Matrix metalloproteinase-2 and -9 contribute to functional integrity and noise‑induced damage to the blood-labyrinth-barrier.

Abstract

The cochlear blood-labyrinth barrier (BLB), located in the stria vascularis, is critical for the homeostasis of cochlear solutes and ion transport. Significant disruption to the BLB occurs early during noise-induced hearing loss. Matrix metalloproteinase (MMP)-2 and −9 are important molecules known to be capable of degrading tight junction (TJ) proteins. The TJ proteins are important components of the extracellular matrix (ECM), required to maintain BLB integrity and permeability. Previous studies have demonstrated that MMP-2 and −9, rich in healthy cochlea, serve an essential role in regulating the cochlear response to acoustic trauma. The present study investigated the localization and function of MMP-2 and −9 in the BLB by determining their associated gene expression and activity under normal conditions and after noise exposure. Analysis of gene expression by RNA-sequencing (RNA-seq) revealed expression of 15 MMP-associated genes, including genes for MMP-2 and −9, in healthy stria vascularis. Expression of these MMP genes was dynamically regulated by noise trauma to the cochlea, and accompanied by alterations in tissue inhibitors of metalloproteinases (TIMPs) and the TJ protein zona-occludens 1 (ZO-1). These alterations suggested that MMP-2 and −9 serve an important role in maintaining the integrity of BLB and in response to acoustic trauma. MMP-2, MMP-9 and ZO-1 protein expression levels in the stria vascularis by immunofluorescence, and observed that the stable expression of MMP-2 and −9 in healthy stria was markedly increased following noise exposure, consistent with the RNA-seq results. The compact structure of ZO-1 in the BLB loosened, and strial capillaries exhibited markedly increased leakage of Evans blue dye following acoustic trauma. These data indicated that mediation of MMP-2 and −9 in structural damage to TJ proteins, including ZO-1, may be an important mechanism in the breakdown of the BLB following acoustic trauma. Additionally, these results indicated that MMPs are involved in regulating the integrity and permeability of the BLB, which may provide a theoretical basis for the prevention of noise-induced hearing loss.