Treatment of collagen induced arthritis by proteolytic enzymes: immunomodulatory and disease modifying effects

J Rheumatol. 2001 Sep;28(9):2049-59.


Objective: To investigate the efficacy of a novel therapy (proteases) in an animal model of rheumatoid arthritis, and to investigate the mechanisms of arthritogenesis.

Methods: We induced progressive arthritis in male DBA/1 mice by immunization and boosting with Type II collagen; groups of mice were treated orally twice daily with either ibuprofen or proteases, or were left untreated. After 2 weeks, joints were scored for clinical, radiographic, and histologic changes. In addition, we measured serum levels of IgG anti-collagen II, the glycosylation of circulating total and anti-collagen II IgG, and cytokine production by lymphocytes isolated from lymph nodes.

Results: Amelioration of joint inflammation, and accentuation of a prototypical Th2 cytokine (interleukin 5) were similar in the ibuprofen and protease treatment groups. However, protease treatment protects and preserves articular cartilage, normalizes the sialylation of IgG and anti-collagen antibody, and fully restores Th1 (interferon-gamma) synthesis, distinct from ibuprofen.

Conclusion: Protease therapy has antiinflammatory efficacy in the early (inflammatory) phase of collagen induced arthritis, similar to ibuprofen. The immunomodulatory effects of proteases, not seen with ibuprofen, may underlie a correction of aberrant IgG glycosylation and/or contribute to the increased capacity of protease to delay or forestall erosive and destructive arthritis or ankylosis. Similar effects may apply to spontaneous RA in humans.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Anti-Idiotypic / analysis*
  • Arthritis, Rheumatoid / diagnostic imaging
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / pathology*
  • Collagen
  • Disease Models, Animal
  • Ibuprofen / pharmacology*
  • Immunoglobulin G / analysis*
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Inbred DBA
  • Peptide Hydrolases / pharmacology*
  • Radiography
  • Reference Values
  • Sensitivity and Specificity
  • Treatment Outcome


  • Antibodies, Anti-Idiotypic
  • Immunoglobulin G
  • Collagen
  • Peptide Hydrolases
  • Ibuprofen