Metalloproteinases and their associated genes contribute to the functional integrity and noise-induced damage in the cochlear sensory epithelium.
Metalloproteinases and their associated genes contribute to the functional integrity and noise-induced damage in the cochlear sensory epithelium.
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DOI：
10.1523/jneurosci.1588-12.2012
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发表时间：
2012-10-24
期刊：
影响因子：
--
通讯作者：
Coling D
中科院分区：
文献类型：
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作者：
Hu BH;Cai Q;Hu Z;Patel M;Bard J;Jamison J;Coling D
基质金属蛋白酶（MMPs）及其相关基因产物调节细胞的基本功能。MMPs的不平衡与各种神经系统疾病有关，包括创伤性损伤。在这里，我们报告了MMPs及其相关基因产物在大鼠耳蜗对声损伤反应的调制中的作用。正常耳蜗被证明是丰富的MMP酶的活性，这种活性降低创伤性噪声损伤后的时间依赖性的方式。通过RNA-seq和qRT-PCR的基因表达分析揭示了MMPs及其相关基因在感觉上皮的功能特化区域之间的差异表达。这些基因的表达在噪声性听力损失的急性期和慢性期之间动态调节。此外，噪声诱导的表达变化的两个内源性MMP抑制剂，TIMP 1和TIMP 2，在感觉细胞依赖于核凝聚的阶段，提示MMP活性在感觉细胞凋亡的特定作用。在噪声暴露前短期应用多西环素（一种MMPs的广谱抑制剂）可减少噪声引起的听力损失和感觉细胞死亡。相比之下，7天的治疗损害了听力灵敏度，并增强了噪声引起的听力损失。使用靶向Mmp 7敲除小鼠进一步证实了MMPs对噪声诱导的听力损失的长期抑制的这种有害作用。总之，这些观察结果表明，基质金属蛋白酶及其相关基因参与调节耳蜗对声过度刺激的反应，MMP活性的调制可以作为一种新的治疗靶点，用于减少噪声引起的耳蜗损伤。
Matrix metalloproteinases (MMPs) and their related gene products regulate essential cellular functions. An imbalance in MMPs has been implicated in various neurological disorders, including traumatic injuries. Here, we report a role for MMPs and their related gene products in the modulation of cochlear responses to acoustic trauma in rats. The normal cochlea was shown to be enriched in MMP enzymatic activity, and this activity was reduced in a time-dependent fashion after traumatic noise injury. The analysis of gene expression by RNA-seq and qRT-PCR revealed the differential expression of MMPs and their related genes between functionally specialized regions of the sensory epithelium. The expression of these genes was dynamically regulated between the acute and chronic phases of noise-induced hearing loss. Moreover, noise-induced expression changes in two endogenous MMP inhibitors, Timp1 and Timp2, in sensory cells were dependent upon the stage of nuclear condensation, suggesting a specific role for MMP activity in sensory cell apoptosis. A short-term application of doxycycline, a broad-spectrum inhibitor of MMPs, prior to noise exposure reduced noise-induced hearing loss and sensory cell death. By contrast, a 7-day treatment compromised hearing sensitivity and potentiated noise-induced hearing loss. This detrimental effect of the long-term inhibition of MMPs on noise-induced hearing loss was further confirmed using targeted Mmp7 knockout mice. Together, these observations suggest that MMPs and their related genes participate in the regulation of cochlear responses to acoustic overstimulation and that the modulation of MMP activity can serve as a novel therapeutic target for the reduction of noise-induced cochlear damage.