Deferoxamine Alleviates Osteoarthritis by Inhibiting Chondrocyte Ferroptosis and Activating the Nrf2 Pathway.
Deferoxamine Alleviates Osteoarthritis by Inhibiting Chondrocyte Ferroptosis and Activating the Nrf2 Pathway.
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去铁胺通过抑制软骨细胞铁死亡和激活 Nrf2 通路减轻骨关节炎
DOI：
10.3389/fphar.2022.791376
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发表时间：
2022
影响因子：
5.6
通讯作者：
Guo F
中科院分区：
文献类型：
--
作者：
Guo Z;Lin J;Sun K;Guo J;Yao X;Wang G;Hou L;Xu J;Guo J;Guo F
目的：骨关节炎（Osteoarthritis，OA）是一种常见病、多发病，其病理机制复杂，包括机械负荷、炎症反应和代谢因素。软骨细胞铁凋亡促进OA进展。由于铁沉积是铁凋亡的主要病理事件，去铁胺（DFO），一种有效的铁螯合剂，已被用于抑制各种退行性疾病模型中的铁凋亡。然而，其治疗OA的疗效仍然未知。本研究旨在探讨DFO是否抑制软骨细胞铁凋亡及其对OA的影响，并探讨其可能的机制。方法：以白细胞介素1β（IL-1β）模拟炎症反应，以erastin诱导软骨细胞铁凋亡。采用手术破坏内侧半月板的小鼠模型在体内模拟OA，并将erastin注射到关节腔内诱导小鼠膝关节软骨细胞铁凋亡。我们确定了DFO对铁细胞下垂和损伤相关事件的影响：软骨细胞炎症、细胞外基质降解、氧化应激和关节软骨降解。结果如下：IL-1β可增加软骨细胞内ROS、脂质ROS和脂质过氧化终产物丙二醛（MDA）的水平，并改变软骨细胞内铁凋亡相关蛋白的表达。此外，经典的铁凋亡抑制剂ferrostatin-1（Fer-1）可挽救IL-1β诱导的II型胶原（collagen II）表达减少和基质金属蛋白酶13（MMP 13）表达增加。Erastin促进软骨细胞MMP 13的表达，但抑制II型胶原的表达。DFO可减轻IL-1β和erastin对软骨细胞的毒性作用，抑制ROS和脂质ROS的积聚，减少MDA的生成，改善软骨细胞OA样改变，促进核因子E2相关因子2（Nrf 2）抗氧化系统的激活。最后，关节内注射DFO增强了OA模型小鼠中II型胶原的表达，抑制了erastin诱导的关节软骨细胞死亡，并延缓了关节软骨降解和OA进展。结论：我们的研究证实，软骨细胞在炎症条件下发生铁凋亡，抑制软骨细胞铁凋亡可以减轻软骨细胞的破坏。Erastin诱导的软骨细胞铁凋亡可刺激软骨细胞中MMP 13表达增加和胶原II表达减少。DFO可以抑制软骨细胞铁凋亡，并促进Nrf 2抗氧化系统的激活，这对于保护软骨细胞是必不可少的。此外，通过关节腔内注射DFO抑制铁凋亡可能是一种新的OA治疗方法。
Objective: Osteoarthritis (OA) is a common disease with a complex pathology including mechanical load, inflammation, and metabolic factors. Chondrocyte ferroptosis contributes to OA progression. Because iron deposition is a major pathological event in ferroptosis, deferoxamine (DFO), an effective iron chelator, has been used to inhibit ferroptosis in various degenerative disease models. Nevertheless, its OA treatment efficacy remains unknown. We aimed to determine whether DFO alleviates chondrocyte ferroptosis and its effect on OA and to explore its possible mechanism. Methods: Interleukin-1β (IL-1β) was used to simulate inflammation, and chondrocyte ferroptosis was induced by erastin, a classic ferroptosis inducer. A surgical destabilized medial meniscus mouse model was also applied to simulate OA in vivo, and erastin was injected into the articular cavity to induce mouse knee chondrocyte ferroptosis. We determined the effects of DFO on ferroptosis and injury-related events: chondrocyte inflammation, extracellular matrix degradation, oxidative stress, and articular cartilage degradation. Results: IL-1β increased the levels of ROS, lipid ROS, and the lipid peroxidation end product malondialdehyde (MDA) and altered ferroptosis-related protein expression in chondrocytes. Moreover, ferrostatin-1 (Fer-1), a classic ferroptosis inhibitor, rescued the IL-1β–induced decrease in collagen type II (collagen II) expression and increase in matrix metalloproteinase 13 (MMP13) expression. Erastin promoted MMP13 expression in chondrocytes but inhibited collagen II expression. DFO alleviated IL-1β– and erastin-induced cytotoxicity in chondrocytes, abrogated ROS and lipid ROS accumulation and the increase in MDA, improved OA-like changes in chondrocytes, and promoted nuclear factor E2–related factor 2 (Nrf2) antioxidant system activation. Finally, intra-articular injection of DFO enhanced collagen II expression in OA model mice, inhibited erastin-induced articular chondrocyte death, and delayed articular cartilage degradation and OA progression. Conclusion: Our research confirms that ferroptosis occurs in chondrocytes under inflammatory conditions, and inhibition of chondrocyte ferroptosis can alleviate chondrocyte destruction. Erastin-induced chondrocyte ferroptosis can stimulate increased MMP13 expression and decreased collagen II expression in chondrocytes. DFO can suppress chondrocyte ferroptosis and promote activation of the Nrf2 antioxidant system, which is essential for protecting chondrocytes. In addition, ferroptosis inhibition by DFO injection into the articular cavity may be a new OA treatment.
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
DOI：
10.1186/ar401
发表时间：
2002
期刊：
Arthritis research
影响因子：
--
作者：
Vincenti MP;Brinckerhoff CE
通讯作者：
Brinckerhoff CE
影响因子：
7
作者：
Bannuru, R. R.;Osani, M. C.;McAlindon, T. E.
通讯作者：
McAlindon, T. E.
虾青素通过 Nrf2 预防骨关节炎：软骨稳态的守护者
影响因子：
5.2
作者：
Sun, Kai;Luo, Jiahui;Guo, Fengjing
通讯作者：
Guo, Fengjing