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

Arthritis Rheum. 1998 Apr;41(4):634-46. doi: 10.1002/1529-0131(199804)41:4<634::AID-ART10>3.0.CO;2-1.


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.

Conclusion: 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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use
  • Arthritis / chemically induced
  • Arthritis / metabolism*
  • Arthritis / physiopathology
  • Cartilage, Articular / chemistry
  • Cartilage, Articular / metabolism
  • Cartilage, Articular / pathology
  • Chondrocytes / chemistry
  • Chondrocytes / metabolism
  • Depression, Chemical
  • Heterozygote
  • Hypertrophy / physiopathology
  • Inflammation Mediators / metabolism
  • Insulin-Like Growth Factor I / metabolism
  • Interleukin-1 / immunology
  • Interleukin-1 / physiology
  • Knee Joint / chemistry
  • Knee Joint / metabolism
  • Knee Joint / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Nitric Oxide / physiology
  • Nitric Oxide Synthase / deficiency
  • Nitric Oxide Synthase / genetics
  • Ossification, Heterotopic / physiopathology
  • Proteoglycans / biosynthesis
  • Proteoglycans / metabolism*
  • Synovial Membrane / chemistry
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology
  • Zymosan


  • Antibodies, Monoclonal
  • Inflammation Mediators
  • Interleukin-1
  • Proteoglycans
  • Nitric Oxide
  • Insulin-Like Growth Factor I
  • Zymosan
  • Nitric Oxide Synthase