A Novel Anti-Osteoporosis Mechanism of VK2: Interfering with Ferroptosis via AMPK/SIRT1 Pathway in Type 2 Diabetic Osteoporosis,Journal of Agricultural and Food Chemistry

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A Novel Anti-Osteoporosis Mechanism of VK2: Interfering with Ferroptosis via AMPK/SIRT1 Pathway in Type 2 Diabetic Osteoporosis
Journal of Agricultural and Food Chemistry ( IF 5.7 ) Pub Date : 2023-01-31 , DOI: 10.1021/acs.jafc.2c05632
Chen Jin _{1,

2} , Kai Tan _{1,

2} , Zhe Yao _{2,

3} , Bing-Hao Lin _{1,

2} , Du-Piao Zhang _{1,

2} , Wei-Kai Chen ₄ , Shu-Ming Mao _{1,

2} , Wei Zhang _{1,

2} , Liang Chen ₅ , Zhen Lin _{1,

2} , She-Ji Weng _{1,

2} , Bing-Li Bai _{1,

2} , Wen-Hao Zheng _{1,

2} , Gang Zheng _{1,

2} , Zong-Yi Wu _{1,

2} , Lei Yang _{1,

2,

4}

Affiliation

Type 2 diabetic osteoporosis (T2DOP) is a chronic bone metabolic disease. Compared with traditional menopausal osteoporosis, the long-term high glucose (HG) microenvironment increases patients’ risk of fracture and osteonecrosis. We were accumulating evidence that implicated ferroptosis as a pivotal mechanism of glucolipotoxicity-mediated death of osteocytes and osteoblast, a novel form of programmed cell death resulting from uncontrolled lipid peroxidation depending on iron. Vitamin K2 (VK2), a fat-soluble vitamin, is clinically applied to prevent osteoporosis and improve coagulation. This study aimed to clarify the role and mechanism of VK2 in HG-mediated ferroptosis. We established the mouse T2DOP model by intraperitoneal injection of streptozotocin solution and a high-fat and high-sugar diet. We also cultured bone marrow mesenchymal stem cells (BMSCs) in HG to simulate the diabetic environment in vitro. Based on our data, VK2 inhibited HG-mediated bone loss and ferroptosis, the latter manifested by decreased levels of mitochondrial reactive oxygen species, lipid peroxidation, and malondialdehyde and increased glutathione in vitro. In addition, VK2 treatment was capable of restoring bone mass and strengthening the expression of SIRT1, GPX4, and osteogenic markers in the distal femurs. As for further mechanism exploration, we found that VK2 could activate AMPK/SIRT1 signaling, and knockdown of SIRT1 by siRNA prevented the VK2-mediated positive effect in HG-cultured BMSCs. Summarily, VK2 could ameliorate T2DOP through the activation of the AMPK/SIRT1 signaling pathway to inhibit ferroptosis.

中文翻译：

VK2 抗骨质疏松的新机制：通过 AMPK/SIRT1 通路干扰 2 型糖尿病性骨质疏松症的铁死亡

2型糖尿病性骨质疏松症（T2DOP）是一种慢性骨代谢疾病。与传统的绝经期骨质疏松症相比，长期高糖（HG）微环境增加了患者骨折和骨坏死的风险。我们正在积累证据，表明铁死亡是糖脂毒性介导的骨细胞和成骨细胞死亡的关键机制，这是一种新的程序性细胞死亡形式，由依赖铁的不受控制的脂质过氧化引起。维生素 K2 (VK2) 是一种脂溶性维生素，临床上用于预防骨质疏松症和改善凝血功能。本研究旨在阐明 VK2 在 HG 介导的铁死亡中的作用和机制。我们通过腹腔注射链脲佐菌素溶液和高脂高糖饮食建立小鼠T2DOP模型。我们还在 HG 中培养了骨髓间充质干细胞 (BMSC)，以在体外模拟糖尿病环境。根据我们的数据，VK2 抑制了 HG 介导的骨丢失和铁死亡，后者表现为线粒体活性氧水平降低、脂质过氧化、丙二醛和体外谷胱甘肽增加。此外，VK2 治疗能够恢复骨量并加强股骨远端 SIRT1、GPX4 和成骨标志物的表达。至于进一步的机制探索，我们发现 VK2 可以激活 AMPK/SIRT1 信号，siRNA 敲低 SIRT1 阻止了 HG 培养的 BMSCs 中 VK2 介导的正效应。总之，VK2 可以通过激活 AMPK/SIRT1 信号通路抑制铁死亡来改善 T2DOP。

更新日期：2023-01-31

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