TNF- Inhibits FoxO1 by Upregulating miR-705 to Aggravate Oxidative Damage in Bone Marrow-Derived Mesenchymal Stem Cells during Osteoporosis

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