Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis
Nobuchika Yamamoto, Fumihiko Sakai, Shigeyuki Kon, Junko Morimoto, Chiemi Kimura, Harumi Yamazaki, Ikuko Okazaki, Nobuo Seki, Takashi Fujii, Toshimitsu Uede
Nobuchika Yamamoto, Fumihiko Sakai, Shigeyuki Kon, Junko Morimoto, Chiemi Kimura, Harumi Yamazaki, Ikuko Okazaki, Nobuo Seki, Takashi Fujii, Toshimitsu Uede
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Article Immunology

Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis

Abstract

It has been shown that osteopontin (OPN) plays a pivotal role in the pathogenesis of rheumatoid arthritis (RA). However, the molecular mechanism of OPN action is yet to be elucidated. Splenic monocytes obtained from arthritic mice exhibited a significant capacity for cell migration toward thrombin-cleaved OPN but not toward full-length OPN. Migratory monocytes expressed α9 and α4 integrins. Since cleavage of OPN by thrombin exposes the cryptic epitope recognized by α9 and α4 integrins, we investigated the role of the cryptic epitope SLAYGLR in a murine RA model by using a specific antibody (M5) reacting to SLAYGLR sequence. The M5 antibody could abrogate monocyte migration toward the thrombin-cleaved form of OPN. Importantly, M5 antibody could inhibit the proliferation of synovium, bone erosion, and inflammatory cell infiltration in arthritic joints. Thus, we demonstrated that a cryptic epitope, the SLAYGLR sequence of murine OPN, is critically involved in the pathogenesis of a murine model of RA.

Authors

Nobuchika Yamamoto, Fumihiko Sakai, Shigeyuki Kon, Junko Morimoto, Chiemi Kimura, Harumi Yamazaki, Ikuko Okazaki, Nobuo Seki, Takashi Fujii, Toshimitsu Uede

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Prophylactic and therapeutic treatment with M5 Ab ameliorated symptoms o...
Prophylactic and therapeutic treatment with M5 Ab ameliorated symptoms of arthritis. M5 Ab was administered intravenously at doses of 40, 150, and 400 μg per mouse before the onset of clinical symptoms on days 0 and 3. The arthritic group was intravenously administered 400 μg of rabbit IgG. Arthritic score (a), incidence of arthritis (b), food intake (d), and body weight (e) were monitored. Representative gross appearances of the forepaw are shown (c). Arthritic mice were therapeutically treated with M5 Ab after the onset of symptoms on day 3, and arthritic scores were monitored (f). Each point represents the mean score ± SEM of five mice. *P < 0.05 and **P < 0.01 for comparison by Mann-Whitney U test with arthritic mice; ##P < 0.01 for comparison by Dunnet’s multiple-comparison test with arthritic mice.