Essential role of the cryptic epitope SLAYGLR within osteopontin in a murine model of rheumatoid arthritis.
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 alpha9 and alpha4 integrins. Since cleavage of OPN by thrombin exposes the cryptic epitope recognized by alpha9 and alpha4 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.
Yamamoto
Nobuchika
N
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co, Ibaraki, Japan. nobuchika_yamamoto@po.fujisawa.co.jp
Sakai
Fumihiko
F
Kon
Shigeyuki
S
Morimoto
Junko
J
Kimura
Chiemi
C
Yamazaki
Harumi
H
Okazaki
Ikuko
I
Seki
Nobuo
N
Fujii
Takashi
T
Uede
Toshimitsu
T
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D001854:Bone Marrow Cells; D002455:Cell Division; D002465:Cell Movement; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000939:Epitopes / Q000276:immunology* / Q000502:physiology; D005434:Flow Cytometry; D039001:Integrin alpha Chains / Q000378:metabolism; D039441:Integrin alpha4 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism; D053495:Osteopontin; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000737:chemistry* / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013997:Time Factors
D000939:Epitopes; D039001:Integrin alpha Chains; D008070:Lipopolysaccharides; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; C084613:integrin alpha9; D053495:Osteopontin; D039441:Integrin alpha4