title: IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation.
abstract: Anti-TNF-alpha treatment of rheumatoid arthritis patients markedly suppresses inflammatory disease activity, but so far no tissue-protective effects have been reported. In contrast, blockade of IL-1 in rheumatoid arthritis patients, by an IL-1 receptor antagonist, was only moderately effective in suppressing inflammatory symptoms but appeared to reduce the rate of progression of joint destruction. We therefore used an established collagen II murine arthritis model (collagen-induced arthritis(CIA)) to study effects on joint structures of neutralization of either TNF-alpha or IL-1. Both soluble TNF binding protein and anti-IL-1 treatment ameliorated disease activity when applied shortly after onset of CIA. Serum analysis revealed that early anti-TNF-alpha treatment of CIA did not decrease the process in the cartilage, as indicated by the elevated COMP levels. In contrast, anti-IL-1 treatment of established CIA normalized COMP levels, apparently alleviating the process in the tissue. Histology of knee and ankle joints corroborated the finding and showed that cartilage and joint destruction was significantly decreased after anti-IL-1 treatment but was hardly affected by anti-TNF-alpha treatment. Radiographic analysis of knee and ankle joints revealed that bone erosions were prevented by anti-IL-1 treatment, whereas the anti-TNF-alpha-treated animals exhibited changes comparable to the controls. In line with these findings, metalloproteinase activity, visualized by VDIPEN production, was almost absent throughout the cartilage layers in anti-IL-1-treated animals, whereas massive VDIPEN appearance was found in control and sTNFbp-treated mice. These results indicate that blocking of IL-1 is a cartilage- and bone-protective therapy in destructive arthritis, whereas the TNF-alpha antagonist has little effect on tissue destruction.
authors.affiliation: Department of Rheumatology, University Hospital Nijmegen, The Netherlands. l.joosten@reuma.azn.nl
authors.forename: L A
authors.initials: LA
authors.lastname: Joosten
authors.forename: M M
authors.initials: MM
authors.lastname: Helsen
authors.forename: T
authors.initials: T
authors.lastname: Saxne
authors.forename: F A
authors.initials: FA
authors.lastname: van De Loo
authors.forename: D
authors.initials: D
authors.lastname: Heinegard
authors.forename: W B
authors.initials: WB
authors.lastname: van Den Berg
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000008:administration & dosage; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology*; D002358:Cartilage, Articular / Q000473:pathology*; D002417:Cattle; D003094:Collagen / Q000276:immunology*; D000939:Epitopes / Q000096:biosynthesis; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000097:blood; D006023:Glycoproteins / Q000037:antagonists & inhibitors / Q000097:blood; D007106:Immune Sera / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D007596:Joints / Q000473:pathology*; D008297:Male; D064235:Matrilin Proteins; D051379:Mice; D008811:Mice, Inbred DBA; D009842:Oligopeptides / Q000096:biosynthesis / Q000276:immunology; D010446:Peptide Fragments / Q000096:biosynthesis / Q000276:immunology; D011859:Radiography; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage; D047888:Receptors, Tumor Necrosis Factor, Type I; D013643:Tarsus, Animal / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D015703:Antigens, CD; D000939:Epitopes; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D007106:Immune Sera; D007375:Interleukin-1; C577540:Matn1 protein, mouse; D064235:Matrilin Proteins; D009842:Oligopeptides; D010446:Peptide Fragments; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C093378:peptide VDIPEN; D003094:Collagen