Liu Hongzhi, Zhou Hang, Fan Yuanhao, Li Jiawei, Guo Ziyu, Xu Qiuchi, Liu Yang, Gao Kun, Ait Lahcine Neima, Zhang Jianing, Zhou Jingjing, Guo Fengjin, Liu Chao
Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.
Guangdong Provincial Key Laboratory of Advanced Biomaterials, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China.
J Bone Miner Res. 2025 Jun 3;40(6):725-737. doi: 10.1093/jbmr/zjae198.
Bone is a mechanosensitive organ, and its regeneration also depends on the ability of bone cells to perceive and react to mechanical stimuli. Macrophages are indispensable for bone formation, regeneration, and maintenance. Depletion of macrophages resulted in poor bone development due to impaired vessel formation and osteogenesis. However, how mechanical stimulation stimulates macrophages during bone regeneration is unclear. As in many cell types, Piezo1 is part of the mechanotransduction in macrophages and modulates macrophage activity. Here, we utilized conditional KO of Piezo1 in LysM+ myeloid cells and in vivo mechanical loading to investigate the mechanoregulation of macrophages and their contribution to bone repair. We found that mechanical loading increased the ratio of CD206+ macrophages, angiogenesis-osteogenesis coupling, and cell proliferation within the defect region, leading to enhanced bone regeneration. However, all the loading-induced upregulations were blunted by the conditional KO of Piezo1 in macrophages. Furthermore, we implanted WT bone marrow-derived macrophages into the defect area in Piezo1 KO mice. WT macrophages rescued mechanosensitive angiogenesis-osteogenesis coupling and promoted bone regeneration in Piezo1 KO mice. Together, our data showed that Piezo1 in macrophages is indispensable for loading-induced bone regeneration by stimulating macrophage polarization into the CD206+ phenotype, thereby facilitating the angiogenesis-osteogenesis coupling, promoting cell proliferation, and finally resulting in enhanced bone regeneration.
骨骼是一种机械敏感器官，其再生也取决于骨细胞感知和响应机械刺激的能力。巨噬细胞对于骨形成、再生和维持不可或缺。巨噬细胞的缺失会导致血管生成和成骨受损，从而致使骨骼发育不良。然而，在骨再生过程中机械刺激如何刺激巨噬细胞尚不清楚。与许多细胞类型一样，Piezo1是巨噬细胞机械转导的一部分，并调节巨噬细胞活性。在此，我们利用Piezo1在LysM+髓系细胞中的条件性敲除以及体内机械加载来研究巨噬细胞的机械调节及其对骨修复的贡献。我们发现，机械加载增加了缺损区域内CD206+巨噬细胞的比例、血管生成-成骨耦合以及细胞增殖，从而促进了骨再生。然而，巨噬细胞中Piezo1的条件性敲除使所有加载诱导的上调作用减弱。此外，我们将野生型骨髓来源的巨噬细胞植入Piezo1敲除小鼠的缺损区域。野生型巨噬细胞挽救了机械敏感的血管生成-成骨耦合，并促进了Piezo1敲除小鼠的骨再生。总之，我们的数据表明，巨噬细胞中的Piezo1通过刺激巨噬细胞极化为CD206+表型，从而促进血管生成-成骨耦合、促进细胞增殖并最终增强骨再生，对于加载诱导的骨再生不可或缺。
