Chondrocyte ferroptosis contribute to the progression of osteoarthritis
Chondrocyte ferroptosis contribute to the progression of osteoarthritis
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软骨细胞铁死亡有助于骨关节炎的进展。
DOI：
10.1016/j.jot.2020.09.006
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发表时间：
2020-12-17
影响因子：
6.6
通讯作者：
Guo F
中科院分区：
文献类型：
--
作者：
Yao X;Sun K;Yu S;Luo J;Guo J;Lin J;Wang G;Guo Z;Ye Y;Guo F
骨关节炎（OA）是一个复杂的过程，包括机械负荷，炎症和代谢因素。目前尚不清楚软骨细胞在OA期间是否发生铁凋亡，以及铁凋亡是否有助于OA的进展。本研究采用白细胞介素-1 β（IL-1β）体外模拟炎症反应，柠檬酸铁铵（FAC）体外模拟铁超载。此外，我们使用手术诱导的不稳定的内侧半月板（DMM）小鼠模型在体内诱导OA。我们通过细胞死亡命名委员会定义的铁凋亡的体外和体内模型进行了验证。我们观察到IL-1β和FAC均能诱导软骨细胞产生活性氧（ROS），并引起脂质ROS积聚和铁凋亡相关蛋白表达的变化。Ferrostatin-1是一种铁凋亡特异性抑制剂，可抑制IL-1β和FAC诱导的细胞毒性、ROS和脂质-ROS蓄积以及铁凋亡相关蛋白表达的变化，促进Nrf 2抗氧化系统的激活。此外，erastin，最经典的诱导剂，促进基质金属蛋白酶13（MMP 13）的表达，而抑制II型胶原（胶原II）的表达在软骨细胞。最后，我们证明关节内注射ferrostatin-1可以挽救小鼠OA模型中II型胶原的表达，并减轻软骨降解和OA进展。综上所述，本研究首次证实了软骨细胞在炎症和铁超载条件下发生铁凋亡。诱导铁凋亡引起软骨细胞中MMP 13表达增加和II型胶原表达减少。此外，在我们的病例中，通过关节内注射ferrostatin-1抑制铁凋亡似乎是预防OA的一种新的有希望的选择。这篇文章的翻译潜力在于，我们首次指出软骨细胞铁凋亡有助于骨关节炎的进展，这为预防OA提供了一种新的策略。
Osteoarthritis (OA) is a complex process comprised of mechanical load, inflammation, and metabolic factors. It is still unknown that if chondrocytes undergo ferroptosis during OA and if ferroptosis contribute to the progression of OA. In our study, we use Interleukin-1 Beta (IL-1β) to simulate inflammation and ferric ammonium citrate (FAC) to simulate the iron overload in vitro. Also, we used the surgery-induced destabilized medial meniscus (DMM) mouse model to induce OA in vivo. We verify ferroptosis by its definition that defined by the Nomenclature Committee on Cell Death with both in vitro and in vivo model. We observed that both IL-1β and FAC induced reactive oxygen species (ROS), and lipid ROS accumulation and ferroptosis related protein expression changes in chondrocytes. Ferrostatin-1, a ferroptosis specific inhibitor, attenuated the cytotoxicity, ROS and lipid-ROS accumulation and ferroptosis related protein expression changes induced by IL-1β and FAC and facilitated the activation of Nrf2 antioxidant system. Moreover, erastin, the most classic inducer of ferroptosis, promoted matrix metalloproteinase 13 (MMP13) expression while inhibited type II collagen (collagen II) expression in chondrocytes. At last, we proved that intraarticular injection of ferrostatin-1 rescued the collagen II expression and attenuated the cartilage degradation and OA progression in mice OA model. In summary, our study firstly proved that chondrocytes underwent ferroptosis under inflammation and iron overload condition. Induction of ferroptosis caused increased MMP13 expression and decreased collagen II expression in chondrocytes. Furthermore, inhibition of ferroptosis, by intraarticular injection of ferrostatin-1, in our case, seems to be a novel and promising option for the prevention of OA. The translation potential of this article is that we first indicated that chondrocyte ferroptosis contribute to the progression of osteoarthritis which provides a novel strategy in the prevention of OA.
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影响因子：
14.8
作者：
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影响因子：
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作者：
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