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.

中文翻译：

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含铜合金作为免疫调节材料通过线粒体氧化应激进行骨再生

在哺乳动物骨骼系统中，骨生成和血管生成在骨再生和修复过程中通过 H 型血管紧密相连。我们之前的研究证实了含铜金属 (CCM) 在体外和体内促进了这些过程。然而，血管生成和成骨的耦合是否以及如何参与体内 CCM 促进骨再生尚不清楚。在这项研究中，M2a 巨噬细胞而非 M2c 巨噬细胞被证明受 CCM 免疫调节。CCM, 316L−5Cu, 被应用于 C57/6 小鼠胫骨钻孔损伤以进行比较。我们观察到 316L-5Cu 组在损伤后 14 天和 21 天的新骨下方形成了皮质骨和 H 型血管。此外，招募 CD206 阳性 M2a 巨噬细胞，被认为是血小板衍生生长因子 BB (PDGF-BB) 的主要来源，在第 14 天和第 21 天在损伤部位得到显着促进。在 CCM 的刺激下，还发现线粒体衍生的活性氧在体外 CD206hi M2a 巨噬细胞中上调，这种上调与 PDGF-BB 的表达相关。总之，我们的结果表明，在骨修复过程中，CCM 通过上调源自 M2a 巨噬细胞的 PDGF-BB 的表达，通过 H 型血管的生成促进愈伤组织的进化。并且这种上调与PDGF-BB的表达相关。总之，我们的结果表明，在骨修复过程中，CCM 通过上调源自 M2a 巨噬细胞的 PDGF-BB 的表达，通过产生 H 型血管促进愈伤组织的进化。并且这种上调与PDGF-BB的表达相关。总之，我们的结果表明，在骨修复过程中，CCM 通过上调源自 M2a 巨噬细胞的 PDGF-BB 的表达，通过 H 型血管的生成促进愈伤组织的进化。