Echinacoside alleviates glucocorticoid induce osteonecrosis of femoral head in rats through PI3K/AKT/FOXO1 pathway

• Published in: Chemico-biological interactions Vol. 391; p. 110893
• Main Authors: Huang, Liang Kun, Zeng, Xiao Shuang, Jiang, Ze Wen, Peng, Hao, Sun, Fei
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.03.2024
• Subjects: Animals; Apoptosis; Dexamethasone; Dexamethasone - pharmacology; Echinacoside; Femur Head - metabolism; Glucocorticoids - pharmacology; Glycosides - pharmacology; Molecular Docking Simulation; Osteoblast; Osteonecrosis - chemically induced; Osteonecrosis - drug therapy; Phosphatidylinositol 3-Kinases - metabolism; PI3K/AKT/FOXO1; Proto-Oncogene Proteins c-akt - metabolism; Rats; SONFH; Osteoblast; SONFH; Dexamethasone; Echinacoside; PI3K/AKT/FOXO1; Apoptosis
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2024.110893

Steroid-induced osteonecrosis of the femoral head (SONFH), caused by glucocorticoid (GC) administration, is known to exhibit a high incidence worldwide. Although osteoblast apoptosis has been reported as an important cytological basis of SONFH, the precise mechanism remains elusive. Echinacoside (Ech), a natural phenylethanoid glycoside, exerts multiple beneficial effects, such as facilitation of cell proliferation and anti-inflammatory and anticancer activities. Herein, we aimed to explore the regulatory mechanism underlying glucocorticoid-induced osteoblast apoptosis and determine the protective efficacy of Ech against SONFH. We comprehensively surveyed multiple public databases to identify SONFH-related genes. Using bioinformatics analysis, we identified that the PI3K/AKT/FOXO1 signaling pathway was most strongly associated with SONFH. We examined the protective effect of Ech against SONFH using in vivo and in vitro experiments. Specifically, dexamethasone (Dex) decreased p-PI3K and p-AKT levels, which were reversed following Ech addition. Validation of the PI3K inhibitor (LY294002) and molecular docking of Ech and PI3K/AKT further indicated that Ech could directly enhance PI3K/AKT activity to alleviate Dex-induced inhibition. Interestingly, Dex upregulated the expression of FOXO1, Bax, cleaved-caspase-9, and cleaved-caspase-3 and enhanced MC3T3-E1 apoptosis; application of Ech and siRNA-FOXO1 reversed these effects. In vitro, Ech decreased the number of empty osteocytic lacunae, reduced TUNEL and FOXO1 positive cells, and improved bone microarchitecture. Our results provide robust evidence that PI3K/AKT/FOXO1 plays a crucial role in the development of SONFH. Moreover, Ech may be a promising candidate drug for the treatment of SONFH. •Combination of bioinformatics analysis and experiments in vitro and vivo validation.•Molecular docking provides solid evidence to demonstrate the regulatory effects of Echinacoside on PI3K/AKT.•FOXO1 may be a potential therapeutic target to alleviate Dexamethasone-induced osteoblast apoptosis.•Echinacoside may be a promising candidate drug for the treatment of Steroid-induced osteonecrosis of the femoral head.