Fig. 7.

Working model of ADM2 restoration of AGE-induced imbalanced macrophage polarization and impaired osteogenesis. Under pathological diabetic conditions, AGEs interact with RAGE in macrophages and BMSCs, activating AGE-RAGE signaling. In macrophages, PPARγ is downregulated, leading to inhibition of IκBα and activation and nuclear translocation of p65, which plays a vital role in the M1 polarization of macrophages. The inflammatory cytokines secreted by M1 macrophages would lead to an inflammatory microenvironment, thus indirectly impairing the osteogenic differentiation of BMSCs. Besides, the activation of AGE-RAGE signaling in BMSCs could directly impair the osteogenic potential of BMSCs. Finally, reduced osteogenesis of BMSCs causes impaired bone regeneration in T1DM. ADM2 reverses AGE-induced M1 polarization of macrophages to M2 phenotype, which contributes to the regenerative microenvironment, by activating PPARγ, and attenuates AGE-impaired osteogenic potential of BMSCs simultaneously, thus accelerating diabetic bone regeneration during DO