Tissue Inhibitor of Metalloproteinase-3 Promotes Schwann Cell Myelination
Tissue Inhibitor of Metalloproteinase-3 Promotes Schwann Cell Myelination
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DOI：
10.1177/1759091417745425
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发表时间：
2017-12-03
期刊：
影响因子：
4.7
通讯作者：
Kim, Haesun A.
中科院分区：
文献类型：
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作者：
Kim, Jihyun;Elias, Anthony;Kim, Haesun A.
金属蛋白酶组织抑制剂-3（TIMP-3）抑制多种金属蛋白酶的活性，包括基质金属蛋白酶和ADAM家族蛋白。在周围神经系统中，ADAM 17，也称为TNF-α转化酶（TACE），切割Nrg 1 III型的细胞外结构域，这是一种对许旺细胞髓鞘形成至关重要的轴突生长因子。ADAM 17的处理减弱Nrg 1信号传导并抑制雪旺细胞髓鞘形成。TIMP-3靶向于ADAM-17，提示TIMP-3可能通过缓解ADAM-17诱导的髓鞘形成阻滞而在雪旺细胞中引发早髓鞘形成功能。为了研究这一点，我们使用髓鞘共培养系统来确定TIMP-3对雪旺细胞髓鞘形成的影响。用TIMP-3处理增强了共培养物中的髓鞘形成，这通过髓鞘节段数量的增加以及Krox 20和髓鞘蛋白的上调表达来证明。TIMP-3的作用伴随着对ADAM 17活性的抑制和共培养物中Nrg 1 III型信号传导的增加。因此，TIMP-3的N-末端片段对ADAM 17表现出选择性抑制功能，引起类似的髓鞘形成促进作用和增加的Nrg 1 III型活性。TIMP-3还增强了共培养物中层粘连蛋白的产生，这可能有助于许旺细胞髓鞘形成。
Tissue inhibitor of metalloproteinase-3 (TIMP-3) inhibits the activities of various metalloproteinases including matrix metalloproteinases and ADAM family proteins. In the peripheral nervous system, ADAM17, also known as TNF-alpha converting enzyme (TACE), cleaves the extracellular domain of Nrg1 type III, an axonal growth factor that is essential for Schwann cell myelination. The processing by ADAM17 attenuates Nrg1 signaling and inhibits Schwann cell myelination. TIMP-3 targets ADAM17, suggesting a possibility that TIMP-3 may elicit a promyelinating function in Schwann cells by relieving ADAM17-induced myelination block. To investigate this, we used a myelinating coculture system to determine the effect of TIMP-3 on Schwann cell myelination. Treatment with TIMP-3 enhanced myelin formation in cocultures, evident by an increase in the number of myelin segments and upregulated expression of Krox20 and myelin protein. The effect of TIMP-3 was accompanied by the inhibition of ADAM17 activity and an increase in Nrg1 type III signaling in cocultures. Accordingly, the N-terminus fragment of TIMP-3, which exhibits a selective inhibitory function toward ADAM17, elicited a similar myelination-promoting effect and increased Nrg1 type III activity. TIMP-3 also enhanced laminin production in cocultures, which is likely to aid Schwann cell myelination.