Glucocorticoid (GC)-associated osteonecrosis of the femoral head (ONFH) is the most common in non-traumatic ONFH. Despite a strong relationship between GC and ONFH, the detailed mechanisms have remained elusive. Recent studies have shown that GC could directly injure the blood vessels and reduce blood supply in the femoral head. Endothelial progenitor cells (EPCs), which were inhibited quantitatively and functionally during ONFH, play an important role in maintaining the normal structure and function of vascular endothelium. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that promotes cell apoptosis, and its expression was found to be elevated in GC-associated ONFH patients. However, whether direct inhibition of PTEN attenuates GC-associated apoptosis and dysfunction of the EPCs remains largely unknown. We investigated the effect of, VO-OHpic, a potent inhibitor of PTEN, in attenuating GC-associated apoptosis and dysfunction of EPCs and the molecular mechanism. SD rats were used to study the effect of VO-OHpic on angiogenesis and osteonecrosis in vivo. The results revealed that methylprednisolone (MPS) obviously inhibit angiogenesis of EPCs by inducing apoptosis, destroying the normal mitochondrial structure, and disrupting function of mitochondria. VO-OHpic treatment is able to reverse the harmful effects by inhibiting the mitochondrial apoptosis pathway and activating the NF-E2-related factor 2 (Nrf2) signaling. Si-Nrf2 transfection significantly reduced the protective effects of VO-OHpic on EPCs. Our in vivo studies also showed that intraperitoneal injection of VO-OHpic obviously attenuates the osteonecrosis of the femoral head induced by MPS and potently increases the blood supply in the femoral head. Taken together, the data suggests that inhibition of PTEN with VO-OHpic attenuates apoptosis and promotes angiogenesis of EPCs in vitro via activating Nrf2 signaling pathway and inhibiting the mitochondrial apoptosis pathway. Moreover, VO-OHpic also mitigates GC-associated ONFH and potentiates angiogenesis in the femoral head.

中文翻译：

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PTEN 抑制剂 VO-OHpic 通过激活 Nrf2 信号通路和抑制线粒体凋亡通路来减轻 GC 相关的内皮祖细胞功能障碍和股骨头坏死。

糖皮质激素 (GC) 相关的股骨头坏死 (ONFH) 在非创伤性 ONFH 中最常见。尽管 GC 和 ONFH 之间有很强的关系，但详细的机制仍然难以捉摸。最近的研究表明，GC可以直接损伤血管，减少股骨头的血液供应。内皮祖细胞 (EPCs) 在 ONFH 过程中受到定量和功能抑制，在维持血管内皮的正常结构和功能方面发挥着重要作用。磷酸酶和张力蛋白同源物 (PTEN) 是一种促进细胞凋亡的抑癌基因，发现其在 GC 相关 ONFH 患者中的表达升高。然而，直接抑制 PTEN 是否会减轻 GC 相关的细胞凋亡和 EPC 的功能障碍仍然很大程度上未知。我们研究了 PTEN 的强效抑制剂 VO-OHpic 在减轻 GC 相关的细胞凋亡和 EPC 功能障碍中的作用及其分子机制。SD大鼠用于研究VO-OHpic对体内血管生成和骨坏死的影响。结果表明，甲基强的松龙（MPS）通过诱导细胞凋亡、破坏线粒体正常结构、破坏线粒体功能，明显抑制EPCs的血管生成。VO-OHpic 治疗能够通过抑制线粒体凋亡途径和激活 NF-E2 相关因子 2 (Nrf2) 信号传导来逆转有害影响。Si-Nrf2转染显着降低了VO-OHpic对EPCs的保护作用。我们的体内研究还表明，腹腔注射 VO-OHpic 可明显减轻 MPS 引起的股骨头坏死，并有效增加股骨头的血液供应。总之，数据表明，VO-OHpic 抑制 PTEN 通过激活 Nrf2 信号通路和抑制线粒体凋亡通路在体外减弱 EPCs 的细胞凋亡并促进血管生成。此外，VO-OHpic 还可以减轻 GC 相关的 ONFH 并增强股骨头的血管生成。