Institute of Orthopaedic Research and Biomechanics, Trauma Research Center Ulm, Ulm University Hospital, Ulm, Germany.
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
J Cell Mol Med. 2018 Dec;22(12):6002-6014. doi: 10.1111/jcmm.13873. Epub 2018 Sep 24.
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.
过敏毒素 C5a 在补体系统激活时产生，补体系统是先天免疫的关键组成部分。C5a 通过 C5a 受体 C5aR1 介导促炎作用，从而促进宿主防御，但也调节组织稳态。有证据表明，C5a/C5aR1 轴在生理骨转换和影响骨的炎症状态中都起着至关重要的作用，包括骨关节炎、牙周炎和骨骨折。C5a 诱导成骨细胞的迁移和促炎细胞因子的分泌。然而，其潜在机制仍不清楚。因此，在这项研究中，我们旨在确定 C5a 在成骨细胞中的介导的下游信号转导。使用全基因组微阵列方法，我们证明 C5a 激活丝裂原活化蛋白激酶 (MAPK)，并调节参与与胰岛素、转化生长因子-β 和激活蛋白-1 转录因子相关途径的基因的表达。有趣的是，通过共免疫沉淀，我们发现 C5aR1 和 Toll 样受体 2 (TLR2) 在成骨细胞中相互作用。C5aR1 和 TLR2 信号通路在 p38 MAPK 的激活和 C-X-C 基序趋化因子 10 的产生上汇聚，后者作为破骨细胞生成因子发挥作用。总之，C5a 刺激的成骨细胞可能调节破骨细胞活性，并有助于炎症性骨疾病中的免疫调节。
