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Peer-reviewedCC BYAdvanced science (Weinheim, Baden-Wurttemberg, Germany)

Thioredoxin-2 Alleviates Osteoporosis by Restraining FOXO3a Nuclear Translocation.

  • Chi Zhan1,2
  • Zhaocai Zhou2
  • Yue Ding1
  • Rong Lian1
  • Xinyu Li1
  • Xintong Zhang2
  • Jie Cao1
  • Zhonghui Tang3
  • Zhengmei Lin2
  • Zhi Song2
  • Feng He1
  1. 1School of Medicine, Guangzhou First People's Hospital, The Second Affiliated Hospital, South China University of Technology, Guangzhou, China.
  2. 2Guangdong Provincial Key Laboratory of Stomatology, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.
  3. 3Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{zhan2026thioredoxin2,
  title = {{Thioredoxin-2 Alleviates Osteoporosis by Restraining FOXO3a Nuclear Translocation.}},
  author = {Chi Zhan and Zhaocai Zhou and Yue Ding and Rong Lian and Xinyu Li and Xintong Zhang and Jie Cao and Zhonghui Tang and Zhengmei Lin and Zhi Song and Feng He},
  journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78304},
  url = {https://europepmc.org/article/MED/42893445},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Thioredoxin-2 Alleviates Osteoporosis by Restraining FOXO3a Nuclear Translocation.
AU  - Chi Zhan
AU  - Zhaocai Zhou
AU  - Yue Ding
AU  - Rong Lian
AU  - Xinyu Li
AU  - Xintong Zhang
AU  - Jie Cao
AU  - Zhonghui Tang
AU  - Zhengmei Lin
AU  - Zhi Song
AU  - Feng He
PY  - 2026
DA  - 2026/10/18
JO  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO  - 10.1002/advs.78304
UR  - https://europepmc.org/article/MED/42893445
AB  - 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.
SN  - 2198-3844
ER  -