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

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 2

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M5 Ab inhibited migration of splenic monocytes from arthritic mice. (a) ...
M5 Ab inhibited migration of splenic monocytes from arthritic mice. (a) Specificity of M5 Ab against OPN peptides was examined by analysis using BIAcore analysis of M5 Ab. Vertical and horizontal axes indicate surface plasmon resonance intensity (units) and flow time of HBS buffer, respectively. M5 Ab was injected at 200 seconds over the surface of the chip and then washed with HBS buffer. The binding of M5 Ab to GRGDSLAYGLR peptide (green), SLAYGLR peptide (red), and GRGDS peptide (blue) is shown. (b) Inhibition by M5 Ab of cell migration toward thrombin-cleaved OPN. M5 Ab, antipolyclonal OPN Abs, anti-β3 integrin Ab, anti-CD44 Ab, and isotype-matched control antibodies were added at the indicated concentrations. Anti–N-terminal OPN was added at a 1:100 dilution to wells. The results are expressed as mean numbers ± SEM of migrated cells. *P < 0.05 and **P < 0.01. Resp. diff., response difference.