ABSTRACT Inflammatory osteolysis is frequently associated with excessive osteoclast (OC) activation triggered by bacterial components such as lipopolysaccharide (LPS), accompanied by bone destruction and resorption. Receptor activator of nuclear factor κB ligand (RANKL) is a pivotal cytokine primarily secreted by osteoblasts, bone marrow stromal cells, and activated T lymphocytes. Wogonoside (WG), a flavonoid extracted from the root of Scutellaria baicalensis , possesses anti‐inflammatory properties; however, its role in inflammatory osteolysis remains unclear. The aim of this study was to investigate the regulatory mechanism of WG in RANKL‐ and LPS‐mediated OC differentiation and its effects on a mouse model of inflammatory osteolysis. Tartrate‐resistant acid phosphatase (TRAP) staining and bone resorption assays were used to evaluate the impact of WG on OC differentiation and function. Intracellular reactive oxygen species (ROS), Fe 2+ , and lipid peroxidation levels during OC differentiation were measured using 2′,7′‐dichlorodihydrofluorescein diacetate (H2DCFDA), FerroOrange, and BODIPY 581/591 C11 fluorescent probes, respectively. The effects of WG on OC differentiation‐related genes and downstream proteins and signaling pathways were examined by qPCR and Western blotting. In an LPS‐induced inflammatory osteolysis model, micro‐CT and histological staining (TRAP and HE) were employed to assess bone mass. Enzyme‐linked immunosorbent (ELISA) and immunohistochemistry were applied to detect inflammatory cytokines in serum and the expression of antioxidant and inflammatory factors in bone tissue. Mechanistically, WG activated nuclear factor erythroid‐2 related factor 2 (Nrf2) and its downstream SLC40A1, suppressed ROS‐related iron metabolism dysregulation, and inhibited the mitogen‐activated protein kinase (MAPK) signaling pathway and nuclear factor of activated T cells 1 (NFATc1), ultimately attenuating osteoclastogenesis. In vivo, WG ameliorated LPS‐mediated inflammatory osteolysis. Thus, WG may represent a novel candidate drug for the treatment of OC‐related inflammatory osteolytic diseases.
Zhang et al. (2026) studied this question.