title: 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 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.
authors.affiliation: Exploratory Research Laboratories, Fujisawa Pharmaceutical Co, Ibaraki, Japan. nobuchika_yamamoto@po.fujisawa.co.jp
authors.forename: Nobuchika
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Sakai
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kon
authors.forename: Junko
authors.initials: J
authors.lastname: Morimoto
authors.forename: Chiemi
authors.initials: C
authors.lastname: Kimura
authors.forename: Harumi
authors.initials: H
authors.lastname: Yamazaki
authors.forename: Ikuko
authors.initials: I
authors.lastname: Okazaki
authors.forename: Nobuo
authors.initials: N
authors.lastname: Seki
authors.forename: Takashi
authors.initials: T
authors.lastname: Fujii
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
mesh_terms: 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
chemical_list: D000939:Epitopes; D039001:Integrin alpha Chains; D008070:Lipopolysaccharides; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; C084613:integrin alpha9; D053495:Osteopontin; D039441:Integrin alpha4