Contribution of ferroptosis and GPX4's dual functions to osteoarthritis progression.
Contribution of ferroptosis and GPX4's dual functions to osteoarthritis progression.
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DOI：
10.1016/j.ebiom.2022.103847
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发表时间：
2022-03
期刊：
影响因子：
11.1
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Miao Y;Chen Y;Xue F;Liu K;Zhu B;Gao J;Yin J;Zhang C;Li G
骨关节炎（OA）是最常见的关节疾病，也是老年人慢性残疾的主要原因。软骨细胞死亡和细胞外基质（ECM）降解参与OA的发病机制。铁凋亡是一种与脂质过氧化有关的铁依赖性细胞死亡。在这里，我们证明了铁凋亡存在于OA和确定谷胱甘肽过氧化物酶4（GPX 4）作为OA的重要调节剂。在人OA和未受损软骨中分析了铁中毒相关的改变。在55对人类OA样本中检测GPX 4的表达。采用铁蛋白抑制素-1（Ferrostatin-1，Fer-1）和去铁胺（Deferoxamine，DFO）治疗骨关节炎（OA）。通过RNA-seq分析鉴定GPX 4介导的信号通路的改变。AAV-Gpx 4-shRNA用于下调GPX 4在体内的表达。转录组学、生物化学和显微镜分析表明，铁凋亡与OA密切相关。55例OA患者骨关节软骨中GPX 4的表达明显低于正常软骨。Fer-1和DFO对骨关节炎的保护作用不依赖于坏死性凋亡，提示骨关节炎患者存在铁凋亡。重要的是，GPX 4下调可通过MAPK/NFκB途径增加软骨细胞对氧化应激的敏感性，加重ECM降解。此外，通过AAV-Gpx 4 shRNA下调GPX 4表达加重了体内OA。铁凋亡参与OA发病机制，GPX 4是调节OA进展的两种机制的交叉点：铁凋亡和ECM降解。
Osteoarthritis (OA) is the most common joint disease and is the leading cause of chronic disability among older people. Chondrocyte death and extracellular matrix (ECM) degradation was involved in OA pathogenesis. Ferroptosis was an iron-dependent cell death associated with peroxidation of lipids. Here, we proved that ferroptosis exists in OA and identified glutathione peroxidase 4 (GPX4) as an important regulator of OA. Ferroptosis-related alterations were analyzed in human OA and undamaged cartilage. Expression of GPX4 was examined in 55 paired human OA samples. Ferrostatin-1 (Fer-1) and Deferoxamine (DFO) were used to treat OA, in vitro and in vivo. Alterations of GPX4-mediated signaling pathway were identified by RNA-seq analysis. AAV-Gpx4-shRNA were used to downregulate GPX4 expression in vivo. Transcriptomic, biochemical, and microscopical analyses indicated that ferroptosis was closely associated with OA. Expression of GPX4 in the OA cartilage from 55 OA patients were significantly lower than undamaged cartilage. Fer-1 and DFO could protect OA in a necroptosis-independent manner, suggesting that ferroptosis exists in OA prog. Importantly, GPX4 downregulation could increase the sensitivity of chondrocytes to oxidative stress and aggravate ECM degradation through the MAPK/NFκB pathway. Furthermore, downregulation of GPX4 expression by AAV-Gpx4 shRNA aggravated OA in vivo. Ferroptosis contributes to OA pathogenesis and GPX4 was the intersection of two mechanisms in regulating OA progression: ferroptosis and ECM degradation.
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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：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
14.9
作者：
Kanehisa M;Araki M;Goto S;Hattori M;Hirakawa M;Itoh M;Katayama T;Kawashima S;Okuda S;Tokimatsu T;Yamanishi Y
通讯作者：
Yamanishi Y
影响因子：
12.7
作者：
Chen D;Shen J;Zhao W;Wang T;Han L;Hamilton JL;Im HJ
通讯作者：
Im HJ
影响因子：
21.3
作者：
Friedmann Angeli JP;Schneider M;Proneth B;Tyurina YY;Tyurin VA;Hammond VJ;Herbach N;Aichler M;Walch A;Eggenhofer E;Basavarajappa D;Rådmark O;Kobayashi S;Seibt T;Beck H;Neff F;Esposito I;Wanke R;Förster H;Yefremova O;Heinrichmeyer M;Bornkamm GW;Geissler EK;Thomas SB;Stockwell BR;O'Donnell VB;Kagan VE;Schick JA;Conrad M
通讯作者：
Conrad M