###### Abstract  
Glucocorticoids could induce injury and apoptosis of bone microvascular endothelial cells (BMECs) in the femoral head, which is associated with the development of osteonecrosis and osteoporosis. Icarini is a prenylated flavonoid glycoside isolated from Epimedium brevicorum, serving as the main active pharmaceutical constituent to treat bone loss. Currently, the impact of the autocrine activity of extracellular vesicles (EVs) induced by icarini on the glucocorticoid-induced injury of BMECs is still to be confirmed. In this study, EVs were isolated from BMECs treated with and without icarini by super-speed centrifugation. Although icarini treatment would not significantly change the size and total protein content of BMECs-derived EVs, expression of EVs-carried vascular endothelial growth factor (VEGF) and transforming growth factor \(\beta\)1 (TGF-\(\beta\)1) was enhanced and numerous miRNAs involved in cell proliferation and apoptosis were upregulated (e.g., hsa-miR-1469 and hsa-miR-133a-5p) or downregulated (e.g., hsa-miR-10b-5p) (\(p<0.05\)). A total of 29 differentially expressed inflammatory factors were detected between the EVs secreted by BMECs from the Icarini-treated group and the Model group. The EVs secreted by BMECs could improve cell viability, decrease cell apoptosis, and promote cell migration and angiogenesis under the intervention of glucocorticoids. Meanwhile, icarini intervention could reinforce these protective effects of BMECs-derived EVs. To sum up, the present study indicates that icarini acts as a promising candidate for treating glucocorticoid-induced injury of BMECs and bone diseases, partially through the autocrine activity of EVs. In vivo or animal studies are still required to better understand the function of BMECs-derived EVs. bone microvascular endothelial cells; glucocorticoid; icarini; protein array; extracellular vesicles 2022111921.12.12.  
systemic lupus erythematosus, and acute urticaria [1]. Glucocorticids bind to the glucocorticoid receptors (e.g., NR3C1, GR) on the cell surface and then target gene transcription in the nucleus, exerting an important role in physiologic function regulation [2]. Meanwhile, exogenous glucocorticoid administration is the principal atrogenic cause for secondary osteeoporosis and nontraumatic osteeoncrosis of the femoral head (ONFH), which adds a tremendous economic burden to individuals and healthcare systems [1; 2]. In patients with glucocorticoid-induced bone loss, angiogenesis is suppressed, accompanied by circulatory impairment, persistent bone destruction, increased apoptosis of osteocytes, disrupted balance of mesenchymal stem cells' (MSCs) differentiation, fat embolism, and intramedullary pressure changes [3; 4]. In addition to damaging bone tissues, glucocorticoids have shown a toxic effect on bone microvascular networks [5]. The bone microvascular endothelial cells (BMECs) constitute a monolayer structure attached to bony trabecula, contact with ingredients in the blood, and supply oxygen and nutrients to bone tissues [6]. Moreover, vascular endothelial cells possess secretory functions and can interact with bone cells by secreting multiple angiogenic and osteogenic factors (e.g., noggin, vascular endothelial growth factor (VEGF)), which is of great significance in the maintenance of bone mass [3; 4]. Last but not least, bone microvasculature provides a specific microenvironment for the colonization of MSCs and other progenitor cells [6]. By elevating the production of hypoxia-induced factor-1\(\alpha\) (HIF-1\(\alpha\)) and reactive oxidative species (ROS), and downregulating the expression of endothelial nitric oxide synthase (eNOS), glucocorticoid could lead to injury and apoptosis of vascular endothelial cells, including BMECs [5]. Considering that normally functioning bone vessel networks are a precondition for skeletal development and regeneration, BMECs' damage is believed to be a common mechanism for glucocorticoid-induced bone diseases [7].