Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Orthopaedics & Traumatology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China.
Cell Prolif. 2023 Nov;56(11):e13485. doi: 10.1111/cpr.13485. Epub 2023 Apr 26.
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.
我们研究了黄芪甲苷（AS-IV）在预防糖皮质激素诱导的股骨头坏死（ANFH）中的作用及其潜在的分子机制。采用网络药理学预测 AS-IV 的分子靶点。进行分子动力学模拟以探讨 AS-IV 与 Akt 之间的结合机制和相互作用模式。建立了糖皮质激素诱导的 ANFH 大鼠模型，并在使用 LY294002 阻断 PI3K/Akt 通路前后评估成骨、血管生成、凋亡和氧化应激情况。检测了糖皮质激素和 AS-IV 对骨髓间充质干细胞和人脐静脉内皮细胞的影响，这些细胞在有无 LY294002 存在的情况下进行孵育。在糖皮质激素诱导的 ANFH 患者和大鼠的股骨头中可检测到下调的 p-Akt 表达。AS-IV 增加了模型大鼠股骨头的小梁骨完整性和血管密度。AS-IV 增加了 Akt 磷酸化并上调了成骨、血管生成、凋亡和氧化应激相关蛋白和 mRNA，并下调了 Bax、cleaved caspase-3 和细胞色素 c 水平。AS-IV 促进了人脐静脉内皮细胞在糖皮质激素影响下的迁移、增殖和管腔形成能力；骨髓间充质干细胞的增殖；以及成骨分化。AS-IV 抑制了细胞凋亡。LY294002 抑制了这些作用。AS-IV 通过促进 Akt/Runx2 和 Akt/HIF-1α/VEGF 通路分别促进成骨和血管生成，通过 Akt/Bad/Bcl-2 和 Akt/Nrf2/HO-1 通路分别抑制凋亡和氧化应激，从而预防糖皮质激素诱导的 ANFH。
