title: TNF-induced structural joint damage is mediated by IL-1.
abstract: 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.
authors.affiliation: Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Kurt
authors.initials: K
authors.lastname: Redlich
authors.forename: Karin
authors.initials: K
authors.lastname: Polzer
authors.forename: Leo
authors.initials: L
authors.lastname: Joosten
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krönke
authors.forename: Joerg
authors.initials: J
authors.lastname: Distler
authors.forename: Andreas
authors.initials: A
authors.lastname: Hess
authors.forename: Noreen
authors.initials: N
authors.lastname: Pundt
authors.forename: Thomas
authors.initials: T
authors.lastname: Pap
authors.forename: Oskar
authors.initials: O
authors.lastname: Hoffmann
authors.forename: Juerg
authors.initials: J
authors.lastname: Gasser
authors.forename: Clemens
authors.initials: C
authors.lastname: Scheinecker
authors.forename: Josef S
authors.initials: JS
authors.lastname: Smolen
authors.forename: Wim
authors.initials: W
authors.lastname: van den Berg
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*; D015431:Weight Loss / Q000235:genetics / Q000276:immunology
chemical_list: D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha