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Published online on July 3, 2007, 10.1073/pnas.0610812104
PNAS | July 10, 2007 | vol. 104 | no. 28 | 11742-11747


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BIOLOGICAL SCIENCES / MEDICAL SCIENCES
TNF-induced structural joint damage is mediated by IL-1

Jochen Zwerina*,{dagger}, Kurt Redlich*, Karin Polzer{dagger}, Leo Joosten{ddagger}, Gerhard Krönke{dagger}, Joerg Distler{dagger}, Andreas Hess§, Noreen Pundt, Thomas Pap, Oskar Hoffmann||, Juerg Gasser**, Clemens Scheinecker*, Josef S. Smolen*, Wim van den Berg{ddagger}, and Georg Schett*,{dagger},{dagger}{dagger}

*Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria; {dagger}Department of Internal Medicine 3, University of Erlangen-Nuremberg, 91054 Erlangen, Germany; {ddagger}Rheumatology Research and Advanced Therapeutics and Departments of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, 7500 AE, Enschede, The Netherlands; §Institute for Pharmacology and Toxicology, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany; Division of Molecular Medicine of Musculoskeletal Tissue, University Hospital Muenster, 48129 Muenster, Germany; ||Institute for Pharmacology and Toxicology, University of Vienna, A-1010 Vienna, Austria; and **Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland

Edited by Charles A. Dinarello, University of Colorado Health Sciences Center, Denver, CO, and approved June 1, 2007 (received for review December 6, 2006)

Blocking TNF effectively inhibits inflammation and structural damage in human rheumatoid arthritis (RA). However, so far it is unclear whether the effect of TNF is a direct one or indirect on up-regulation of other mediators. IL-1 may be one of these candidates because it has a central role in animal models of arthritis, and inhibition of IL-1 is used as a therapy of human RA. We removed the effects of IL-1 from a TNF-mediated inflammatory joint disease by crossing IL-1{alpha} and beta-deficient mice (IL-1–/–) with arthritic human TNF-transgenic (hTNFtg) mice. Development of synovial inflammation was almost unaffected on IL-1 deficiency, but bone erosion and osteoclast formation were significantly reduced in IL-1–/–hTNFtg mice, compared with hTNFtg mice based on an intrinsic differentiation defect of IL-1-deficient monocytes. Most dramatically, however, cartilage damage was absent in IL-1–/–hTNFtg mice. Chimera studies revealed that protection of cartilage is based on the loss of IL-1 on hematopoietic, but not mesenchymal, cells, leading to decreased expression of ADAMTS-5 and MMP-3. These data show that TNF-mediated cartilage damage is completely and TNF-mediated bone damage is partially dependent on IL-1, suggesting that IL-1 is a crucial mediator for inflammatory cartilage and bone degradation.

cytokines | rheumatoid arthritis | cartilage

Author contributions: J.Z. and K.R. contributed equally to this work; J.Z., T.P., W.v.d.B., and G.S. designed research; J.Z., K.P., G.K., J.D., A.H., N.P., O.H., J.G., and C.S. performed research; L.J. contributed new reagents/analytic tools; J.Z., K.R., K.P., T.P., J.S.S., W.v.d.B., and G.S. analyzed data; and J.Z. and G.S. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0610812104/DC1.

{dagger}{dagger}To whom correspondence should be addressed. E-mail: georg.schett{at}med3.imed.uni-erlangen.de

© 2007 by The National Academy of Sciences of the USA


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