Homocysteine causes dysfunction of chondrocytes and oxidative stress through repression of SIRT1/AMPK pathway: A possible link between hyperhomocysteinemia and osteoarthritis.
Homocysteine causes dysfunction of chondrocytes and oxidative stress through repression of SIRT1/AMPK pathway: A possible link between hyperhomocysteinemia and osteoarthritis.
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DOI：
10.1016/j.redox.2018.01.010
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发表时间：
2018-05
期刊：
影响因子：
11.4
通讯作者：
Tsai KL
中科院分区：
文献类型：
--
作者：
Ma CH;Chiua YC;Wu CH;Jou IM;Tu YK;Hung CH;Hsieh PL;Tsai KL
新的证据表明，同型半胱氨酸（homocysteine，Hcy）的表达异常可导致线粒体功能紊乱，从而影响骨代谢。Sirtuin 1（SIRT 1）和AMP活化蛋白激酶（AMPK）是调节线粒体生物合成的两个关键传感器，并已被认为是骨关节炎（OA）的治疗靶点。本研究旨在检测Hcy是否通过调节SIRT 1和AMPK引起骨关节炎前的变化。我们的研究结果表明，Hcy的施用减少了软骨细胞中的SIRT 1/AMPK/PGC-1α信号传导，导致线粒体功能障碍，这是由于氧化应激和凋亡增加的结果。此外，我们证明，NF-κB，考克斯-2，IL-8和MMP-13的表达升高后，抑制SIRT 1/AMPK/PGC-1α/PPAR-γ通路的同型半胱氨酸，从而导致对软骨细胞的不利影响。在饮食诱导的高同型半胱氨酸血症（HHcy）动物模型中，我们观察到了相似的发现，即SIRT 1/PGC-1α/PPAR-γ级联反应随着MMP-13和考克斯-2的升高而下调。综上所述，本研究的数据显示，Hcy降低SIRT 1可能有助于软骨降解过程，这为OA的病因学提供了深入了解。同型半胱氨酸减少SIRT 1导致磷酸化AMPK和PGC-1α下调。同型半胱氨酸抑制SIRT 1导致线粒体功能障碍。同型半胱氨酸诱导的氧化应激可通过SIRT 1/AMPK/PGC-1α信号通路的激活而逆转。高同型半胱氨酸诱导的促凋亡作用可通过SIRT 1/AMPK/PGC-1α级联的过表达来挽救。同型半胱氨酸抑制PPAR-γ后，促炎介质和MMP 13的表达水平升高。
Emerging evidence has indicated that the perturbed expression of homocysteine (Hcy) may induce mitochondrial dysfunction and disturb bone metabolism. Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) are two critical sensors that regulate mitochondrial biogenesis and have been recognized as therapeutic targets in osteoarthritis (OA). This study was designed to test whether Hcy caused pro-osteoarthritic changes through modulation of SIRT1 and AMPK. Our results showed that administration of Hcy reduced the SIRT1/AMPK/PGC-1α signaling in chondrocytes, leading to mitochondrial dysfunction as a result of increased oxidative stress and apoptosis. Moreover, we demonstrated that the expression of NF-κB, COX-2, IL-8, and MMP-13 were elevated subsequent to inhibition of SIRT1/AMPK/PGC-1α/PPAR-γ pathway by homocysteine, thereby causing detrimental effects on chondrocytes. In the animal model of diet-induced hyperhomocysteinemia (HHcy), we observed the similar findings that SIRT1/PGC-1α/PPAR-γ cascades were downregulated with elevated MMP-13 and COX-2. Taken together, data from the current study revealed that the reduced SIRT1 by Hcy may contribute to degradative cartilage process, which provided insight into the etiology of OA. Homocysteine-reduced SIRT1 leads to downregulation of phosphorylated AMPK and PGC-1α. Homocysteine-inhibited SIRT1 results in mitochondrial dysfunction. Homocysteine-induced oxidative stress is reversed by activation of SIRT1/AMPK/PGC-1α signaling. Homocysteine-induced pro-apoptosis effect is rescued by overexpression of SIRT1/AMPK/PGC-1α cascades. Expression levels of pro-inflammatory mediators and MMP13 are elevated subsequent to suppression of PPAR-γ by homocysteine.
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