Macrophages regulate angiogenesis-osteogenesis coupling induced by mechanical loading through the Piezo1 pathway.

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.