Apoptosis Is a Novel Therapeutic Strategy for RA: Investigations Using an Experimental Arthritis Animal Model

  • Hiroaki Matsuno
  • Kazuo Yudoh
  • Isaya Morita
  • Takashi Sawai
  • Miwa Uzuki
  • Tomoko Hasunuma
  • Kusuki Nishioka
  • Haruo Tsuji
  • Tomoatsu Kimura


To investigate the time at which apoptotic cells appear during the course of synovitis in rheumatoid arthritis (RA) patients, we conducted a time-course observation of changes of apoptotic cells in collagen-induced arthritis mice as a RA model. No apoptotic cells were detected before the onset of synovitis. The number of such cells increased parallel to the progress of the arthritis in its initial stages, and the number of cells decreased in the proliferative stage of arthritis. These results suggest that apoptotic cells appear to maintain homeostasis when there is synovium proliferation which is undesirable for the morphological maintenance of a joint. If the induction of apoptosis is possible in RA synovitis, this procedure might lead to a cure for RA. Based on this hypothesis, apoptosis therapeutic experiments using the anti-Fas m Ab and Fas-ligand were performed in SCID-HuRAg mice implanted with human RA synovial tissues. It was found, that the synovitis implanted in mice was reduced markedly, suggesting that apoptosis induction therapy may be a novel treatment strategy for RA.

