Acid α-Glucosidase Impairs Diabetic Bone Regeneration via Altering Macrophage Polarization

The diabetic microenvironment intensifies M1-type macrophage-mediated inflammation and impairs bone regeneration. Glycophagy-a process of glycogen-selective autophagy that degrades intracellular glycogen into glucose-is essential for maintaining glucose homeostasis under metabolic stress. The role of glycophagy in regulating M1-type polarization remains unclear. In this study, we found that M1-type polarization correlated with increased glycophagy in a diabetic mandibular bone defect model. Proteomic analysis revealed the involvement of the glycophagy mediator acid α-glucosidase (GAA) in M1-type polarization in diabetic bone callus. Mechanistically, the upregulation of GAA drove M1-type polarization to inhibit osteogenesis under high-glucose conditions by activating the mTORC1 signaling pathway. Transplant of GAA-silenced macrophages restored the osteogenic capability in mandibular injury in diabetic rats. In conclusion, our study unravels the regulation of a fundamental mechanism of M1-type polarization by the glycophagy mediator GAA, providing insights relevant for promoting bone generation in diabetic individuals.