Author(s):
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Zwerina, J.; Redlich, K.; Polzer, K.;
Joosten, L.A.B.
; Kronke, G.; Distler, J.; Hess, A.; Pundt, N.; Pap, T.; Hoffmann, O.; Gasser, J.; Scheinecker, C.; Smolen, J.S.;
Berg, W.B. van den
; Schett, G.
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Subject:
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DCN 1: Perception and Action N4i 1: Pathogenesis and modulation of inflammation N4i 4: Auto-immunity, transplantation and immunotherapy NCMLS 1: Immunity, infection and tissue repair NCMLS 1: Infection and autoimmunity UMCN 4.1: Microbial pathogenesis and host defense UMCN 4.2: Chronic inflammation and autoimmunity |
Organization:
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Internal Medicine Rheumatology |
Journal title:
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Proceedings of the National Academy of Sciences USA
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Abstract:
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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-1alpha 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.
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