TNF- Inhibits FoxO1 by Upregulating miR-705 to Aggravate Oxidative Damage in Bone Marrow-Derived Mesenchymal Stem Cells during Osteoporosis
TNF- Inhibits FoxO1 by Upregulating miR-705 to Aggravate Oxidative Damage in Bone Marrow-Derived Mesenchymal Stem Cells during Osteoporosis
复制标题
TNF-通过上调 miR-705 抑制 FoxO1，加重骨质疏松症期间骨髓间充质干细胞的氧化损伤
DOI：
10.1002/stem.2274
复制
发表时间：
2016-04-01
期刊：
影响因子：
5.2
通讯作者：
Jin, Yan
中科院分区：
文献类型：
--
作者：
Liao, Li;Su, Xiaoxia;Jin, Yan
雌激素缺乏导致骨髓间充质干细胞(BMMSCs)氧化损伤，导致骨质疏松时骨形成缺陷。叉头盒O1(Forkhead Box O1，FoxO1)蛋白在防御骨骼生理性氧化损伤中起着至关重要的作用。但FoxO1是否参与骨质疏松症时的氧化损伤在很大程度上是未知的。在本研究中，我们发现去卵巢小鼠骨髓间充质干细胞中FoxO1蛋白积聚减少。FoxO1的表达减少可抑制超氧化物歧化酶(Sod2)和过氧化氢酶(Cat)的表达，抑制活性氧(ROS)的积累，从而抑制BMMSCs的成骨分化。FoxO1蛋白的下降是由于雌激素缺乏后肿瘤坏死因子-α(TNF-α)积聚所致。机制上，肿瘤坏死因子激活核因子-B途径促进microRNA-705的表达，通过转录后调节发挥抑制FoxO1的作用。抑制NF-B途径或敲除miR-705在很大程度上阻止了FoxO1介导的抗氧化防御能力的下降，改善了骨质疏松BMMSCs的氧化损伤。此外，积累的ROS进一步激活了与肿瘤坏死因子-1结合的核因子-B通路，形成了一个前馈回路，持续抑制FoxO1蛋白在骨髓间充质干细胞中的积聚。综上所述，我们的研究揭示了FoxO1的减少是骨质疏松症的一个重要的病因因素，并揭示了FoxO1受肿瘤坏死因子-α调节的新机制。这些发现表明，在退行性骨骼疾病中，炎症和氧化应激与干细胞功能障碍密切相关。干细胞2016；34：1054-1067
Decline of antioxidant defense after estrogen deficiency leads to oxidative damage in bone marrow-derived mesenchymal stem cells (BMMSCs), resulting a defect of bone formation in osteoporosis. Forkhead box O1 (FoxO1) protein is crucial for defending physiological oxidative damage in bone. But whether FoxO1 is involved in the oxidative damage during osteoporosis is largely unknown. In this study, we found that FoxO1 protein accumulation was decreased in BMMSCs of ovariectomized mice. The decrease of FoxO1 resulted in the suppression of manganese superoxide dismutase (Sod2) and catalase (Cat) expression and accumulation of reactive oxygen species (ROS), inhibiting the osteogenic differentiation of BMMSCs. The decline of FoxO1 protein was caused by tumor necrosis factor-alpha (TNF-) accumulated after estrogen deficiency. Mechanistically, TNF- activated NF-B pathway to promote microRNA-705 expression, which function as a repressor of FoxO1 through post-transcriptional regulation. Inhibition of NF-B pathway or knockdown of miR-705 largely prevented the decline of FoxO1-mediated antioxidant defense caused by TNF- and ameliorated the oxidative damage in osteoporotic BMMSCs. Moreover, the accumulated ROS further activated NF-B pathway with TNF-, which formed a feed-forward loop to persistently inhibiting FoxO1 protein accumulation in BMMSCs. In conclusion, our study revealed that the decline of FoxO1 is an important etiology factor of osteoporosis and unclosed a novel mechanism of FoxO1 regulation by TNF-. These findings suggested a close correlation between inflammation and oxidative stress in stem cell dysfunction during degenerative bone diseases. Stem Cells2016;34:1054-1067