Zhang Fei, Wei Lei, Wang Lei, Wang Tao, Xie Zhihong, Luo Hong, Li Fanchao, Zhang Jian, Dong Wentao, Liu Gang, Kang Qinglin, Zhu Xuesong, Peng Wuxun
Department of Emergency Orthopedics, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, China.
School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou, 550004, China.
Bone Res. 2023 May 22;11(1):27. doi: 10.1038/s41413-023-00259-8.
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.
糖皮质激素诱导的股骨头坏死（SONFH）的具体发病机制仍未完全明确，目前尚无有效的早期治愈方法。了解长链非编码RNA（lncRNAs）在SONFH发病机制中的作用和机制，将有助于揭示SONFH的发病机制，并为其早期预防和治疗提供新的靶点。在本研究中，我们首先证实糖皮质激素（GC）诱导的骨微血管内皮细胞（BMECs）凋亡是SONFH发病机制和进展中的一个前期事件。然后，我们通过lncRNA/mRNA微阵列在BMECs中鉴定出一种新的lncRNA，称为Fos相关长链非编码RNA ENSRNOT00000088059.1（FAR591）。FAR591在GC诱导的BMEC凋亡和股骨头坏死过程中高表达。敲除FAR591可有效阻断GC诱导的BMEC凋亡，进而减轻GC对股骨头微循环的损伤，抑制SONFH的发病机制和进展。相反，FAR591的过表达显著促进GC诱导的BMEC凋亡，进而加重GC对股骨头微循环的损伤，促进SONFH的发病机制和进展。机制上，GC激活糖皮质激素受体，该受体易位至细胞核并直接作用于FAR591基因启动子，诱导FAR591基因过表达。随后，FAR591与Fos基因启动子（-245∼-51）结合形成稳定的RNA:DNA三联体结构，然后招募TATA盒结合蛋白相关因子15和RNA聚合酶II，通过转录激活促进Fos表达。Fos通过调节细胞死亡的Bcl-2相互作用介质（Bim）和p53上调凋亡调节因子（Puma）的表达来激活线粒体凋亡途径从而介导GC诱导的BMEC凋亡，进而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发病机制之间的机制联系，有助于揭示SONFH的发病机制，并为SONFH的早期预防和治疗提供了新的靶点。
