PTEN inhibitor VO-OHpic attenuates GC-associated endothelial progenitor cell dysfunction and osteonecrosis of the femoral head via activating Nrf2 signaling and inhibiting mitochondrial apoptosis pathway
单位：[1]Department of Orthopedics,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,Hubei,China华中科技大学同济医学院附属同济医院外科学系骨科[2]Department of Oncology,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Hubei,China.华中科技大学同济医学院附属同济医院肿瘤科[3]Department of Orthopedics, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China.
Background 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. Methods 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. Results 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. Conclusion 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.
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81702155, 81874020]
基金编号：81702155 81874020
语种：
外文
被引次数：
WOS：
PubmedID：
中科院(CAS)分区：
出版当年[2019]版：
大类|2 区医学
小类|2 区医学：研究与实验3 区细胞生物学
最新[2025]版：
大类|2 区医学
小类|2 区细胞与组织工程2 区细胞生物学2 区医学：研究与实验
JCR分区：
出版当年[2018]版：
Q1MEDICINE, RESEARCH & EXPERIMENTALQ2CELL BIOLOGY
最新[2024]版：
Q1CELL & TISSUE ENGINEERINGQ1CELL BIOLOGYQ1MEDICINE, RESEARCH & EXPERIMENTAL
第一作者单位：[1]Department of Orthopedics,Tongji Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430030,Hubei,China
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推荐引用方式(GB/T 7714)：
yao xudong,yu shengnan,jing xingzhi,et al.PTEN inhibitor VO-OHpic attenuates GC-associated endothelial progenitor cell dysfunction and osteonecrosis of the femoral head via activating Nrf2 signaling and inhibiting mitochondrial apoptosis pathway[J].STEM CELL RESEARCH & THERAPY.2020,11(1):doi:10.1186/s13287-020-01658-y.
APA：
yao,xudong,yu,shengnan,jing,xingzhi,guo,jiachao,sun,kai...&ye,yaping.(2020).PTEN inhibitor VO-OHpic attenuates GC-associated endothelial progenitor cell dysfunction and osteonecrosis of the femoral head via activating Nrf2 signaling and inhibiting mitochondrial apoptosis pathway.STEM CELL RESEARCH & THERAPY,11,(1)
MLA：
yao,xudong,et al."PTEN inhibitor VO-OHpic attenuates GC-associated endothelial progenitor cell dysfunction and osteonecrosis of the femoral head via activating Nrf2 signaling and inhibiting mitochondrial apoptosis pathway".STEM CELL RESEARCH & THERAPY 11..1(2020)
医学