Arg972 insulin receptor substrate‑1 enhances tumor necrosis factor‑α‑induced apoptosis in osteoblasts

You,Yunhui; Liu,Shiqing; Peng,Lijuan; Long,Mei; Deng,Hongxiang; Zhao,Hongjun

doi:10.3892/mmr.2015.3457

Arg972 insulin receptor substrate‑1 enhances tumor necrosis factor‑α‑induced apoptosis in osteoblasts

Authors:
- Yunhui You
- Shiqing Liu
- Lijuan Peng
- Mei Long
- Hongxiang Deng
- Hongjun Zhao
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Affiliations: Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
Published online on: March 9, 2015 https://doi.org/10.3892/mmr.2015.3457
Pages: 255-260

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Abstract

The presence of Arg972 insulin receptor substrate‑1 (IRS‑1) is associated with impaired insulin/IRS‑1 signaling to activate phosphatidylinositol‑3 kinase (PI3K). Tumor necrosis factor‑α (TNF‑α), 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 Arg972 IRS‑1 and a high risk and severity of RA was identified. In the present study, the effects of Arg972 IRS‑1 and IRS‑1 on TNF‑α‑induced apoptosis in human osteoblasts were examined. Normal and RA osteoblasts were stably transfected with Arg972 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 Arg972 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‑α‑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‑α‑induced apoptosis, which was eliminated by pretreatment with 50 µn 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 Arg972 IRS‑1 and IRS‑1 enhanced and inhibited TNF‑α‑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.

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