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Isolation and Culture of Primary Synovial Macrophages and Fibroblasts from Murine Arthritis Tissue
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mTOR regulates the invasive properties of synovial fibroblasts in rheumatoid arthritis

Teresina Laragione1, Pércio S Gulko

  • 1Laboratory of Experimental Rheumatology, Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.

Molecular Medicine (Cambridge, Mass.)
|June 3, 2010
PubMed

Insights

Rapamycin significantly reduced fibroblast-like synoviocytes (FLS) invasion in rheumatoid arthritis (RA) models by inhibiting the mTOR pathway. This suggests rapamycin may be a potential therapy to reduce joint damage in RA.

Area of Science:

  • Immunology
  • Rheumatology
  • Molecular Biology

Background:

  • Fibroblast-like synoviocytes (FLS) invasiveness correlates with joint damage in rheumatoid arthritis (RA) and pristane-induced arthritis (PIA).
  • Highly invasive FLS express cancer-associated genes like Villin-2/ezrin, which mediates invasion via the mTOR pathway.

Purpose of the Study:

  • To investigate the role of the ezrin-mTOR pathway in FLS invasion using the mTOR inhibitor rapamycin.
  • To assess rapamycin's effect on FLS invasiveness and related molecular signaling in RA and PIA models.

Main Methods:

  • FLS were isolated from arthritic DA rats (PIA model) and RA patients.
  • Cells were treated with rapamycin or DMSO and analyzed using Matrigel-invasion assays.
  • Western blotting and immunofluorescence were used to quantify signaling proteins (mTOR, p70S6K1, 4EBP1, FAK) and assess cytoskeletal changes.

Main Results:

  • Rapamycin significantly reduced FLS invasion by 93% in DA rats and 82% in RA patients.
  • Rapamycin inhibited mTOR signaling, evidenced by reduced phosphorylation of mTOR, p70S6K1, and 4EBP1.
  • Rapamycin prevented actin reorganization and lamellipodia formation, and reduced FAK phosphorylation, without significantly affecting MMP activity.

Conclusions:

  • Rapamycin effectively suppresses FLS invasion in both RA and PIA models by inhibiting the mTOR signaling pathway.
  • The ezrin-mTOR pathway is crucial for FLS invasiveness and cytoskeletal rearrangements.
  • Rapamycin shows potential as a therapeutic agent to mitigate joint damage in rheumatoid arthritis.

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