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Inhibition of forkhead box class O family member transcription factors in rheumatoid synovial tissue

J Ludikhuize1, D de Launay, D Groot

  • 1Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Arthritis and Rheumatism
|June 30, 2007
PubMed
Abstract

Insights

In rheumatoid arthritis (RA) synovial tissue, forkhead box O (FoxO) transcription factors are differentially inactivated, particularly FoxO4 in macrophages, correlating with disease activity markers. This suggests cell-specific FoxO inactivation regulates cell survival and proliferation in RA.

Area of Science:

  • Immunology
  • Molecular Biology
  • Rheumatology

Background:

  • Phosphatidylinositol 3-kinase/protein kinase B (PKB) pathway activation is implicated in rheumatoid arthritis (RA) pathogenesis.
  • PKB regulates cell survival and proliferation by inactivating forkhead box O (FoxO) transcription factors.
  • Understanding FoxO regulation in RA synovium may reveal therapeutic targets.

Purpose of the Study:

  • To investigate differential inactivation of FoxO transcription factors in RA synovial tissue.
  • To correlate FoxO inactivation with clinical and laboratory parameters of RA disease activity.

Main Methods:

  • Immunohistochemistry and quantitative image analysis of synovial biopsy tissue from RA and osteoarthritis (OA) patients.
  • Western blotting to assess IL-1beta and TNFalpha-induced FoxO phosphorylation in cultured synoviocytes and macrophages.
  • Assessment of FoxO1, FoxO3a, and FoxO4 expression and phosphorylation.

Main Results:

  • FoxO1, FoxO3a, and FoxO4 were expressed and phosphorylated in RA and OA synovial tissues.
  • FoxO4 inactivation was significantly enhanced in macrophages from RA synovial sublining compared to OA.
  • Enhanced FoxO4 inactivation in RA correlated negatively with serum C-reactive protein and erythrocyte sedimentation rate.

Conclusions:

  • All three FoxO family members are phosphorylated in RA and OA synovium.
  • Cell-specific inactivation of FoxO, particularly FoxO4 in macrophages, is enhanced in RA.
  • Differential FoxO inactivation likely plays a role in regulating cell survival and proliferation in the RA synovium.

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