PI3Kγ regulates cartilage damage in chronic inflammatory arthritis

The gamma isoform of phosphoinositide 3-kinase (PI3K gamma) has been viewed as restricted to leukocytes mediating the regulation of chemokine-induced migration and recruitment of neutrophils, monocytes, and macrophages. In line with the observation that PI3K gamma-deficient mice display defects in adaptive immunity, inhibition of PI3K gamma reduces synovial inflammation in the collagen-induced arthritis mouse model of inflammatory arthritis [rheumatoid arthritis (RA)], which has been attributed to reduced influx of inflammatory cells. Challenging the concept of leukocyte-restricted PI3K gamma function, we report here a novel, nonredundant function of PI3K gamma as an important regulator of fibroblast-induced cartilage destruction during chronic destructive arthritis. We show that in human tumor necrosis factor transgenic mice, the loss of PI3K gamma leads to a milder inflammatory arthritis. Interestingly, PI3K gamma deficiency does not alter the recruitment of inflammatory cells, but significantly reduces cartilage damage through reduced expression of matrix metalloproteinases in fibroblasts and chondrocytes. In vitro analyses demonstrate that the decreased invasiveness of fibroblasts is mediated by reduced phosphorylation of Akt and extracellular signal-regulated kinase. Using a PI3K gamma specific inhibitor, these data are confirmed in human synovial fibroblasts from patients with RA who exhibit a disease-specific up-regulation of PI3K gamma. Our data indicate that in addition to mediating the recruitment of inflammatory cells, PI3K gamma is an important regulator of fibroblast-mediated joint destruction in RA and suggest that specific inhibitors of PI3K gamma will interfere with the activation of RA synovial fibroblasts and reduce cartilage destruction in RA.-Hayer, S., Pundt, N., Peters, M. A., Wunrau, C., Kuhnel, I., Neugebauer, K., Strietholt, S., Zwerina, J., Korb, A., Penninger, J., Joosten, L. A. B., Gay, S., Ruckle, T., Schett, G., Pap, T. Phosphatidylinositol 3-kinase-gamma regulates cartilage damage in chronic inflammatory arthritis. FASEB J. 23, 4288-4298 (2009). www.fasebj.org