The Immunomodulatory Role of BMP-2 on Macrophages to Accelerate Osteogenesis

Bone morphogenetic protein-2 (BMP-2) is one of the most frequently used osteogenic factors for osteogenesis. Macrophages, acting as both immune cells and osteoclast precursors, have an indispensable functional input during multiple stages of bone healing. This study aims to investigate the immunoregulatory role of BMP-2 on macrophages and the subsequent effects on osteogenesis. In the subcutaneous implantation study, gelatin sponge incorporated with 20 μg/mL BMP-2 rendered significantly enhanced macrophage infiltration compared with the gelatin sponge control. Further in vitro study using murine macrophage cell line has shown that BMP-2 could function as a potent attractant for macrophage recruitment. The supplementation of BMP-2 dramatically diminished the expression of M1 phenotypic markers, including interleukin (IL)-1β, IL-6, and iNOS in M1 polarized macrophages, indicating a positive immunoregulatory role of BMP-2 under inflammatory status. In addition, BMP-2 alone could robustly activate macrophages through pSmad1/5/8 signaling pathway and generate a positive feedback loop by increasing the expression of angiogenic factors. Conditioned medium collected from BMP2-stimulated macrophages accelerated the osteogenic differentiation of bone marrow stromal cells. Our finding suggests that BMP-2-induced osteogenesis may also involve the regulation of the local osteoimmune environment. The positive effect of BMP-2 on regulating immune response makes it possible to utilize the immunomodulatory properties of BMP-2 to manipulate the osteoimmune environment for favorable bone regeneration.