PMID- 25760103
OWN - NLM
STAT- MEDLINE
DCOM- 20160105
LR  - 20191210
IS  - 1791-3004 (Electronic)
IS  - 1791-2997 (Linking)
VI  - 12
IP  - 1
DP  - 2015 Jul
TI  - Arg972 insulin receptor substrate-1 enhances tumor necrosis factor-alpha-induced 
      apoptosis in osteoblasts.
PG  - 255-60
LID - 10.3892/mmr.2015.3457 [doi]
AB  - 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-alpha (TNF-alpha), 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-alpha-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-alpha-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-alpha-induced apoptosis, which was eliminated by pretreatment with 50 micron 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-alpha-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.
FAU - You, Yunhui
AU  - You Y
AD  - Department of Rheumatology and Immunology, Xiangya Hospital, Central South 
      University, Changsha, Hunan 410008, P.R. China.
FAU - Liu, Shiqing
AU  - Liu S
AD  - Department of Rheumatology and Immunology, Xiangya Hospital, Central South 
      University, Changsha, Hunan 410008, P.R. China.
FAU - Peng, Lijuan
AU  - Peng L
AD  - Department of Rheumatology and Immunology, Xiangya Hospital, Central South 
      University, Changsha, Hunan 410008, P.R. China.
FAU - Long, Mei
AU  - Long M
AD  - Department of Rheumatology and Immunology, Xiangya Hospital, Central South 
      University, Changsha, Hunan 410008, P.R. China.
FAU - Deng, Hongxiang
AU  - Deng H
AD  - Department of Rheumatology and Immunology, Xiangya Hospital, Central South 
      University, Changsha, Hunan 410008, P.R. China.
FAU - Zhao, Hongjun
AU  - Zhao H
AD  - Department of Rheumatology and Immunology, Xiangya Hospital, Central South 
      University, Changsha, Hunan 410008, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20150309
PL  - Greece
TA  - Mol Med Rep
JT  - Molecular medicine reports
JID - 101475259
RN  - 0 (IRS1 protein, human)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 94ZLA3W45F (Arginine)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Arginine/metabolism
MH  - Arthritis, Rheumatoid/*genetics/metabolism/pathology
MH  - Cells, Cultured
MH  - Gene Expression Regulation
MH  - Humans
MH  - Insulin/metabolism/*pharmacology
MH  - Insulin Receptor Substrate Proteins/antagonists & inhibitors/*genetics/metabolism
MH  - Insulin Resistance/genetics
MH  - Osteoblasts/*drug effects/metabolism/pathology
MH  - Phosphatidylinositol 3-Kinases/genetics/metabolism
MH  - Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - Polymorphism, Single Nucleotide
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proto-Oncogene Proteins c-akt/genetics/metabolism
MH  - RNA, Small Interfering/genetics/metabolism
MH  - Signal Transduction
MH  - Transfection
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 2015/03/12 06:00
MHDA- 2016/01/06 06:00
CRDT- 2015/03/12 06:00
PHST- 2014/03/30 00:00 [received]
PHST- 2014/12/02 00:00 [accepted]
PHST- 2015/03/12 06:00 [entrez]
PHST- 2015/03/12 06:00 [pubmed]
PHST- 2016/01/06 06:00 [medline]
AID - 10.3892/mmr.2015.3457 [doi]
PST - ppublish
SO  - Mol Med Rep. 2015 Jul;12(1):255-60. doi: 10.3892/mmr.2015.3457. Epub 2015 Mar 9.