Open AccessTNF-induced structural joint damage is mediated by IL-1
Author(s) -
Jochen Zwerina,
Kurt Redlich,
K Polzer,
Leo A. B. Joosten,
Gerhard Krönke,
J. Distler,
Andreas Heß,
Noreen Pundt,
Thomas Pap,
Oskar Hoffmann,
Jürg A. Gasser,
Clemens Scheinecker,
Josef S. Smolen,
W. van den Berg,
Georg Schett
Publication year - 2007
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0610812104
Subject(s) - inflammation , tumor necrosis factor alpha , cartilage , arthritis , immunology , rheumatoid arthritis , microbiology and biotechnology , osteoclast , medicine , biology , receptor , anatomy
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-1α and β-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.