Syndecan-4 protects against osteopontin-mediated acute hepatic injury by masking functional domains of osteopontin.
Syndecan-4 protects against osteopontin-mediated acute hepatic injury by masking functional domains of osteopontin.
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Syndecan-4通过掩盖骨桥蛋白的功能结构域来预防骨桥蛋白介导的急性肝损伤。
DOI：
10.1084/jem.20071324
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发表时间：
2008-01-21
影响因子：
15.3
通讯作者：
Uede, Toshimitsu
中科院分区：
文献类型：
--
作者：
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
骨桥蛋白(OPN)是一种辅助性T细胞1型免疫调节细胞因子，在多种炎症性疾病中发挥重要作用。OPN通过与整合素受体相互作用而发挥促炎反应。OPN的功能可以通过蛋白酶的消化来调节。然而，在体内调节骨桥蛋白功能的分子机制尚未阐明。在OPN分子中有两个假定的肝素结合域(HBD)，它们可以结合肝素和肝素样糖胺聚糖(如Syndecan)。我们发现在刀豆蛋白A(ConA)注射后，OPN和Syndecan-4的表达显著上调。Syndecan-4与OPN的HBD结合，该HBD与OPN的凝血酶裂解位点重叠。当OPN与Syndecan-4相关时，Syndecan-4会同时屏蔽OPN中的凝血酶裂解和整合素结合位点。重要的是，Syndecan-4缺陷(Syn4KO)小鼠更容易受到肝损伤，注射ConA后，Syn4KO小鼠的凝血酶裂解OPN形式显著高于野生型小鼠。最后，我们证明，给予纯化的Syndecan-4可以保护小鼠免受ConA诱导的肝损伤。因此，Syndecan-4通过对OPN功能的影响是炎症反应的重要内在调节因子，是治疗炎症性疾病的一种潜在的新的治疗工具。
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.
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影响因子：
15.9
作者：
Bruemmer, D;Collins, AR;Hsueh, WA
通讯作者：
Hsueh, WA
影响因子：
15.3
作者：
Weiss, JM;Renkl, AC;Simon, JC
通讯作者：
Simon, JC
DOI：
10.1073/pnas.052523599
发表时间：
2002-04-02
影响因子：
11.1
作者：
Yumoto, K;Ishijima, M;Noda, M
通讯作者：
Noda, M
影响因子：
4.8
作者：
Bao, XF;Mikami, T;Sugahara, K
通讯作者：
Sugahara, K
影响因子：
4.8
作者：
Deepa, SS;Yamada, S;Sugahara, K
通讯作者：
Sugahara, K