title: Resistin and insulin/insulin-like growth factor signaling in rheumatoid arthritis.
abstract: OBJECTIVE
  Human resistin has proinflammatory properties that activate NF-κB-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.
  
  
  CONCLUSIONS
  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.
authors: Department of Rheumatology and Inflammation Research, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
authors: Elisabeth A
authors: EA
authors: Boström
authors: Mattias
authors: M
authors: Svensson
authors: Sofia
authors: S
authors: Andersson
authors: Ing-Marie
authors: IM
authors: Jonsson
authors: Anna-Karin H
authors: AK
authors: Ekwall
authors: Thomas
authors: T
authors: Eisler
authors: Leif E
authors: LE
authors: Dahlberg
authors: Ulf
authors: U
authors: Smith
authors: Maria I
authors: MI
authors: Bokarewa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D052243:Resistin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013582:Synovial Fluid / Q000378:metabolism; D013583:Synovial Membrane / Q000378:metabolism
chemical_list: C515497:IGFBP3 protein, human; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; D052243:Resistin; D007334:Insulin-Like Growth Factor I