Ginsenoside Rh2 alleviates osteoporosis by attenuating oxidative stress-induced osteoblast dysfunction via the FoxO1/β-catenin pathway

The degree of oxidative stress decreases osteoblast function with age, which leads to a decline in bone compressive capacity. Ginsenoside Rh2 is a known clinical or adjuvant therapy for various tissues. This study investigates the pharmacological effects of Rh2 against oxidative stress-induced osteoblasts. Osteoblasts were pretreated with Rh2 for 48 h and then exposed to hydrogen peroxide (H2O2), which results in significantly decreased ROS levels, increased antioxidant enzyme activity, and enhanced mitochondrial function. Functionally, Rh2 increases alkaline phosphatase (ALP) expression, together with enhanced mineralization and expression of osteogenesis-associated genes. Rh2 also promotes the nuclear translocation of FoxO1 and β-catenin, whereas it does not reverse reduced mineralization caused by decreased FoxO1 or β-catenin activity, indicating that its effect is mediated through the functional interaction between FoxO1 and β-catenin. In a mouse model of lipopolysaccharide (LPS)-induced bone loss, Rh2 administration improves trabecular microstructure, increases osteoblast numbers, and up-regulates serum metabolites associated with bone formation. Immunofluorescence analysis further reveals that Rh2 promotes the nuclear co‑localization of FoxO1 and β‑catenin in femurs, indicating their coordinated action within this signaling axis. These findings indicate that Rh2 mitigates oxidative stress-induced osteoblast dysfunction via the FoxO1/β-catenin pathway, highlighting the pivotal role of redox balance in bone remodeling and suggesting a promising therapeutic strategy for osteoporosis.