Thioredoxin‐2 Alleviates Osteoporosis by Restraining FOXO3a Nuclear Translocation

Osteoporosis is a prevalent age- and disease-associated skeletal disorder characterized by bone loss, remodeling imbalance, and vascular niche deterioration, yet how endothelial redox dysfunction drives this process remains unclear. Here, we identify mitochondrial thioredoxin-2 (TRX2) as an endothelial safeguard against osteoporotic bone loss. TRX2 was markedly reduced in aging bone vascular endothelial cells, and endothelial Trx2 deficiency accelerated skeletal degeneration by suppressing osteogenic activity and enhancing osteoclastogenesis. Mechanistically, TRX2 directly bound FOXO3a through a redox-sensitive Cys90-Cys31 disulfide interaction, retaining FOXO3a at the mitochondrial outer membrane and limiting its nuclear translocation. TRX2 loss or oxidative stress disrupted this complex, enabling FOXO3a-dependent transcriptional activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and generating a pro-osteoclastogenic vascular niche. TRAIL neutralization or endothelial TRX2 restoration attenuated ovariectomy-induced osteoporosis by preserving angiogenic-osteogenic coupling. These findings establish the endothelial TRX2-FOXO3a-TRAIL axis as a vascular redox checkpoint and potential therapeutic target for osteoporosis.