Institute of Sports Medicine, College of Sports Medicine and Rehabilitation, Shandong First Medical University & Shandong Academy Medical Sciences, 619 Changcheng Road, Taian, 271016, Shandong, People's Republic of China.
Medical School of Nanjing University, Nanjing University, Nanjing, 210093, Jiangsu, People's Republic of China.
Sci Rep. 2024 Jul 15;14(1):16270. doi: 10.1038/s41598-024-66799-z.
Steroid-induced osteonecrosis of the femoral head (SONFH) is the predominant cause of non-traumatic osteonecrosis of the femoral head (ONFH). Impaired blood supply and reduced osteogenic activity of the femoral head are the key pathogenic mechanisms of SONFH. Fibroblast growth factor 23 (FGF23) levels are not only a biomarker for early vascular lesions caused by abnormal mineral metabolism, but can also act directly on the peripheral vascular system, leading to vascular pathology. The aim of this study was to observe the role of FGF23 on bone microarchitecture and vascular endothelium, and to investigate activation of pyroptosis in SONFH. Lipopolysaccharide (LPS) combined with methylprednisolone (MPS) was applied for SONFH mouse models, and adenovirus was used to increase or decrease the level of FGF23. Micro-CT and histopathological staining were used to observe the structure of the femoral head, and immunohistochemical staining was used to observe the vascular density. The cells were further cultured in vitro and placed in a hypoxic environment for 12 h to simulate the microenvironment of vascular injury during SONFH. The effect of FGF23 on osteogenic differentiation was evaluated using alkaline phosphatase staining, alizarin red S staining and expression of bone formation-related proteins. Matrigel tube formation assay in vitro and immunofluorescence were used to detect the ability of FGF23 to affect endothelial cell angiogenesis. Steroids activated the pyroptosis signaling pathway, promoted the secretion of inflammatory factors in SONFH models, led to vascular endothelial dysfunction and damaged the femoral head structure. In addition, FGF23 inhibited the HUVECs angiogenesis and BMSCs osteogenic differentiation. FGF23 silencing attenuated steroid-induced osteonecrosis of the femoral head by inhibiting the pyroptosis signaling pathway, and promoting osteogenic differentiation of BMSCs and angiogenesis of HUVECs in vitro.
激素诱导性股骨头坏死（SONFH）是股骨头非创伤性坏死（ONFH）的主要原因。股骨头血供受损和成骨活性降低是 SONFH 的关键发病机制。成纤维细胞生长因子 23（FGF23）水平不仅是异常矿物质代谢引起的早期血管病变的生物标志物，而且可以直接作用于外周血管系统，导致血管病理学改变。本研究旨在观察 FGF23 对骨微结构和血管内皮的作用，并研究 SONFH 中细胞焦亡的激活。采用脂多糖（LPS）联合甲泼尼龙（MPS）建立 SONFH 小鼠模型，应用腺病毒增加或减少 FGF23 水平。采用 micro-CT 和组织病理学染色观察股骨头结构，免疫组织化学染色观察血管密度。进一步在体外培养细胞，并置于缺氧环境中 12 h，模拟 SONFH 期间血管损伤的微环境。采用碱性磷酸酶染色、茜素红 S 染色和骨形成相关蛋白表达评估 FGF23 对成骨分化的影响。体外进行 Matrigel 管形成实验和免疫荧光实验，检测 FGF23 影响内皮细胞血管生成的能力。激素激活了 SONFH 模型中的细胞焦亡信号通路，促进了炎症因子的分泌，导致了血管内皮功能障碍和股骨头结构损伤。此外，FGF23 抑制了 HUVECs 的血管生成和 BMSCs 的成骨分化。沉默 FGF23 通过抑制细胞焦亡信号通路，促进了体外 BMSCs 的成骨分化和 HUVECs 的血管生成，从而减轻了激素诱导的股骨头坏死。
