Arg(972) insulin receptor substrate-1 enhances tumor necrosis factor--induced apoptosis in osteoblasts

作者：You, Yunhui; Liu, Shiqing; Peng, Lijuan; Long, Mei; Deng, Hongxiang; Zhao, Hongjun^*

来源：Molecular Medicine Reports, 2015, 12(1): 255-260.

DOI：10.3892/mmr.2015.3457

• insulin receptor substrate-1
• tumor necrosis factor-
• osteoblast
• rheumatoid arthritis
• apoptosis
• phosphatidylinositol-3 kinase

The presence of Arg(972) insulin receptor substrate-1 (IRS-1) is associated with impaired insulin/IRS-1 signaling to activate phosphatidylinositol-3 kinase (PI3K). Tumor necrosis factor- (TNF-), an inflammatory cytokine with a central role in the pathogenesis of rheumatoid arthritis (RA), induces apoptosis in osteoblasts, which are the principal cell type responsible for bone loss in RA. In our previous study, an association between Arg(972) IRS-1 and a high risk and severity of RA was identified. In the present study, the effects of Arg(972) IRS-1 and IRS-1 on TNF--induced apoptosis in human osteoblasts were examined. Normal and RA osteoblasts were stably transfected with Arg(972) IRS-1 and IRS-1. In addition, cells were stably transduced with IRS-1-shRNA to knock down IRS-1. Following stimulation with 10 nM insulin for 30 min, the stable overexpression of Arg(972) IRS-1 and knock down of IRS-1 significantly decreased IRS-1-associated PI3K activity and Akt activation/phosphorylation at serine 473 (ser473) and enhanced TNF--induced apoptosis in normal and in RA osteoblasts. By contrast, the stable overexpression of IRS-1 significantly increased the levels of IRS-1-associated PI3K activity and Akt phosphorylation (ser473) and inhibited TNF--induced apoptosis, which was eliminated by pretreatment with 50 n BJM120, a selective PI3K inhibitor, for 30 min. In conclusion, the present study provided the first evidence, to the best of our knowledge, that insulin stimulation of Arg(972) IRS-1 and IRS-1 enhanced and inhibited TNF--induced apoptosis, respectively in normal and RA osteoblasts by a PI3K-dependent mechanism. These findings suggest that insulin/IRS-1 signaling is important in the pathogenesis of RA.

• 出版日期2015-7
• 单位中南大学