Department of Orthopedics, The First Hospital of China Medical University, 155 North Nanjing Street, Shenyang, 110001, Liaoning, China.
Department of Orthopedics, The Third Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China.
Biol Trace Elem Res. 2022 Jan;200(1):298-307. doi: 10.1007/s12011-021-02627-z. Epub 2021 Feb 16.
The incidence of type 2 diabetic osteoporosis (T2DOP), which seriously threatens elderly people's health, is rapidly increasing in recent years. However, the specific mechanism of the T2DOP is still unclear. Studies have shown the relationship between iron overload and T2DOP. Mitochondrial ferritin (FtMt) is a protein that stores iron ions and intercepts toxic ferrous ions in cells mitochondria. Ferroptosis, an iron-dependent cell injured way, may be related to the pathogenesis of T2DOP. In this study, we intend to elucidate the effect of FtMt on ferroptosis in osteoblasts and explain the possible mechanism. We first detected the occurrence of ferroptosis in bone tissue and the expression of FtMt after inducing T2DOP rat model. Then we used hFOB1.19 cells to study the influence of high glucose on FtMt, ferroptosis, and osteogenic function of osteoblasts. Then we observed the effect of FtMt on ferroptosis and osteoblast function by lentiviral silencing and overexpression of FtMt. We found ferroptosis in T2DOP rats bone. Overexpression of FtMt reduced osteoblastic ferroptosis under high glucose condition while silent FtMt induced mitophagy through ROS / PINK1/Parkin pathway. Then we found increased ferroptosis in osteoblasts after activating mitophagy by carbonyl cyanide-m-chlorophenyl-hydrazine (CCCP, a mitophagy agonist). Our study demonstrated that FtMt inhibited the occurrence of ferroptosis in osteoblasts by reducing oxidative stress caused by excess ferrous ions, and FtMt deficiency induced mitophagy in the pathogenesis of T2DOP. This study suggested that FtMt might serve as a potential target for T2DOP therapy.
2 型糖尿病性骨质疏松症（T2DOP）的发病率近年来迅速上升，严重威胁着老年人的健康。然而，T2DOP 的具体机制尚不清楚。研究表明，铁过载与 T2DOP 之间存在关系。线粒体铁蛋白（FtMt）是一种在细胞线粒体中储存铁离子并拦截有毒二价铁离子的蛋白质。铁依赖性细胞损伤方式——铁死亡，可能与 T2DOP 的发病机制有关。在本研究中，我们旨在阐明 FtMt 对成骨细胞中铁死亡的影响，并解释其可能的机制。我们首先检测了 T2DOP 大鼠模型骨组织中发生铁死亡的情况和 FtMt 的表达。然后，我们使用 hFOB1.19 细胞研究了高葡萄糖对 FtMt、成骨细胞铁死亡和成骨功能的影响。然后，我们通过慢病毒沉默和 FtMt 过表达观察 FtMt 对铁死亡和成骨细胞功能的影响。我们发现 T2DOP 大鼠骨组织中存在铁死亡。高葡萄糖条件下 FtMt 过表达可减少成骨细胞铁死亡，而沉默 FtMt 通过 ROS/PINK1/Parkin 通路诱导自噬。然后我们发现通过羰基氰化物 m-氯苯腙（CCCP，一种自噬激动剂）激活自噬后，成骨细胞中的铁死亡增加。我们的研究表明，FtMt 通过减少过量二价铁离子引起的氧化应激抑制成骨细胞中铁死亡的发生，而 FtMt 缺乏则通过自噬在 T2DOP 的发病机制中诱导铁死亡。本研究提示 FtMt 可能成为 T2DOP 治疗的潜在靶点。
