IMP2 enhances M2 macrophage polarization via LKB1-AMPK-mediated mitochondrial dynamics and fatty acid β-oxidation to ameliorate diabetic osteoporosis.

A reduction in M2 macrophage polarization is a key pathogenic contributor to diabetic osteoporosis (DOP). In this study, we revealed that IMP2 affects mitochondrial dynamics and fatty acid β-oxidation (FAO) via the LKB1-AMPK pathway, influencing the M2 polarization pattern and thereby improving DOP. Leveraging Cre-loxp technology, we generated macrophage-specific IMP2 knockout mice. Under diabetic settings, IMP2 knockout further disrupted M2 macrophage polarization and intensified bone deterioration. Mechanistically, IMP2 enhances LKB1 mRNA stability through the N6-methyladenosine (m6A) pathway, activating the LKB1-AMPK signaling cascade. This pathway promotes mitochondrial fusion and boosts FAO, fueling M2 macrophage polarization. Enhanced M2 polarization, in turn bolsters the osteogenic differentiation potential of bone marrow mesenchymal stem cells (BMSCs). However, in the diabetic milieu, IMP2’s regulatory role in M2 macrophages is compromised, diminishing the osteogenic support provided by M2 macrophages to BMSCs and exacerbating bone loss.