Key words

Rheumatoid arthritis SCID mouse Treatment Apoptosis Collagen-induced arthritis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Hurle JM, Ros MA, Garcia-Martinez V, Macias D, Ganan Y (1995) Cell death in the embryonic developing limb. Scan Microscop 9(2):519–534Google Scholar
  2. 2.
    von Boehmer H (1992) Thymic selection: a matter of life and death. Immunol Today 13(11):454–458CrossRefGoogle Scholar
  3. 3.
    Wyllie AH (1980) Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation. Nature 284(5756):555–556PubMedCrossRefGoogle Scholar
  4. 4.
    Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119(3):493–501PubMedCrossRefGoogle Scholar
  5. 5.
    Nakajima T, Aono H, Hasunuma T, Yamamoto K, Shirai T, Hirohata K, Nishioka K (1995) Apoptosis and functional Fas antigen in rheumatoid arthritis synoviocytes. Arthritis Rheum 38(4):485–491PubMedCrossRefGoogle Scholar
  6. 6.
    Hirohata S, Hirohata K (1994) Interactions between lymphocytes and type A synoviocytes in rheumatoid synovium (letter). Lancet 344(8930):1158PubMedCrossRefGoogle Scholar
  7. 7.
    Firestein GS, Yeo M, Zvaifler NJ (1995) Apoptosis in rheumatoid arthritis synovium. J Clin Invest 96(3):1631–1638PubMedCrossRefGoogle Scholar
  8. 8.
    Harris ED Jr (1990) Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 322(18):1277–1289PubMedCrossRefGoogle Scholar
  9. 9.
    Stamenkovic I, Stegagno M, Wright KA, Krane SM, Amento EP, Colvin RB, Duquesnoy RJ, Kurnick JT (1988) Clonal dominance among T-lymphocyte infiltrates in arthritis. Proc Natl Acad Sei USA 85(4):1179–1183CrossRefGoogle Scholar
  10. 10.
    Ogden JA, Grogan DP (1987) Prenatal development and growth of the musculoskeletal system. In: Albright JA, Brand RA (eds) The scientific basis of orthopaedics (2nd edn). Appleton & Lange, New York, pp 47–89Google Scholar
  11. 11.
    Steinbroker O, Traeger CH, Batterman RC (1949) Therapeutic criteria in rheumatoid arthritis. JAMA 140:659–662CrossRefGoogle Scholar
  12. 12.
    Morita I, Matsuno H, Sakai K, Nezuka T, Tsuji H, Shirai T, Nishioka K (1998) Time course of apoptosis in collagen-induced arthritis. Int J Tissue React 20(2):37–43PubMedGoogle Scholar
  13. 13.
    Matsuno H, Matsushita I, Okada C, Suzuki M, Tsuji H, Ochiai H (1991) Role of lymphocytes in collagen induced arthritis. J Rheumatol 18:1344–1349PubMedGoogle Scholar
  14. 14.
    Kadowaki KM, Matsuno H, Tsuji H, Tunru I (1994) CD4+ T cells from collagen induced arthritic mice are essential to transfer arthritis into severe combined immunodeficient mice. Clin Exp Immunol 97:212–218PubMedCrossRefGoogle Scholar
  15. 15.
    Jones SA, Kennedy AJ, Roberts NA (1982) Assessment of drugs for activity in established type II collagen arthritis. Agents Actions 12:650–656PubMedCrossRefGoogle Scholar
  16. 16.
    Horneff G, Burmester GR, Emmrich F, Kalden JR (1991) Treatment of rheumatoid arthritis with an anti-CD4 monoclonal antibody. Arthritis Rheum 34(2):129–140PubMedCrossRefGoogle Scholar
  17. 17.
    Choy EH, Chikanza IC, Kingsley GH, Corrigall V, Panayi GS (1992) Treatment of rheumatoid arthritis with single dose or weekly pulses of chimaeric anti-CD4 monoclonal antibody. Scand J Immunol 36(2):291–298PubMedCrossRefGoogle Scholar
  18. 18.
    Verhoeyen M, Mustein C, Winter G (1988) Reshaping human antibodies: grafting an antilysozyme activity. Science 239(4847):1534–1536PubMedCrossRefGoogle Scholar
  19. 19.
    Riechmann L, Clark M, Waldmann H, Winter G (1988) Reshaping human antibodies for therapy. Nature 332(6162):323–327PubMedCrossRefGoogle Scholar
  20. 20.
    Sakai K, Matsuno H, Nezuka T, Tsuji H, Nishioka K, Shirai T, Yonehara S (1996) Inhibitory effect on rheumatoid synovitis by induction of apoptosis using in vivo model of human rheumatoid arthritis. 8th APLAR Congress of Rheumatology s25, MelbourneGoogle Scholar
  21. 21.
    Matsuno H, Nezuka T, Sakai K, Morita I, Nishioka K, Shirai T, Tsuji H (1997) Etiology and treatment effects of apoptosis in RA patients using animal model study. Arthritis Rheum 40(9):S294Google Scholar
  22. 22.
    Matsuno H, Sawai T, Nezuka T, Uzuki M, Tsuji H, Nishimoto N, Yoshizaki K (1998) Treatment of RA synovitis with anti-reshaping human IL-6 receptor monoclonal antibody: using a RA tissue implants in SCID mouse model. Rheum 41(11):2014–2021CrossRefGoogle Scholar
  23. 23.
    Nezuka T, Matsuno H, Sawai T, Saeki Y, Uzuki M, Tsuji H (1997) Inhibitory effects of TNF-oc in engraftment RA synovium into SCID model. Arthritis Rheum 40(9): S79Google Scholar
  24. 24.
    Okamoto K, Asahara T, Kobayashi H, Matsuno H, Hasunuma T, Kobata T, Sumida T, Nishioka K (1998) Fas ligand transfectants induce apoptosis in human rheumatoid synoviocytes. Gene Therapy, 5:331–338PubMedCrossRefGoogle Scholar
  25. 25.
