Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
Department of International Medical, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, China.
Mol Cell Endocrinol. 2022 Mar 15;544:111541. doi: 10.1016/j.mce.2021.111541. Epub 2021 Dec 29.
Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) accounts for a big portion of non-traumatic ONFH; nevertheless, the pathogenesis has not yet been fully understood. GC-induced endothelial dysfunction might be a major contributor to ONFH progression. The Gene Expression Omnibus (GEO) dataset was analyzed to identify deregulated miRNAs in ONFH; among deregulated miRNAs, the physiological functions of miR-122-5p on ONFH and endothelial dysfunction remain unclear. In the present study, miR-122-5p showed to be under-expressed within GC-induced ONFH femoral head tissues and GC-stimulated bone microvascular endothelial cells (BMECs). In human umbilical vein endothelial cells (HUVECs) and BMECs, GC stimulation significantly repressed cell viability, promoted cell apoptosis and increased the mRNA expression of proinflammatory cytokines, such as TNF-α, IL-1β, and IFN-γ. After overexpressing miR-122-5p, GC-induced endothelial injuries were attenuated, as manifested by rescued cell viability, cell migration, and tube formation capacity. Regarding the BMP signaling, GC decreased the protein levels of BMP-2/6/7 and SMAD-1/5/8, whereas miR-122-5p overexpression significantly attenuated the inhibitory effects of GC on these proteins. Online tool and experimental analyses revealed the direct binding between miR-122-5p and GREM2, a specific antagonist of BMP-2. In contrast to miR-122-5p overexpression, GREM2 overexpression aggravated GC-induced endothelial injury; GREM2 silencing partially eliminated the effects of miR-122-5p inhibition on GC-stimulated HUVECs and BMECs. Finally, GREM2 silencing reversed the suppressive effects of GC on BMP-2/6/7 and SMAD-1/5/8, and attenuated the effects of miR-122-5p inhibition on these proteins upon GC stimulation. Conclusively, the present study demonstrates a miR-122-5p/GREM2 axis modulating the GC-induced endothelial damage via the BMP/SMAD signaling. Considering the critical role of endothelial function in ONFH pathogenesis, the in vivo role and clinical application of the miR-122-5p/GREM2 axis is worthy of further investigation.
糖皮质激素（GC）诱导的股骨头坏死（ONFH）占非创伤性 ONFH 的很大一部分；然而，其发病机制尚未完全阐明。GC 诱导的内皮功能障碍可能是 ONFH 进展的主要原因。通过分析基因表达综合数据库（GEO）数据集，确定了 ONFH 中失调的 miRNA；在失调的 miRNA 中，miR-122-5p 对 ONFH 和内皮功能障碍的生理功能仍不清楚。本研究表明，miR-122-5p 在 GC 诱导的 ONFH 股骨头组织和 GC 刺激的骨微血管内皮细胞（BMEC）中表达下调。在人脐静脉内皮细胞（HUVEC）和 BMEC 中，GC 刺激显著抑制细胞活力，促进细胞凋亡，并增加促炎细胞因子 TNF-α、IL-1β 和 IFN-γ 的 mRNA 表达。过表达 miR-122-5p 后，GC 诱导的内皮损伤减轻，表现为细胞活力、细胞迁移和管形成能力得到恢复。关于 BMP 信号通路，GC 降低了 BMP-2/6/7 和 SMAD-1/5/8 的蛋白水平，而过表达 miR-122-5p 则显著减弱了 GC 对这些蛋白的抑制作用。在线工具和实验分析表明，miR-122-5p 与 GREM2 之间存在直接结合，GREM2 是 BMP-2 的特异性拮抗剂。与过表达 miR-122-5p 相反，过表达 GREM2 加重了 GC 诱导的内皮损伤；沉默 GREM2 部分消除了 miR-122-5p 抑制对 GC 刺激的 HUVEC 和 BMEC 的影响。最后，沉默 GREM2 逆转了 GC 对 BMP-2/6/7 和 SMAD-1/5/8 的抑制作用，并减弱了 miR-122-5p 抑制对 GC 刺激后这些蛋白的作用。总之，本研究表明，miR-122-5p/GREM2 轴通过 BMP/SMAD 信号调节 GC 诱导的内皮损伤。鉴于内皮功能在 ONFH 发病机制中的关键作用，miR-122-5p/GREM2 轴的体内作用和临床应用值得进一步研究。
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