Center for Hearing and Deafness, State University of New York at Buffalo, Buffalo, New York 14214, USA.
J Neurosci. 2012 Oct 24;32(43):14927-41. doi: 10.1523/JNEUROSCI.1588-12.2012.
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 manner after traumatic noise injury. The analysis of gene expression by RNA sequencing 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 on 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, before noise exposure reduced noise-induced hearing loss and sensory cell death. In contrast, a 7 d 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 knock-out 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.
基质金属蛋白酶（MMPs）及其相关基因产物调节着重要的细胞功能。MMPs 的失衡与多种神经紊乱有关，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调节大鼠耳蜗对声创伤反应中的作用。正常耳蜗富含 MMP 酶活性，这种活性在创伤性噪声损伤后呈时间依赖性降低。通过 RNA 测序和 qRT-PCR 分析基因表达，揭示了 MMPs 及其相关基因在感觉上皮功能特化区域的差异表达。这些基因的表达在噪声诱导听力损失的急性和慢性阶段之间呈动态调节。此外，噪声诱导的两个内源性 MMP 抑制剂 Timp1 和 Timp2 在感觉细胞中的表达变化依赖于核浓缩的阶段，表明 MMP 活性在感觉细胞凋亡中具有特定的作用。在噪声暴露前短期应用多西环素（一种 MMP 的广谱抑制剂）可减少噪声诱导的听力损失和感觉细胞死亡。相比之下，7 天的治疗会损害听力敏感性并加剧噪声诱导的听力损失。使用靶向 Mmp7 敲除小鼠进一步证实了 MMP 长期抑制对噪声诱导听力损失的这种有害影响。综上所述，这些观察结果表明 MMPs 及其相关基因参与了耳蜗对声过度刺激的反应的调节，并且 MMP 活性的调节可以作为减少噪声诱导耳蜗损伤的新的治疗靶点。
