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Iron overload disrupts bone homeostasis via TfR1-dependent ferroptosis and cGAS/STING-driven pyroptosis in pyogenic
Wenchao Xu1, Qinpeng Xu1, Hongdong Tan2
1Department of Spine Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
Introduction:
Pyogenic spondylitis (PS) accompanies with diverse destruction, especially the subsequent bone destruction, which leads to spine instability and severe neurological disability. However, the mechanism underlying bone loss induced by infection has not been elucidated. In this study, we aimed to reveal a novel mechanism of bone destruction in PS.
Methods:
To certify the involvement of iron overload in PS-induced bone loss, vertebrae samples were collected and evaluated from patients with PS. Next Staphylococcus aureus (S. aureus, ATCC 25923) was used to induce bone infection in vivo and in vitro, and relevant markers were investigated. Then, experiments using siRNA targeting transferrin receptor-1 (TfR1), an iron chelator (DFO), and the TfR1 inhibitor Ferristatin II were conducted to investigate the role of TfR1-induced iron overload and ferroptosis in PS-induced bone destruction.
Results:
Infected vertebral specimens from PS patients showed iron overload and increased TfR1 expression, which was also observed in S. aureus -infected MC3T3-E1 cells. Excessive iron leads to osteoblast ferroptosis and osteogenic activity via iron overload and oxidative stress injury, which was inhibited by TfR1 siRNA or DFO. Meanwhile, iron overload promoted mtDNA leakage and activated the cGAS/STING pathway, contributing to NLRP3-associated pyroptosis and impaired osteogenesis. In addition, S. aureus -induced iron overload in osteoclasts promoted osteoclastogenesis, which was also ameliorated by TfR1 siRNA or DFO. In vivo, Ferristatin II reduced iron deposition, suppressed TfR1 expression, and preserved trabecular architecture in PS rats.
Conclusions:
Our research indicates that S. aureus infection triggers iron overload in infected bone tissue via the promotion of TfR1 expression, finally contributing to osteoblast ferroptosis and bone destruction. Targeting TfR1-mediated iron influx and ferroptosis is a novel therapeutic strategy for the treatment of bone loss induced by PS.
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