There is evidence that the C5a/C5aR1 axis is critically involved both in physiological bone turnover and in inflammatory conditions affecting bone, including osteoarthritis, periodontitis, and bone fractures. C5a induces the migration and secretion of proinflammatory cytokines of osteoblasts. However, the underlying mechanisms remain elusive. Therefore, in this study we aimed to determine C5a‐mediated downstream signalling in osteoblasts. Using a whole‐genome microarray approach, we demonstrate that C5a activates mitogen‐activated protein kinases (MAPKs) and regulates the expression of genes involved in pathways related to insulin, transforming growth factor‐β and the activator protein‐1 transcription factor. Interestingly, using coimmunoprecipitation, we found an interaction between C5aR1 and Toll‐like receptor 2 (TLR2) in osteoblasts. The C5aR1‐ and TLR2‐signalling pathways converge on the activation of p38 MAPK and the generation of C‐X‐C motif chemokine 10, which functions, among others, as an osteoclastogenic factor. In conclusion, C5a‐stimulated osteoblasts might modulate osteoclast activity and contribute to immunomodulation in inflammatory bone disorders.
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