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PI3Kgamma regulates cartilage damage in chronic inflammatory arthritis

Silvia Hayer1, Noreen Pundt, Marvin A Peters

  • 1Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|September 8, 2009
PubMed

Insights

Phosphoinositide 3-kinase gamma (PI3Kgamma) regulates fibroblast activity, reducing cartilage destruction in inflammatory arthritis. Targeting PI3Kgamma may treat rheumatoid arthritis by inhibiting fibroblast activation and joint damage.

Area of Science:

  • Immunology
  • Molecular Biology
  • Rheumatology

Background:

  • Phosphoinositide 3-kinase gamma (PI3Kgamma) was traditionally considered exclusive to leukocytes, regulating inflammatory cell recruitment.
  • PI3Kgamma deficiency in mice impairs adaptive immunity and reduces inflammation in a rheumatoid arthritis model, linked to decreased inflammatory cell influx.

Purpose of the Study:

  • To investigate the role of PI3Kgamma in fibroblast-mediated cartilage destruction in chronic destructive arthritis.
  • To challenge the established view of PI3Kgamma's leukocyte-restricted function.

Main Methods:

  • Utilized human tumor necrosis factor transgenic mice and PI3Kgamma-deficient models.
  • Assessed inflammatory cell recruitment, cartilage damage, and matrix metalloproteinase expression.
  • Performed in vitro analyses on fibroblast invasiveness, Akt, and extracellular signal-regulated kinase phosphorylation.
  • Tested a PI3Kgamma-specific inhibitor on human rheumatoid arthritis synovial fibroblasts.

Main Results:

  • PI3Kgamma deficiency resulted in milder inflammatory arthritis without altering inflammatory cell recruitment.
  • Cartilage damage was significantly reduced due to decreased matrix metalloproteinase expression in fibroblasts and chondrocytes.
  • In vitro studies showed reduced fibroblast invasiveness mediated by decreased Akt and extracellular signal-regulated kinase phosphorylation.
  • A PI3Kgamma inhibitor confirmed these findings in human rheumatoid arthritis synovial fibroblasts, which showed disease-specific PI3Kgamma upregulation.

Conclusions:

  • PI3Kgamma plays a crucial, nonredundant role in regulating fibroblast-mediated cartilage destruction in rheumatoid arthritis.
  • Beyond inflammatory cell recruitment, PI3Kgamma is a key mediator of joint destruction in RA.
  • Targeting PI3Kgamma with specific inhibitors could disrupt RA synovial fibroblast activation and mitigate cartilage damage in rheumatoid arthritis.

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