Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, UMR 6184, Centre National de la Recherche Scientifique-Université de la Méditerranée, Marseille, France.
PLoS One. 2009 Dec 14;4(12):e8289. doi: 10.1371/journal.pone.0008289.
Tissue inhibitor of metalloproteinases-1 (TIMP-1) displays pleiotropic activities, both dependent and independent of its inhibitory activity on matrix metalloproteinases (MMPs). In the central nervous system (CNS), TIMP-1 is strongly upregulated in reactive astrocytes and cortical neurons following excitotoxic/inflammatory stimuli, but no information exists on its effects on growth and morphology of cortical neurons.
We found that 24 h incubation with recombinant TIMP-1 induced a 35% reduction in neurite length and significantly increased growth cones size and the number of F-actin rich microprocesses. TIMP-1 mediated reduction in neurite length affected both dendrites and axons after 48 h treatment. The effects on neurite length and morphology were not elicited by a mutated form of TIMP-1 inactive against MMP-1, -2 and -3, and still inhibitory for MMP-9, but were mimicked by a broad spectrum MMP inhibitor. MMP-9 was poorly expressed in developing cortical neurons, unlike MMP-2 which was present in growth cones and whose selective inhibition caused neurite length reductions similar to those induced by TIMP-1. Moreover, TIMP-1 mediated changes in cytoskeleton reorganisation were not accompanied by modifications in the expression levels of actin, betaIII-tubulin, or microtubule assembly regulatory protein MAP2c. Transfection-mediated overexpression of TIMP-1 dramatically reduced neuritic arbour extension in the absence of detectable levels of released extracellular TIMP-1.
Altogether, TIMP-1 emerges as a modulator of neuronal outgrowth and morphology in a paracrine and autrocrine manner through the inhibition, at least in part, of MMP-2 and not MMP-9. These findings may help us understand the role of the MMP/TIMP system in post-lesion pre-scarring conditions.
组织金属蛋白酶抑制剂-1（TIMP-1）具有多种活性，包括依赖于和不依赖于其对基质金属蛋白酶（MMPs）的抑制活性的活性。在中枢神经系统（CNS）中，TIMP-1 在兴奋性/炎症刺激后，在反应性星形胶质细胞和皮质神经元中强烈上调，但关于其对皮质神经元生长和形态的影响尚无信息。
我们发现，重组 TIMP-1 孵育 24 小时可导致神经突长度减少 35%，并显著增加生长锥的大小和富含 F-肌动蛋白的微丝数量。TIMP-1 介导的神经突长度减少在 48 小时处理后影响树突和轴突。对神经突长度和形态的影响不是由针对 MMP-1、-2 和 -3 无活性的突变形式的 TIMP-1 引起的，尽管它仍然对 MMP-9 具有抑制作用，但被广谱 MMP 抑制剂模拟。与 MMP-2 不同，MMP-9 在发育中的皮质神经元中表达水平较低，MMP-2 存在于生长锥中，其选择性抑制导致的神经突长度减少类似于 TIMP-1 诱导的长度减少。此外，TIMP-1 介导的细胞骨架重组变化不伴有肌动蛋白、βIII-微管蛋白或微管组装调节蛋白 MAP2c 的表达水平的改变。TIMP-1 的转染介导过表达在没有可检测到的细胞外 TIMP-1 释放的情况下，显著减少了神经突树突的延伸。
总之，TIMP-1 以旁分泌和自分泌的方式通过抑制 MMP-2（至少部分）而不是 MMP-9 成为神经元生长和形态的调节剂。这些发现可能有助于我们理解 MMP/TIMP 系统在损伤后瘢痕前条件下的作用。
