Abstract
In the mammalian skeletal system, osteogenesis and angiogenesis are closely linked by type H vessels during bone regeneration and repair. Our previous studies confirmed the promotion of these processes by copper-containing metal (CCM) in vitro and in vivo. However, whether and how the coupling of angiogenesis and osteogenesis participates in the promotion of bone regeneration by CCM in vivo is unknown. In this study, M2a macrophages but not M2c macrophages were shown to be immunoregulated by CCM. A CCM, 316L−5Cu, was applied to drilling hole injuries of the tibia of C57/6 mice for comparison. We observed advanced formation of cortical bone and type H vessels beneath the new bone in the 316L−5Cu group 14 and 21 days postinjury. Moreover, the recruitment of CD206-positive M2a macrophages, which are regarded as the primary source of platelet-derived growth factor type BB (PDGF-BB), was significantly promoted at the injury site at days 14 and 21. Under the stimulation of CCM, mitochondria-derived reactive oxygen species were also found to be upregulated in CD206hi M2a macrophages in vitro, and this upregulation was correlated with the expression of PDGF-BB. In conclusion, our results indicate that CCM promotes the evolution of callus through the generation of type H vessels during the process of bone repair by upregulating the expression of PDGF-BB derived from M2a macrophages.
Highlights
Bone fracture is an increasingly common medical incident that results from both traumatic injury and disease-related bone fragility
The expression levels of Plateletderived growth factor type BB (PDGF-BB) and CD206 were higher in M2a macrophages stimulated by 316L−5Cu extract (Figure 1A), and CD206 and CD163 were identified in this distinct type of macrophage (Figures 1A,B)
The expression levels of MMP9 and CD163 showed no difference between the 316L and 316L−5Cu groups (Figure 1B), indicating that M2a macrophages predominantly promoted the expression of PDGF-BB under the stimulation of 316L– Cu extract
Summary
Bone fracture is an increasingly common medical incident that results from both traumatic injury and disease-related bone fragility. Plateletderived growth factor type BB (PDGF-BB), which is derived from macrophages, contributes to the generation of type H vessels in the first stages of these processes. It was noted in a recent study that emcnhiCD31hi endothelium was present during endochondral bone formation in the osteotomy gap (Stefanowski et al, 2019). Administration of recombinant SLIT3, which is derived from osteoblasts and promotes formation of type H vessels, effectively accelerated bone fracture healing in a mouse bone fracture model (Xu et al, 2018). It was proposed that fracture healing could be enhanced by promoting type H vessel angiogenesis, providing a potential therapeutic approach, for cases of delayed union or non-union
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