Periostin+ macrophages improved long bone regeneration in a mechanosensitive manner

Abstract Macrophages are pivotal in the inflammatory and remodeling phases of fracture repair. Here, we investigate the effect of periostin expressed by macrophages on bone regeneration in a monocortical tibial defect (MTD) model. In this study, we show that periostin is expressed by periosteal macrophages, primarily the M2 subtype during bone regeneration. The deletion of periostin in macrophages reduces cortical bone thickness, disrupts trabecular bone connectivity, exacerbates repair impairment, and hinders M2 macrophage polarization. Mechanical stimulation has been shown to be as a regulator of periostin in macrophages. By activating transforming growth factor-β (TGF-β) and phosphorylating Smad2/3, it increases periostin expression in macrophages and induces M2 polarization. This mechanosensitive effect also reverses the delayed bone repair induced by periostin deficiency in macrophages by strengthening the angiogenesis-osteogenesis coupling. In addition, transplantation of mechanically-conditioned macrophages into the periosteum over a bone defect results in substantially enhanced repair, confirming the critical role of macrophage-secreted periostin in bone repair. In summary, our results suggest one mechanism of mechanically stimulated bone formation is the regulation of periostin expression and M2 subtype polarization in macrophages via the TGF-β/Smad2/3 signaling pathway, and demonstrates mechanically-conditioned macrophages as a promising therapeutic strategy for enhancing bone repair.