The specific pathogenesis of steroid-induced osteonecrosis of the femoral head (SONFH) is still not fully understood, and there is currently no effective early cure. Understanding the role and mechanism of long noncoding RNAs (lncRNAs) in the pathogenesis of SONFH will help reveal the pathogenesis of SONFH and provide new targets for its early prevention and treatment. In this study, we first confirmed that glucocorticoid (GC)-induced apoptosis of bone microvascular endothelial cells (BMECs) is a pre-event in the pathogenesis and progression of SONFH. Then, we identified a new lncRNA in BMECs via lncRNA/mRNA microarray, termed Fos-associated lincRNA ENSRNOT00000088059.1 (FAR591). FAR591 is highly expressed during GC-induced BMEC apoptosis and femoral head necrosis. Knockout of FAR591 effectively blocked the GC-induced apoptosis of BMECs, which then alleviated the damage of GCs to the femoral head microcirculation and inhibited the pathogenesis and progression of SONFH. In contrast, overexpression of FAR591 significantly promoted the GC-induced apoptosis of BMECs, which then aggravated the damage of GCs to the femoral head microcirculation and promoted the pathogenesis and progression of SONFH. Mechanistically, GCs activate the glucocorticoid receptor, which translocates to the nucleus and directly acts on the FAR591 gene promoter to induce FAR591 gene overexpression. Subsequently, FAR591 binds to the Fos gene promoter (–245∼–51) to form a stable RNA:DNA triplet structure and then recruits TATA-box binding protein associated factor 15 and RNA polymerase II to promote Fos expression through transcriptional activation. Fos activates the mitochondrial apoptotic pathway by regulating the expression of Bcl-2 interacting mediator of cell death (Bim) and P53 upregulated modulator of apoptosis (Puma) to mediate GC-induced apoptosis of BMECs, which leads to femoral head microcirculation dysfunction and femoral head necrosis. In conclusion, these results confirm the mechanistic link between lncRNAs and the pathogenesis of SONFH, which helps reveal the pathogenesis of SONFH and provides a new target for the early prevention and treatment of SONFH.

激素性股骨头坏死（SONFH）的具体发病机制尚不完全清楚，目前尚无有效的早期治愈方法。了解长链非编码RNA（lncRNA）在SONFH发病中的作用和机制，有助于揭示SONFH的发病机制，为其早期防治提供新的靶点。在这项研究中，我们首先证实糖皮质激素 (GC) 诱导的骨微血管内皮细胞 (BMEC) 凋亡是 SONFH 发病机制和进展的前期事件。然后，我们通过 lncRNA/mRNA 微阵列在 BMEC 中鉴定出一个新的 lncRNA，称为 Fos 相关 lincRNA ENSRNOT00000088059.1 (FAR591)。FAR591 在 GC 诱导的 BMEC 凋亡和股骨头坏死期间高表达。FAR591 的敲除有效地阻断了 GC 诱导的 BMEC 细胞凋亡，从而减轻 GCs 对股骨头微循环的损伤，抑制 SONFH 的发病和进展。相反，FAR591过表达显着促进了GC诱导的BMECs凋亡，进而加重了GCs对股骨头微循环的损伤，促进了SONFH的发生和发展。从机制上讲，GCs 激活糖皮质激素受体，后者易位至细胞核并直接作用于 FAR591 基因启动子以诱导 FAR591 基因过表达。随后，FAR591 结合 Fos 基因启动子 (–245 进而加重 GCs 对股骨头微循环的损伤,促进 SONFH 的发生发展. 从机制上讲，GCs 激活糖皮质激素受体，后者易位至细胞核并直接作用于 FAR591 基因启动子以诱导 FAR591 基因过表达。随后，FAR591 结合 Fos 基因启动子 (–245 进而加重 GCs 对股骨头微循环的损伤,促进 SONFH 的发生发展. 从机制上讲，GCs 激活糖皮质激素受体，后者易位至细胞核并直接作用于 FAR591 基因启动子以诱导 FAR591 基因过表达。随后，FAR591 结合 Fos 基因启动子 (–245∼ –51) 形成稳定的 RNA:DNA 三联体结构，然后募集 TATA-box 结合蛋白相关因子 15 和 RNA 聚合酶 II，通过转录激活促进 Fos 表达。Fos通过调节Bcl-2相互作用细胞死亡介质（Bim）和P53上调细胞凋亡调节剂（Puma）的表达激活线粒体凋亡通路，介导GC诱导的BMECs凋亡，导致股骨头微循环功能障碍和股骨头坏死。总之，这些结果证实了lncRNAs与SONFH发病机制之间的联系，有助于揭示SONFH的发病机制，为SONFH的早期防治提供新的靶点。