Yaran Zang

Background: The immune response is essential for bone regeneration, and macrophages in the immune microenvironment contribute to bone metabolism and angiogenesis. Emerging evidence demonstrates that simvastatin is a promising candidate for bone repair and promotes bone formation both in vitro and in vivo. However, the effect of simvastatin on macrophages and the following outcomes are still unclear. Objectives: This study aimed to investigate the potential immunomodulatory effect of simvastatin on M1 macrophages and its subsequent impact on osteogenesis and angiogenesis. Methods: Cell viability was assessed by CCK-8. Osteogenic and angiogenic markers were evaluated by RT-qPCR, Western blotting, and immunofluorescence. M1 macrophage phenotype was analyzed by flow cytometry. Osteogenesis was examined by histological staining, and angiogenic capacity was assessed using functional assays. Results: The present study found that simvastatin decreased M1 macrophage markers (CD86) and stimulated M1 macrophages to express high levels of pro-regenerative cytokines (BMP-2 and VEGF). In addition, simvastatin promoted osteogenic differentiation in MC3T3-E1 cells and angiogenic gene expression in HUVECs. Importantly, simvastatin enhanced the osteogenic capacity of MC3T3-E1 and the angiogenic potential of HUVECs by inhibiting M1 macrophage polarization in vitro. Conclusions: We demonstrated that simvastatin could confer favorable bone immunomodulatory properties and influence the crosstalk behavior between immune cells and osteoblasts and vascular endothelial cells to promote bone healing.

The development of osteogenic biomaterials relies on updates in research methodologies. Establishing reasonable modes is the basis for obtaining reliable experimental conclusions. With the advancement in bone immunology, osteoimmunomodulatory properties have become one of the crucial indexes for evaluating osteogenic biomaterials. Summarizing the current models of bone immunomodulation is beneficial for optimizing experimental protocols and promoting the clinical application of osteogenic biomaterials. In this review, we introduced the crosstalk between the skeletal system and the immune system, in particular, the roles of different immune cells in the process of bone regeneration. Moreover, the mechanisms of osteogenic biomaterials in regulating the osteoimmune microenvironment were analyzed, followed by summarizing the benefits and limitations of current osteoimmunomodulation models in evaluating osteogenic biomaterials. Finally, we discussed the expected future directions of the applications of osteoimmunomodulation models.