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Resistin and Insulin/Insulin-like Growth Factor Signaling in Rheumatoid Arthritis

Bostrom, Elisabeth A.; Svensson, Mattias; Andersson, Sofia; Jonsson, Ing-Marie; Ekwall, Anna-Karin H.; Eisler, Thomas; Dahlberg, Leif LU ; Smith, Ulf and Bokarewa, Maria I. (2011) In Arthritis and Rheumatism 63(10). p.2894-2904
Abstract
Objective. Human resistin has proinflammatory properties that activate NF-kappa B-dependent pathways, whereas its murine counterpart is associated with insulin resistance. The aim of this study was to examine potential cross-talk between resistin and insulin/insulin-like growth factor (IGF) signaling in rheumatoid arthritis (RA). Methods. Levels of IGF-1, IGF binding protein 3, and resistin were measured in the blood and synovial fluid of 60 patients with RA and 39 healthy control subjects. Human RA synovium was implanted subcutaneously into SCID mice, and the mice were treated with resistin-targeting small interfering RNA. Primary synovial fibroblasts from patients with RA, as well as those from patients with osteoarthritis, and the human... (More)
Objective. Human resistin has proinflammatory properties that activate NF-kappa B-dependent pathways, whereas its murine counterpart is associated with insulin resistance. The aim of this study was to examine potential cross-talk between resistin and insulin/insulin-like growth factor (IGF) signaling in rheumatoid arthritis (RA). Methods. Levels of IGF-1, IGF binding protein 3, and resistin were measured in the blood and synovial fluid of 60 patients with RA and 39 healthy control subjects. Human RA synovium was implanted subcutaneously into SCID mice, and the mice were treated with resistin-targeting small interfering RNA. Primary synovial fibroblasts from patients with RA, as well as those from patients with osteoarthritis, and the human fibroblast cell line MRC-5 were stimulated with resistin. Changes in the IGF-1 receptor (IGF-1R) signaling pathway were evaluated using histologic analysis, immunohistochemistry, and reverse transcription-polymerase chain reaction. Results. Resistin and IGF-1R showed different expression profiles in RA synovia. Low levels of IGF-1 in RA synovial fluid were associated with systemic inflammation and inversely related to the levels of resistin. Stimulation of synovial fibroblasts with resistin induced phosphorylation of IGF-1R to a degree similar to that with insulin, and also induced phosphorylation of transcription factor Akt. This was followed by gene expression of GLUT1, IRS1, GSK3B, and the Akt inhibitors PTPN and PTEN. Abrogation of resistin expression in vivo reduced the expression of IGF-1R, the phosphorylation of Akt, and the expression of PTPN and PTEN messenger RNA in RA synovium implanted into SCID mice. Conclusion. Resistin utilizes the IGF-1R pathway in RA synovia. Abrogation of resistin synthesis in the RA synovium in vivo leads to reductions in the expression of IGF-1R and level of phosphorylation of Akt. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Arthritis and Rheumatism
volume
63
issue
10
pages
2894 - 2904
publisher
John Wiley & Sons
external identifiers
  • wos:000295293000008
  • scopus:80053547638
ISSN
1529-0131
DOI
10.1002/art.30527
language
English
LU publication?
yes
id
659f91ae-768a-4a90-850b-9781c7ab8a70 (old id 2179730)
date added to LUP
2011-11-01 07:47:35
date last changed
2017-11-19 03:12:01
@article{659f91ae-768a-4a90-850b-9781c7ab8a70,
  abstract     = {Objective. Human resistin has proinflammatory properties that activate NF-kappa B-dependent pathways, whereas its murine counterpart is associated with insulin resistance. The aim of this study was to examine potential cross-talk between resistin and insulin/insulin-like growth factor (IGF) signaling in rheumatoid arthritis (RA). Methods. Levels of IGF-1, IGF binding protein 3, and resistin were measured in the blood and synovial fluid of 60 patients with RA and 39 healthy control subjects. Human RA synovium was implanted subcutaneously into SCID mice, and the mice were treated with resistin-targeting small interfering RNA. Primary synovial fibroblasts from patients with RA, as well as those from patients with osteoarthritis, and the human fibroblast cell line MRC-5 were stimulated with resistin. Changes in the IGF-1 receptor (IGF-1R) signaling pathway were evaluated using histologic analysis, immunohistochemistry, and reverse transcription-polymerase chain reaction. Results. Resistin and IGF-1R showed different expression profiles in RA synovia. Low levels of IGF-1 in RA synovial fluid were associated with systemic inflammation and inversely related to the levels of resistin. Stimulation of synovial fibroblasts with resistin induced phosphorylation of IGF-1R to a degree similar to that with insulin, and also induced phosphorylation of transcription factor Akt. This was followed by gene expression of GLUT1, IRS1, GSK3B, and the Akt inhibitors PTPN and PTEN. Abrogation of resistin expression in vivo reduced the expression of IGF-1R, the phosphorylation of Akt, and the expression of PTPN and PTEN messenger RNA in RA synovium implanted into SCID mice. Conclusion. Resistin utilizes the IGF-1R pathway in RA synovia. Abrogation of resistin synthesis in the RA synovium in vivo leads to reductions in the expression of IGF-1R and level of phosphorylation of Akt.},
  author       = {Bostrom, Elisabeth A. and Svensson, Mattias and Andersson, Sofia and Jonsson, Ing-Marie and Ekwall, Anna-Karin H. and Eisler, Thomas and Dahlberg, Leif and Smith, Ulf and Bokarewa, Maria I.},
  issn         = {1529-0131},
  language     = {eng},
  number       = {10},
  pages        = {2894--2904},
  publisher    = {John Wiley & Sons},
  series       = {Arthritis and Rheumatism},
  title        = {Resistin and Insulin/Insulin-like Growth Factor Signaling in Rheumatoid Arthritis},
  url          = {http://dx.doi.org/10.1002/art.30527},
  volume       = {63},
  year         = {2011},
}