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Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis
Nobuchika Yamamoto, … , Takashi Fujii, Toshimitsu Uede
Nobuchika Yamamoto, … , Takashi Fujii, Toshimitsu Uede
Published July 15, 2003
Citation Information: J Clin Invest. 2003;112(2):181-188. https://doi.org/10.1172/JCI17778.
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Article Immunology

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

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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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Figure 1

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Monocyte migration in response to thrombin-cleaved OPN. (a) Splenic mono...
Monocyte migration in response to thrombin-cleaved OPN. (a) Splenic monocytes from normal (white bars) and arthritic (black bars) mice on day 6 of migration in response to full-length murine OPN (FL-mOPN) and thrombin-cleaved murine OPN (Thr-mOPN) at 10 μg/ml. (b) The time course of the migration response toward medium (square), full-length (triangle), and thrombin-cleaved OPN (circle) was evaluated. The results are expressed as mean numbers ± SEM of migrated cells. *P < 0.05 and **P < 0.01. (c) Expression of α9 integrin mRNA levels in spleen of arthritic mice on days 0, 1, 3, and 6 after LPS administration was analyzed using RT-PCR and GAPDH as a housekeeping gene. Template cDNA was diluted sequentially (left to right) and amplified by PCR. (d) Expressions of α4 and β3 integrins and CD44 on splenocytes obtained from normal (dotted line) and arthritic (solid line) mice were analyzed by FACS. Histograms represent the mean fluorescence intensity. Controls are from isotype-matched irrelevant antibodies.

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