Involvement of endoplasmic reticulum stress in homocysteine-induced apoptosis of osteoblastic cells
Involvement of endoplasmic reticulum stress in homocysteine-induced apoptosis of osteoblastic cells
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DOI：
10.1007/s00774-011-0346-9
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发表时间：
2012-07-01
影响因子：
3.3
通讯作者：
Cho, Chul-Soo
中科院分区：
文献类型：
--
作者：
Park, Su-Jung;Kim, Ki-Jo;Cho, Chul-Soo
高同型半胱氨酸血症已被证明会增加骨质疏松症和骨质疏松性骨折的发生率。内质网（ER）应激最近被证明与几种类型细胞的凋亡有关。本研究通过检测同型半胱氨酸（Hcy）对成骨细胞凋亡的影响，探讨内质网应激是否参与了Hcy诱导的成骨细胞凋亡。人成骨细胞用Hcy孵育。Hcy剂量依赖性降低成骨细胞活力，增加细胞凋亡。成骨细胞比其他类型的细胞更容易受到hcy介导的细胞死亡的影响。Hcy可显著提高裂解型caspase-3的表达，用caspase-3抑制剂预处理可挽救Hcy作用下的细胞活力。Hcy处理导致线粒体细胞色素c的释放增加，并通过增加葡萄糖调节蛋白78、肌醇需要的跨膜激酶和内切酶1 α (IRE-1 α)、剪接的X-box结合蛋白、激活转录因子4和c /EBP同源蛋白的表达引发内质网应激。小干扰RNA沉默IRE-1 α表达可有效抑制hcy诱导的成骨细胞凋亡。我们的研究结果表明，高同型半胱氨酸血症通过内质网应激诱导成骨细胞凋亡。
Hyperhomocysteinemia has been shown to increase the incidence of osteoporosis and osteoporotic fractures. Endoplasmic reticulum (ER) stress was recently shown to be associated with apoptosis in several types of cells. In this study, we determined the effect of homocysteine (Hcy) on the apoptosis of osteoblastic cells and investigated whether ER stress participates in Hcy-induced osteoblast apoptosis. Human osteoblastic cells were incubated with Hcy. Hcy dose-dependently decreased cell viability and increased apoptosis in osteoblastic cells. Osteoblastic cells are more susceptible to Hcy-mediated cell death than other cell types. Expression of cleaved caspase-3 was significantly increased by Hcy, and pretreatment with caspase-3 inhibitor rescued the cell viability by Hcy. Hcy treatment led to an increase in release of mitochondrial cytochrome c. It also triggered ER stress by increased expression of glucose-regulated protein 78, inositol-requiring transmembrane kinase and endonuclease 1 alpha (IRE-1 alpha), spliced X-box binding protein, activating transcription factor 4, and C/EBP homologous protein. Silencing IRE-1 alpha expression by small interfering RNA effectively suppressed Hcy-induced apoptosis of osteoblastic cells. Our results suggest that hyperhomocysteinemia induces apoptotic cell death in osteoblasts via ER stress.