    Rendt KE, Barry TS, Jones DM, Richter CB, McCachren SS, Haynes BF (1993) Engraftment of human synovium into severe combined immune deficient mice. Migration of human peripheral blood T cells to engrafted human synovium and to mouse lymph nodes. J Immunol 151:7324–7336PubMedGoogle Scholar
  26. 26.
    Geiler T, Kriegsmann J, Keyszer GM, Gay RE, Gay S (1994) A new model for rheumatoid arthritis generated by engraftment of rheumatoid synovial tissue and normal human cartilage into SCID mice. Arthritis Rheum 37:1664–1671PubMedCrossRefGoogle Scholar
  27. 27.
    Sack U, Kuhn H, Ermann J, Kinne RW, Vogt S, Jungmichel D, Emmrich F (1994) Synovial tissue implants from patients with rheumatoid arthritis cause cartilage destruction in knee joints of SCID. bg mice. J Rheumatol 21:10–16PubMedGoogle Scholar
  28. 28.
    Sack U, Kuhn H, Kampfer I, Genest M, Arnold S, Pfeiffer G, Emmrich F (1996) Orthotopic implantation of inflamed synovial tissue from RA patients induces a characteristic arthritis in immunodeficient (SCID) mice. J Autoimmun 9:51–58PubMedCrossRefGoogle Scholar
  29. 29.
    Sakai K, Matsuno H, Morita I, Nezuka T, Tsuji H, Shirai T, Yonehara S, Hasunuma T, Nishioka K (1998) Potential withdrawal of rheumatoid synovium by the induction of apoptosis using a novel in vivo model of rheumatoid arthritis. Arthritis Rheum 41(7):1251–1257PubMedCrossRefGoogle Scholar
  30. 30.
    Deleuran BW, Chu CQ, Field M, Brennan FM, Mitchell T, Feldmann M, Maini RN (1992) Localization of tumor necrosis factor receptors in the synovial tissue and cartilage-pannus junction in patients with rheumatoid arthritis—Implication for local actions of tumor necrosis factor-α. Arthritis Rheum 35:1170–1178PubMedCrossRefGoogle Scholar
  31. 31.
    Fukamachi T, Uzuki M, Tamura H, Nakai H, Koishihara Y, Sawai T (1994) Interleukin-6 receptor (IL-6R) dynamics in patients with rheumatoid arthritis (in Japanese with English abstract). Jpn J Inflamm 14:489–496Google Scholar
  32. 32.
    Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H (1984) Cell cycle analysis of a proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133.1710–1715PubMedGoogle Scholar
  33. 33.
    Tokano Y, Kobayashi S (1997) Methotrexate therapy (in Japanese). Rheumatology 17(3):288–292Google Scholar
  34. 34.
    Nagata S, Golstein P (1995) The Fas death factor. Science 267(5203):1449–1456PubMedCrossRefGoogle Scholar
  35. 35.
    Fujisawa K, Asahara H, Okamoto K, Aono H, Hasunuma T, Kobata T, Iwakura Y, Yonehara S, Sumida T, Nishioka K (1996) Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-1 tax transgenic mice. J Clin Invest 98(2):271–278PubMedCrossRefGoogle Scholar
  36. 36.
    Fadeel B, Thorpe CJ, Yonehara S, Chiodi F (1997) Anti-Fas IgGl antibodies recognizing the same epitope of Fas/APO-1 mediate different biological effects in vitro. Int Immunol 9(2):201–209PubMedCrossRefGoogle Scholar
  37. 37.
    Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H, Woody JN (1994) Randomised double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 344(8930):1105–1110PubMedCrossRefGoogle Scholar
  38. 38.
    Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Bijl H, Woody JN (1994) Repeated therapy with monoclonal antibody to tumor necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet 344(8930):1125–1127PubMedCrossRefGoogle Scholar
  39. 39.
    Brennan FM, Browne KA, Green PA, Jaspar JM, Maini RN, Feldmann M (1997) Reduction of serum matrix metalloproteinase 1 and matrix metalloproteinase 3 in rheumatoid arthritis patients following anti-tumor necrosis factor-alpha (cA2) therapy. Brit J Rheumatol 36(6):643–650CrossRefGoogle Scholar
  40. 40.
    Yuan J. Transducing signals of life and death. Curr Opin Cell Biol 9(2):247–251Google Scholar
  41. 41.
    Ohsima S, Saeki Y, Mima T, Sasai M, Shimizu M, Murata N, Nakanishi K, Suemura M, McCloskey RV, Kishimoto T (1997) Tumor necrosis factor-α (TNF-α)interferes with Fas mediated apoptotic cell death on RA synovial cells. Arthritis Rheum 40(9):S289Google Scholar
  42. 42.
    Asahara H, Hasunuma T, Kobata T, Inoue H, Muller-Ladner U, Gay S, Sumida T, Nishioka K (1997) In situ expression of protooncogenes and Fas/Fas ligand in rheumatoid arthritis synovium. J Rheumatol 24(3):430–305PubMedGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 1999

Authors and Affiliations

  • Hiroaki Matsuno
    • 1
  • Kazuo Yudoh
    • 1
  • Isaya Morita
    • 1
  • Takashi Sawai
    • 2
  • Miwa Uzuki
    • 2
  • Tomoko Hasunuma
    • 3
  • Kusuki Nishioka
    • 3
  • Haruo Tsuji
    • 1
  • Tomoatsu Kimura
    • 1
  1. 1.Department of Orthopaedic SurgeryToyama Medical and Pharmaceutical UniversityToyamaJapan
  2. 2.Department of PathologyIwate Medical University School of MedicineMorioka 020Japan
  3. 3.Institute of Medical of ScienceSt. Marianna University School of MedicineMiyamae-ku, Kawasaki 216Japan

Personalised recommendations