Mangiferin reverses high glucose-induced osteoblast damage and ameliorates osteoporosis by targeting SOX9

Osteoporosis (OP), a systemic metabolic bone disease, severely threatens middle-aged and elderly populations. Diabetic osteoporosis (DOP) presents exacerbated challenges due to high-glucose (HG)-induced osteoblast dysfunction.

To investigate protective effects of mangiferin on HG-induced osteoblast damage and elucidate its anti-OP mechanisms via SOX9 targeting.

In vitro: HG-damaged MC3T3-E1 osteoblasts treated with mangiferin (5-80 μM) were assessed for proliferation (CCK-8), oxidative stress (ROS/SOD/MDA), osteogenic differentiation (ALP/ARS), and signaling via network pharmacology/proteomics. Mechanistic validation: SOX9 siRNA knockdown and PI3K inhibition (LY294002). In vivo: Dexamethasone-induced OP mice administered mangiferin (100 mg/kg) were evaluated via Micro-CT, histology (HE), serum biomarkers (CTX-1/PINP), and molecular profiling (WB/RT-qPCR).

Mangiferin significantly increases bone density and improves bone morphology in OP mice. Specifically, it enhances the expression of p-AKT, p-FOXO1, and SOX9 in osteoblasts. This effect is attenuated by the PI3K inhibitor LY294002 but potentiated by the AKT agonist SC79. SOX9 knockdown suppressed osteogenic genes, and mangiferin rescued this suppression, revealing SOX9 as a key downstream target of the PI3K/AKT/FOXO1 pathway in osteoblasts.

This study is the first to demonstrate that mangiferin activates the PI3K/AKT/FOXO1/SOX9 axis to reverse HG-induced osteoblast damage, providing a novel multi-target treatment strategy for DOP.