Kon Shigeyuki, Ikesue Masahiro, Kimura Chiemi, Aoki Momoe, Nakayama Yosuke, Saito Yoshinari, Kurotaki Daisuke, Diao Hongyan, Matsui Yutaka, Segawa Tatsuya, Maeda Masahiro, Kojima Tetsuhito, Uede Toshimitsu
Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo 060-0815, Japan.
J Exp Med. 2008 Jan 21;205(1):25-33. doi: 10.1084/jem.20071324. Epub 2007 Dec 24.
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.
骨桥蛋白（OPN）是一种1型辅助性T细胞免疫调节细胞因子，在多种炎症性疾病中起关键作用。OPN通过与整合素受体相互作用发挥促炎反应。OPN的功能可通过蛋白酶消化进行调节。然而，体内调节OPN功能的分子机制尚未阐明。OPN分子内有两个假定的肝素结合结构域（HBDs），它们可能与肝素和肝素样糖胺聚糖（如syndecan）结合。我们发现，注射伴刀豆球蛋白A（ConA）后，OPN和syndecan-4的表达显著上调。Syndecan-4与OPN的一个HBD结合，该HBD与OPN的凝血酶切割位点重叠。当OPN与syndecan-4结合时，syndecan-4会掩盖OPN内的凝血酶切割位点和整合素结合位点。重要的是，syndecan-4缺陷（Syn4KO）小鼠更容易受到肝损伤，与野生型小鼠相比，ConA注射后，Syn4KO小鼠中凝血酶切割形式的OPN显著升高。最后，我们证明给予纯化的syndecan-4可保护小鼠免受ConA诱导的肝损伤。因此，syndecan-4通过其对OPN功能的影响，是炎症反应的关键内在调节因子，也是治疗炎症性疾病的潜在新型治疗工具。
