TNF-induced structural joint damage is mediated by IL-1.
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.
Zwerina
Jochen
J
Department of Internal Medicine III, Medical University of Vienna, A-1090 Vienna, Austria.
Redlich
Kurt
K
Polzer
Karin
K
Joosten
Leo
L
Krönke
Gerhard
G
Distler
Joerg
J
Hess
Andreas
A
Pundt
Noreen
N
Pap
Thomas
T
Hoffmann
Oskar
O
Gasser
Juerg
J
Scheinecker
Clemens
C
Smolen
Josef S
JS
van den Berg
Wim
W
Schett
Georg
G
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
D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha