FAR591 promotes the pathogenesis and progression of SONFH by regulating Fos expression to mediate the apoptosis of bone microvascular endothelial cells

Fei Zhang; Lei Wei; Lei Wang; Tao Wang; Zhihong Xie; Hong Luo; Fanchao Li; Jian Zhang; Wentao Dong; Gang Liu; Qinglin Kang; Xuesong Zhu; Wuxun Peng

doi:10.1038/s41413-023-00259-8

FAR591 promotes the pathogenesis and progression of SONFH by regulating Fos expression to mediate the apoptosis of bone microvascular endothelial cells

Bone Res. 2023 May 22;11(1):27. doi: 10.1038/s41413-023-00259-8.

Authors

Fei Zhang^{1

2}, Lei Wei³, Lei Wang², Tao Wang², Zhihong Xie², Hong Luo², Fanchao Li², Jian Zhang^{1

2}, Wentao Dong^{1

2}, Gang Liu^{1

2}, Qinglin Kang⁴, Xuesong Zhu⁵, Wuxun Peng^{6

7}

Affiliations

¹ Department of Emergency Orthopedics, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, China.
² School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou, 550004, China.
³ Department of Orthopedics, Rhode Island Hospital, Brown University, Providence, Rhode Island, 02903, USA.
⁴ Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
⁵ Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215000, China.
⁶ Department of Emergency Orthopedics, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, China. 903463644@qq.com.
⁷ School of Clinical Medicine, Guizhou Medical University, Guiyang, Guizhou, 550004, China. 903463644@qq.com.

Abstract

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.

Abstract

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