Endostatin binds nerve growth factor and thereby inhibits neurite outgrowth and neuronal migration in-vitro.
Endostatin binds nerve growth factor and thereby inhibits neurite outgrowth and neuronal migration in-vitro.
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DOI：
10.1016/j.brainres.2010.09.023
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发表时间：
2010-11-11
期刊：
影响因子：
2.9
通讯作者：
Bix GJ
中科院分区：
文献类型：
--
作者：
Al Ahmad A;Lee B;Stack J;Parham C;Campbell J;Clarke D;Fertala A;Bix GJ
内皮抑素(Endostatin，ES)是XVIII胶原蛋白的C端片段，具有抗血管生成的特性，与哺乳动物的神经系统疾病有关。在这项研究中，我们研究了ES对神经生长因子(NGF)诱导的神经元分化、迁移、神经发生和轴突延伸的影响。ES部分抑制PC12细胞分化和小脑颗粒细胞迁移。此外，轴突生长受到抑制，呈浓度依赖关系。这种作用也依赖于基质，因为我们观察到与层粘连蛋白基质相比，胶原蛋白对PC12细胞生长的抑制作用更好。此外，我们观察到部分NGF被胶原和ES耗尽，但不被层粘连蛋白耗尽，这表明NGF与基质的相互作用可能在促进神经发生中起重要作用，ES或低亲和力基质的竞争抑制削弱了PC12的分化和突起的生长。最后，利用生物传感器技术，我们证明了NGF和ES之间的直接相互作用，表明ES的作用机制可能涉及NGF的隔离。综上所述，我们的研究证实了ES对神经发生的不同阶段的抑制作用，包括细胞分化和迁移以及NGF隔离对神经发生的抑制作用。这种隔离可能会损害损伤后的大脑修复，但也可能在轴突发现方面发挥重要作用，以及成为涉及神经营养生长因子水平异常升高的疾病的有效治疗靶点。综上所述，这项研究提出了ES是一把双刃剑的观点，既有有害的，也有假定的治疗效果。
Endostatin (ES), the C-terminal fragment of collagen XVIII known for its anti-angiogenic properties, is associated with neurological diseases in mammals. In this study, we investigated the effect of ES on nerve growth factor (NGF)-induced neuronal differentiation, migration, neuritogenesis, and neurite extension. ES partially inhibited PC12 cell differentiation and cerebellar granule cell migration. In addition, neurite outgrowth was inhibited in a concentration-dependent manner. This effect was also matrix-dependent, as we observed better inhibition on PC12 cells grown on collagen compared to laminin matrices. Furthermore, we observed partial NGF depletion by collagen and ES, but not by laminin suggesting that NGF–matrix interactions may be important for promoting neuritogenesis, competitive inhibition by ES or low affinity matrix impairs PC12 differentiation and neurite outgrowth. Finally, using a biosensor technique, we demonstrated a direct interaction between NGF and ES suggesting the mechanism of action of ES may involve NGF sequestration. In conclusion, our study demonstrates the inhibitory effect of ES on different steps of neurogenesis including cell differentiation and migration and neuritogenesis by NGF sequestration. Such sequestration may compromise brain repair following injury, but also may play important role in axon finding as well as a potent therapeutical target in diseases involving abnormal elevated neurotrophic growth factor levels. Taken together, this study raises the consideration of ES as a double-edge sword that carries both deleterious and putative therapeutical effects.
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