title: Syndecan-4 protects against osteopontin-mediated acute hepatic injury by masking functional domains of osteopontin.
abstract: Osteopontin (OPN) is a T helper type 1 immunoregulatory cytokine that plays a critical role in various inflammatory disorders. OPN exerts proinflammatory reactions through interaction with integrin receptors. OPN function can be modulated by protease digestion. However, the molecular mechanisms that regulate OPN function in vivo have not been elucidated. There are two putative heparin-binding domains (HBDs) within the OPN molecule, which may bind both heparin and heparin-like glycosaminoglycans such as syndecan. We show that expression of OPN and syndecan-4 is significantly up-regulated after concanavalin-A (ConA) injection. Syndecan-4 binds to one of the HBDs of OPN, which overlaps with the thrombin cleavage site of OPN. When OPN is associated with syndecan-4, syndecan-4 masks both the thrombin cleavage and the integrin binding sites within OPN. Importantly, syndecan-4-deficient (Syn4KO) mice are more susceptible to hepatic injury, and the thrombin-cleaved form of OPN is significantly elevated in Syn4KO mice as compared with wild-type mice after ConA injection. Finally, we demonstrate that administration of purified syndecan-4 protects mice from ConA-induced hepatic injury. Thus, syndecan-4 is a critical intrinsic regulator of inflammatory reactions via its effects on OPN function and is a potential novel therapeutic tool for treating inflammatory diseases.
authors.affiliation: Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo 060-0815, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kon
authors.forename: Masahiro
authors.initials: M
authors.lastname: Ikesue
authors.forename: Chiemi
authors.initials: C
authors.lastname: Kimura
authors.forename: Momoe
authors.initials: M
authors.lastname: Aoki
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Saito
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kurotaki
authors.forename: Hongyan
authors.initials: H
authors.lastname: Diao
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Matsui
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Segawa
authors.forename: Masahiro
authors.initials: M
authors.lastname: Maeda
authors.forename: Tetsuhito
authors.initials: T
authors.lastname: Kojima
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
mesh_terms: D000818:Animals; D003208:Concanavalin A / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry; D006493:Heparin / Q000737:chemistry; D006801:Humans; D007249:Inflammation; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D053671:Syndecan-4 / Q000378:metabolism / Q000502:physiology*
chemical_list: D019812:Heparan Sulfate Proteoglycans; D053671:Syndecan-4; D053495:Osteopontin; D003208:Concanavalin A; D006493:Heparin