Bone-protective Functions of Netrin 1 Protein
Bone-protective Functions of Netrin 1 Protein
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DOI：
10.1074/jbc.m116.738518
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发表时间：
2016-11-11
影响因子：
4.8
通讯作者：
Akira, Shizuo
中科院分区：
文献类型：
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作者：
Maruyama, Kenta;Kawasaki, Takahiko;Akira, Shizuo
Netrin 1最初被鉴定为轴突导向因子，最近的研究表明它抑制趋化因子指导的单核细胞迁移。尽管netrin 1作为神经免疫引导因子的重要性，但其在破骨细胞中的作用在很大程度上是未知的。我们在类风湿关节炎患者的滑液中检测到高水平的netrin 1。Netrin 1在成骨细胞和滑膜成纤维细胞中有效表达，IL-17强烈增强netrin 1在这些细胞中的表达。netrin 1与破骨细胞上其受体UNC 5 b的结合导致SHP 1的活化，SHP 1抑制VAV 3磷酸化和RAC 1活化。这显著损害肌动蛋白的聚合和融合，但不影响破骨细胞的分化。引人注目的是，netrin 1治疗预防了自身免疫性关节炎模型中的骨侵蚀和年龄相关的骨破坏。因此，netrin 1-UNC 5 b轴是骨破坏性疾病的新治疗靶点。
Netrin 1 was initially identified as an axon guidance factor, and recent studies indicate that it inhibits chemokine-directed monocyte migration. Despite its importance as a neuroimmune guidance cue, the role of netrin 1 in osteoclasts is largely unknown. Here we detected high netrin 1 levels in the synovial fluid of rheumatoid arthritis patients. Netrin 1 is potently expressed in osteoblasts and synovial fibroblasts, and IL-17 robustly enhances netrin 1 expression in these cells. The binding of netrin 1 to its receptor UNC5b on osteoclasts resulted in activation of SHP1, which inhibited VAV3 phosphorylation and RAC1 activation. This significantly impaired the actin polymerization and fusion, but not the differentiation of osteoclast. Strikingly, netrin 1 treatment prevented bone erosion in an autoimmune arthritis model and age-related bone destruction. Therefore, the netrin 1-UNC5b axis is a novel therapeutic target for bone-destructive diseases.