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PI3K regulates cartilage damage in chronic inflammatory arthritis

Silvia Hayer^*,1, Noreen Pundt^,1, Marvin A. Peters, Christina Wunrau, Inga Kühnel, Katja Neugebauer, Simon Strietholt, Jochen Zwerina, Adelheid Korb, Josef Penninger^||, Leo A. B. Joosten^¶, Steffen Gay^#, Thomas Rückle^**, Georg Schett^,1,2 and Thomas Pap^,1

^* Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria;

Division of Molecular Medicine of Musculoskeletal Tissue and

Department of Internal Medicine, Nephrology, and Rheumatology, University Hospital Muenster, Muenster, Germany;

Department of Internal Medicine III, University Erlangen-Nuremberg, Erlangen-Nuremberg, Germany;

^|| Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria;

^¶ Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands;

^# Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland; and

^** Operational Excellence, Merck Serono International, Geneva, Switzerland

² Correspondence: Department of Internal Medicine III, University of Erlangen, Krankenhausstrasse 12, 91054 Erlangen, Germany. E-mail: georg.schett{at}uk-erlangen.de

The isoform of phosphoinositide 3-kinase (PI3K) 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-deficient mice display defects in adaptive immunity, inhibition of PI3K 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 function, we report here a novel, nonredundant function of PI3K 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 leads to a milder inflammatory arthritis. Interestingly, PI3K 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 specific inhibitor, these data are confirmed in human synovial fibroblasts from patients with RA who exhibit a disease-specific up-regulation of PI3K. Our data indicate that in addition to mediating the recruitment of inflammatory cells, PI3K is an important regulator of fibroblast-mediated joint destruction in RA and suggest that specific inhibitors of PI3K will interfere with the activation of RA synovial fibroblasts and reduce cartilage destruction in RA.—Hayer, S., Pundt, N., Peters, M. A., Wunrau, C., Kühnel, I., Neugebauer, K., Strietholt, S., Zwerina, J., Korb, A., Penninger, J., Joosten, L. A. B., Gay, S., Rückle, T., Schett, G., Pap, T. Phosphatidylinositol 3-kinase- regulates cartilage damage in chronic inflammatory arthritis.

Key Words: inflammation • rheumatoid arthritis • synovial fibroblast • chondrocytes • signaling