Notch/NICD/RBP-J Signaling Axis Regulates M1 Polarization of Macrophages Mediated by Advanced Glycation End Products

Abstract Advanced glycation end products (AGEs) aggregation and macrophages polarization both play essential roles in degenerative bone diseases caused by aging or diabetes, such as senile or diabetic osteoporosis. Here, we aimed to understand the involvement and potential mechanism of AGEs in macrophages polarization and osteoclastogenesis. We found that RAW264.7 macrophages treated with AGEs highly expressed M1-associated genes and surface antigen markers CD86, and released a large amount of NO to the extracellular environment. Through the detection of osteoclast-related markers and TRAP staining, we revealed that the osteoclastogenesis of M1 macrophages could be markedly enhanced by AGEs. To explore the potential mechanisms of AGEs-mediated M1 polarization, we first demonstrated that AGEs effectively activated the transduction of Notch signaling pathway, including nuclear translocation of NICD1. Subsequently, it was observed that the M1 polarization effects induced by AGEs were significantly mitigated, when γ-secretase inhibitor DAPT and siRNA targeting silencing RBP-J were applied to block the signal transduction of Notch. In conclusion, our findings revealed a series of phenomena that AGEs induce macrophage M1 polarization and enhance its osteoclastogenesis ability, and Notch/NICD/RBP-J signaling axis is involved in the regulation of this polarization process.