The MMP-9/TIMP-1 axis controls the status of differentiation and function of myelin-forming Schwann cells in nerve regeneration.
The MMP-9/TIMP-1 axis controls the status of differentiation and function of myelin-forming Schwann cells in nerve regeneration.
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DOI：
10.1371/journal.pone.0033664
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Shubayev VI
中科院分区：
文献类型：
--
作者：
Kim Y;Remacle AG;Chernov AV;Liu H;Shubayev I;Lai C;Dolkas J;Shiryaev SA;Golubkov VS;Mizisin AP;Strongin AY;Shubayev VI
髓鞘化雪旺细胞（mSCs）在周围神经系统中形成髓鞘。由于我们和其他人的工作，基质金属蛋白酶-9（MMP-9）最近已成为坐骨神经再生过程中雪旺细胞信号网络的重要组成部分。在本研究中，使用全基因组转录谱的正常和损伤的坐骨神经在小鼠中，随后广泛的生物信息学分析的数据，我们确定，内源性，特异性MMP-9抑制剂[金属蛋白酶组织抑制剂（TIMP）-1]是一个顶部上调基因在损伤的神经。MMP-9捕获，然后明胶酶谱和Western印迹的分离的样品揭示了MMP-9/TIMP-1异二聚体和激活的MMP-9酶在损伤后的第一个24小时内在损伤的神经中的存在。MMP-9和TIMP-1共定位于mSCs中。在小鼠中敲除MMP-9基因导致受损神经中去分化/未成熟mSCs数量增加。我们使用MMP-9基因敲除小鼠和野生型小鼠的比较研究记录了异常增强的增殖活性，因此，有丝分裂后雪旺细胞的数量增加，短节间和额外的结异常的MMP-9基因敲除小鼠的有髓神经。这些数据表明，在损伤后的第一天，MMP-9在野生型小鼠中表现出功能上重要的抗促有丝分裂活性。MMP活性的药理学抑制抑制了压碎神经中Nav1.7/1.8通道的表达。总的来说，我们的数据确立了MMP-9/TIMP-1轴在神经修复过程中指导mSC分化和髓鞘结构域分子组装的重要作用。我们的研究结果MMP-依赖性调节的Nav通道，我们在这里首次记录，提供了一个基础的感觉运动病理和疼痛的治疗干预。
Myelinating Schwann cells (mSCs) form myelin in the peripheral nervous system. Because of the works by us and others, matrix metalloproteinase-9 (MMP-9) has recently emerged as an essential component of the Schwann cell signaling network during sciatic nerve regeneration. In the present study, using the genome-wide transcriptional profiling of normal and injured sciatic nerves in mice followed by extensive bioinformatics analyses of the data, we determined that an endogenous, specific MMP-9 inhibitor [tissue inhibitor of metalloproteinases (TIMP)-1] was a top up-regulated gene in the injured nerve. MMP-9 capture followed by gelatin zymography and Western blotting of the isolated samples revealed the presence of the MMP-9/TIMP-1 heterodimers and the activated MMP-9 enzyme in the injured nerve within the first 24 h post-injury. MMP-9 and TIMP-1 co-localized in mSCs. Knockout of the MMP-9 gene in mice resulted in elevated numbers of de-differentiated/immature mSCs in the damaged nerve. Our comparative studies using MMP-9 knockout and wild-type mice documented an aberrantly enhanced proliferative activity and, accordingly, an increased number of post-mitotic Schwann cells, short internodes and additional nodal abnormalities in remyelinated nerves of MMP-9 knockout mice. These data imply that during the first days post-injury MMP-9 exhibits a functionally important anti-mitogenic activity in the wild-type mice. Pharmacological inhibition of MMP activity suppressed the expression of Nav1.7/1.8 channels in the crushed nerves. Collectively, our data established an essential role of the MMP-9/TIMP-1 axis in guiding the mSC differentiation and the molecular assembly of myelin domains in the course of the nerve repair process. Our findings of the MMP-dependent regulation of Nav channels, which we document here for the first time, provide a basis for therapeutic intervention in sensorimotor pathologies and pain.
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DOI：
10.1097/01.jnen.0000171650.94341.46
发表时间：
2005-07-01
影响因子：
3.2
作者：
Chen, YY;McDonald, D;Zochodne, DW
通讯作者：
Zochodne, DW
DOI：
10.1111/j.1749-6632.1999.tb08584.x
发表时间：
1999-01-01
期刊：
CHARCOT-MARIE-TOOTH DISORDERS
影响因子：
--
作者：
Hall, SM
通讯作者：
Hall, SM
DOI：
10.1007/bf01206661
发表时间：
1989-04-01
期刊：
JOURNAL OF NEUROCYTOLOGY
影响因子：
--
作者：
CLEMENCE, A;MIRSKY, R;JESSEN, KR
通讯作者：
JESSEN, KR
DOI：
10.1523/jneurosci.4569-09.2009
发表时间：
2009-11-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Costigan M;Moss A;Latremoliere A;Johnston C;Verma-Gandhu M;Herbert TA;Barrett L;Brenner GJ;Vardeh D;Woolf CJ;Fitzgerald M
通讯作者：
Fitzgerald M
影响因子：
15.1
作者：
Chattopadhyay, Sharmila;Myers, Robert R.;Shubayev, Veronica
通讯作者：
Shubayev, Veronica