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

Molecular Medicine Reports
Yunhui YouHongjun Zhao

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 IRS1. 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...Continue Reading

References

Jun 4, 1998·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·R L JilkaS C Manolagas
Aug 3, 1999·The Journal of Clinical Investigation·O PorzioG Sesti
Jun 8, 2001·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·J M HockD Stanislaus
Jun 9, 2005·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Chang-Hyun ByunGhi Su Kim
Jul 12, 2005·The Journal of Clinical Investigation·Tomohisa NagoshiAnthony Rosenzweig
Aug 26, 2006·Nature Clinical Practice. Rheumatology·Iain B McInnes, Foo Y Liew
Oct 19, 2006·Metabolism: Clinical and Experimental·Franco FalluccaAnnunziata Lapolla
Jun 3, 2010·Cell Biochemistry and Function·Jianhong YangJing Liu
Dec 2, 2010·Cell and Tissue Research·Anna NeveFrancesco Paolo Cantatore
Mar 22, 2014·Biomedical Reports·Xixi Ma, Shengqian Xu
Nov 27, 2014·International Journal of Rheumatic Diseases·Hongjun ZhaoYunhui You

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