Effects of astragaloside IV on glucocorticoid‐induced avascular necrosis of the femoral head via regulating Akt‐related pathways

We investigated the role of astragaloside IV (AS‐IV) in preventing glucocorticoid‐induced avascular necrosis of the femoral head (ANFH) and the underlying molecular mechanisms. Network pharmacology was used to predict the molecular targets of AS‐IV. Molecular dynamic simulations were performed to explore the binding mechanism and interaction mode between AS‐IV and Akt. Rat models of glucocorticoid‐induced ANFH with AS‐IV intervention were established, and osteogenesis, angiogenesis, apoptosis and oxidative stress were evaluated before and after blocking the PI3K/Akt pathway with LY294002. The effects of glucocorticoid and AS‐IV on bone marrow mesenchymal stem cells and human umbilical vein endothelial cells incubated with and without LY294002 were determined. Downregulated p‐Akt expression could be detected in the femoral heads of glucocorticoid‐induced ANFH patients and rats. AS‐IV increased trabecular bone integrity and vessel density of the femoral head in the model rats. AS‐IV increased Akt phosphorylation and upregulated osteogenesis‐, angiogenesis‐, apoptosis‐ and oxidative stress‐related proteins and mRNA and downregulated Bax, cleaved caspase‐3 and cytochrome c levels. AS‐IV promoted human umbilical vein endothelial cell migration, proliferation and tube formation ability; bone marrow mesenchymal stem cell proliferation; and osteogenic differentiation under glucocorticoid influence. AS‐IV inhibited apoptosis. LY294002 inhibited these effects. AS‐IV prevented glucocorticoid‐induced ANFH by promoting osteogenesis and angiogenesis via the Akt/Runx2 and Akt/HIF‐1α/VEGF pathways, respectively, and suppressing apoptosis and oxidative stress via the Akt/Bad/Bcl‐2 and Akt/Nrf2/HO‐1 pathways, respectively.