Iron overload promotes intervertebral disc degeneration via inducing oxidative stress and ferroptosis in endplate chondrocytes.
Iron overload promotes intervertebral disc degeneration via inducing oxidative stress and ferroptosis in endplate chondrocytes.
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DOI：
10.1016/j.freeradbiomed.2022.08.018
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发表时间：
2022-08
影响因子：
7.4
通讯作者：
Wenchao Wang;Xingzhi Jing;Ting Du;Jiabin Ren;Xiaoyang Liu;Feifei Chen;Yuandong Shao;Shengyao Sun;Guihe Yang;Xingang Cui
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文献类型：
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作者：
Wenchao Wang;Xingzhi Jing;Ting Du;Jiabin Ren;Xiaoyang Liu;Feifei Chen;Yuandong Shao;Shengyao Sun;Guihe Yang;Xingang Cui
铁超负荷是老年人群中的常见现象。许多临床研究表明，铁超载与椎间盘退变（IVDD）的发病率和病理进展之间存在相关性。然而，铁参与IVDD进展的作用和潜在机制尚未报道。本研究旨在阐明铁超载与IVDD之间的关系，并探讨疾病的潜在机制。首先，进行了临床流行病学研究，发现铁过载是人类IVDD的独立危险因素。为了阐明铁超载在IVDD中的作用，我们建立了铁超载小鼠模型，观察到铁超载以剂量依赖的方式促进IVDD和软骨终板退变。进一步分离终板软骨细胞，用FAC处理以模拟体外铁过载。过量的铁显着促进终板软骨细胞的矿化，除了他们的退化通过氧化应激。此外，高剂量的过量铁促进软骨细胞铁凋亡。铁螯合剂（DFO）、抗氧化剂（NAC）和铁凋亡抑制剂（Fer-1）可有效抑制铁超载诱导的终板软骨细胞退变，体内实验进一步证实DFO、NAC和Fer-1可挽救高剂量铁诱导的IVDD和软骨终板钙化。总之，我们的研究结果表明铁超载通过氧化应激和铁凋亡与IVDD的发生和发展密切相关。因此，抑制氧化应激或铁凋亡可能是铁超载诱导的IVDD的有希望的治疗策略。
Iron overload is a common phenomenon in the elderly population. Many clinical studies have indicated an association between iron overload and the incidence and pathological progression of intervertebral disc degeneration (IVDD). However, the role and underlying mechanism by which iron participates in the progression of IVDD has not yet been reported. In the present study, we aimed to elucidate the connection between iron overload and IVDD, and explore the underlying mechanisms of disease. Firstly, a clinical epidemiology study was conducted and revealed that iron overload is an independent risk factor for human IVDD. To elucidate the role of iron overload in IVDD, an iron overload mouse model was established, and we observed that iron overload promoted IVDD and cartilage endplate degeneration in a dose dependent manner. Endplate chondrocytes were further isolated and treated with FAC to mimic iron overloadin vitro. Excess iron significantly promoted mineralization of endplate chondrocytes in addition to their degeneration via oxidative stress. Moreover, a high dose of excess iron promoted chondrocytes ferroptosis. An iron chelator (DFO), an antioxidant (NAC) and a ferroptosis inhibitor (Fer-1) demonstrated effective inhibition of endplate chondrocyte degeneration induced by iron overload, and ourin vivostudies further demonstrated that DFO, NAC and Fer-1 could rescue high dose iron-induced IVDD and cartilage endplate calcification. In conclusion, our results indicate that iron overload is strongly associated with the onset and development of IVDD via oxidative stress and ferroptosis. Inhibiting oxidative stress or ferroptosis could therefore be promising therapeutic strategies for IVDD induced by iron overload.