title: Reduced cartilage proteoglycan loss during zymosan-induced gonarthritis in NOS2-deficient mice and in anti-interleukin-1-treated wild-type mice with unabated joint inflammation.
abstract: OBJECTIVE
  To investigate the role of nitric oxide (NO) and interleukin-1 in (IL-1) joint inflammation and cartilage destruction during zymosan-induced gonarthritis (ZIA).
  
  
  METHODS
  Monarticular arthritis was elicited by intraarticular injection of zymosan. The effect of NO deficiency on arthritis was studied in mice with genetically disrupted NOS2. The role of IL-1 was examined by treating wild-type mice with neutralizing anti-murine IL-1(alpha+beta) antibodies. Joint swelling was measured externally by the increased uptake of circulating 99mtechnetium pertechnetate. Proteoglycan (PG) synthesis was assessed using 35S-sulfate incorporation into patellae ex vivo. Histology evaluated exudation and infiltration of leukocytes and the extent of cartilage destruction.
  
  
  RESULTS
  The proinflammatory mediators NO, IL-1, and IL-6 were released by the articular tissues during the first hours of inflammation. Interestingly, anti-IL-1 treatment moderately reduced, and NOS2 deficiency moderately enhanced, joint swelling. However, the influx of neutrophils into the joint occurred independently of IL-1 and NOS2 activities. In the first week of inflammation, chondrocyte PG synthesis was significantly suppressed and chondrocytes became unresponsive to their essential anabolic factor, insulin-like growth factor 1 (IGF-1). Anti-IL-1 treatment or NOS2 deficiency prevented the inhibition of PG synthesis, and the chondrocytes remained IGF-1 responsive. Intraarticular injections of IL-1alpha into NOS2-deficient mice did not affect PG synthesis, thus proving that NO mediated this IL-1 effect in vivo. Furthermore, histology showed that cartilage PG loss was markedly ameliorated in NOS2-deficient and anti-IL-1-treated mice. Intermediate cartilage pathology was found in mice that were heterozygous for disrupted NOS2.
  
  
  CONCLUSIONS
  IL-1 and NO play a minor role in edema and neutrophil influx, but a major role in cartilage destruction of ZIA. In this model of murine arthritis, cartilage destruction was, for the most part, caused by pronounced suppression of PG synthesis and IGF-1 unresponsiveness of the chondrocytes, which were induced by de novo-synthesized IL-1 and were mediated by NOS2 activation.
authors.affiliation: University Hospital Nijmegen, The Netherlands.
authors.forename: F A
authors.initials: FA
authors.lastname: van de Loo
authors.forename: O J
authors.initials: OJ
authors.lastname: Arntz
authors.forename: F H
authors.initials: FH
authors.lastname: van Enckevort
authors.forename: P L
authors.initials: PL
authors.lastname: van Lent
authors.forename: W B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D001168:Arthritis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D002358:Cartilage, Articular / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D019902:Chondrocytes / Q000737:chemistry / Q000378:metabolism; D003864:Depression, Chemical; D006579:Heterozygote; D006984:Hypertrophy / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007375:Interleukin-1 / Q000276:immunology / Q000502:physiology; D007719:Knee Joint / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000172:deficiency / Q000235:genetics; D009999:Ossification, Heterotopic / Q000503:physiopathology; D011509:Proteoglycans / Q000096:biosynthesis / Q000378:metabolism*; D013583:Synovial Membrane / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D015054:Zymosan
chemical_list: D000911:Antibodies, Monoclonal; D018836:Inflammation Mediators; D007375:Interleukin-1; D011509:Proteoglycans; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; D015054:Zymosan; D019001:Nitric Oxide Synthase