Division of Orthopaedics and Traumatology, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, Guangzhou, China; Guangdong Provincial Key Laboratory of Bone and Cartilage Regenerative Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Huiqiao Medical Center, Nanfang Hospital of Southern Medical University, Guangzhou, China.
Int Immunopharmacol. 2024 Nov 15;141:112959. doi: 10.1016/j.intimp.2024.112959. Epub 2024 Aug 19.
Staphylococcus aureus (S. aureus)-induced bone loss is a significant challenge in the treatment of osteomyelitis. Our previous study was the first to confirm that granulocyte colony-stimulating factor (G-CSF) mediates S. aureus-induced bone loss. However, the underlying mechanism remains unknown. The objective of this study was to elucidate this. We found G-CSF mediated BMSC senescence and increased IL-1β concentration of serum and bone marrow in mice after S. aureus infection. Furthermore, we demonstrated that G-CSF promoted the expression of IL1b in murine bone marrow-derived neutrophils. Notably, we identified that IL-1β mediated BMSC (bone marrow mesenchymal stromal cell) senescence in mice after S. aureus infection. Importantly, IL-1β neutralizing antibody effectively alleviated BMSC senescence and bone loss caused by S. aureus infection in mice. In terms of molecular mechanism, we found IL-1β induced BMSC senescence by JNK/P53 and JNK/BCL2 pathways. Collectively, G-CSF promotes IL-1β production which induces BMSC senescence via JNK/P53 and JNK/BCL2 pathways, leading to S. aureus-induced bone loss. This study identified novel targets for preventing and treating S. aureus-induced bone loss in osteomyelitis.
金黄色葡萄球菌（S. aureus）诱导的骨质流失是治疗骨髓炎的重大挑战。我们之前的研究首次证实，粒细胞集落刺激因子（G-CSF）介导了 S. aureus 诱导的骨质流失。然而，其潜在机制尚不清楚。本研究旨在阐明这一点。我们发现，在 S. aureus 感染后，G-CSF 介导了骨髓间充质干细胞（BMSC）衰老，并增加了血清和骨髓中白细胞介素-1β（IL-1β）的浓度。此外，我们证明 G-CSF 促进了鼠骨髓源性中性粒细胞中 IL1b 的表达。值得注意的是，我们确定了在 S. aureus 感染后，IL-1β介导了 BMSC 的衰老。重要的是，IL-1β 中和抗体有效缓解了 S. aureus 感染引起的 BMSC 衰老和骨质流失。在分子机制方面，我们发现 IL-1β 通过 JNK/P53 和 JNK/BCL2 通路诱导 BMSC 衰老。综上所述，G-CSF 通过 JNK/P53 和 JNK/BCL2 通路促进 IL-1β 的产生，从而诱导 BMSC 衰老，导致 S. aureus 诱导的骨质流失。本研究确定了预防和治疗骨髓炎中 S. aureus 诱导的骨质流失的新靶点。
