Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Inhibition of c-Fos/AP-1 Suppresses Passive Anti-Collagen Antibody-Induced Arthritis in Mice.

Mikami4,  Masaaki, Aikawa5,  Yukihiko, Hashiramoto3,  Akira, Yamamoto5,  Mari, Murao5,  Hidetoshi, Chaki5,  Hisaaki, Narita5,  Hirokazu

Department of Pharmaceutical Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan
Division of Rheumatology, Kobe University Graduate School of Health Sciences and Medicine/ The Center for Rheumatic Diseases, Kobe University Hospital, Kobe, Japan
Division of Rheumatology, Kobe University Graduate School of Health Sciences and Medicine/ The Center for Rheumatic Diseases, Kobe University Hospital, Kobe, Japan
Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan
Research Laboratories, Toyama Chemical Co., Ltd., Toyama, Japan

Purpose:

Activator protein-1 (AP-1) directly regulates the genes that participate in rheumatoid arthritis (RA), including inflammatory cytokines and matrix metalloproteinases (MMPs). Anti-collagen antibody (Ab)-induced arthritis (CAIA) in mice is beneficial to study the inflammatory phase of arthritis without involving the priming phase of the immune response. Therefore, to elucidate the involvement of c-Fos/AP-1 in the development of arthritis, the levels of c-Fos/AP-1 in the hind paws were determined, and the effect of a novel c-Fos/AP-1 inhibitor T-5224 on CAIA was investigated.

Methods:

CAIA was induced in BALB/c mice by i.p. injection of the mixture of anti-type II collagen (CII) Abs on day 0 and LPS on day 3. The levels of c-Fos/AP-1 in extracts from hind paws were determined using TransAM™ kit on day 0, 3, 4, 7, and 15. T-5224 was orally administered once daily. The effect was assessed by arthritis score, pathological examination, and serum biological analysis of IL-1b and MMP-3. Furthermore, effects of methotrexate (MTX) and leflunomide were also evaluated in the same procedure for the comparison.

Results:

c-Fos/AP-1 activity increased in the hind paws of mice after day 4 in coincidence with onset of the arthritis. The administration of T-5224 from day 5 efficiently suppressed the development of arthritis at 1 to 30 mg/kg, and the arthritis score on day 14 was inhibited by 81% at 30 mg/kg (ED50: 6.0 mg/kg). Histological changes such as cartilage degradation in the joints of hind paws of mice with T-5224 were also suppressed on day 14. In addition, the increases of IL-1b and MMP-3 levels in sera were reduced by T-5224, and the inhibition rates at 30 mg/kg were 97% and 89%, respectively. On the other hand, either MTX at 3 mg/kg or leflunomide at 30 mg/kg had no effects on passive CAIA.

Conclusions:

The activation of c-Fos/AP-1 was observed in the arthritic lesion of mouse CAIA in which the priming phase of the immune response is skipped. Inhibition of c-Fos/AP-1 by T-5224 attenuated the arthritis through suppressing the inflammatory cytokine and matrix degrading MMP. On the other hand, immunosuppressive treatment with MTX and leflunomide did not show the inhibitory effects on CAIA. These data support a key role of c-Fos/AP-1 in the development of arthritis and joint destruction, and suggest that T-5224 with the novel mechanism of action is expected to exert anti-arthritic effects in the therapy of RA.

To cite this abstract, please use the following information:
Mikami, Masaaki, Aikawa, Yukihiko, Hashiramoto, Akira, Yamamoto, Mari, Murao, Hidetoshi, Chaki, Hisaaki, et al; Inhibition of c-Fos/AP-1 Suppresses Passive Anti-Collagen Antibody-Induced Arthritis in Mice. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :280
DOI: 10.1002/art.28049

Abstract Supplement

Meeting Menu

2010 ACR/ARHP