骨性关节炎（OA）是临床最常见的致残性关节疾病。铁色素在关节滑膜和软骨的沉积是OA发生发展过程中的重要病理过程，大量研究提示铁过载是OA进展的重要危险因素，但铁离子参与OA发生发展的具体机制不详。申请人前期的研究显示炎症因子可导致软骨细胞铁代谢的紊乱和铁稳态的失衡，铁代谢相关蛋白DMT1在OA小鼠的关节软骨和炎症环境下的软骨细胞中均表达升高，沉默软骨细胞DMT1可抑制炎症因子诱导的OA相关蛋白的表达。我们猜测“炎症因子导致的软骨细胞铁代谢失衡可能是铁离子参与OA发生发展的前提条件，DMT1介导的软骨细胞铁过载、铁死亡参与了OA的发生发展”。本课题拟在前期研究的基础上系统研究OA病理过程中铁代谢失衡、铁过载、铁死亡和OA的联系；探究软骨炎性环境下铁代谢的调控机制，重点研究HIF-2α/DMT1信号通路介导的铁代谢失衡对铁死亡的调控及对软骨细胞的影响，为早期预防和治疗OA提供新的思路和方法。

Osteoarthritis (OA) is the most common cause of disabling arthritis. A large number of studies indicate that iron overload plays an important role in the development of OA, but the underlying mechanism remains unknown. Our previous study showed that pro-inflammatory cytokines could lead to chondrocytes iron metabolism dysregulation and iron homeostasis disturbance, the divalent metal transporter1 (DMT1) was upregulated in OA chondrocytes and pro-inflammaroty cytokines treated chondrocytes, DMT1 silence with siRNA significantly inhibited pro-inflammatory cytokines induced OA related proteins expression. We speculate that DMT1 mediated iron metabolism dysregulation and ferroptosis play important roles in OA development. In this study, gene expression regulation, histology and molecular biology were used to systemically study the interaction of iron metabolism, ferroptosis and OA. We aim to explore the mechanism of iron metabolism induced by pro-inflammatory cytokines, how iron metabolism is regulated by HIF-2α / DMT1 signaling pathways and its effect to chondrocytes. We aim to demonstrate the relationship between iron metabolism dysregulation and OA in molecular level, provide new experimental and theoretical basis for early prevention and treatment of OA.