Matrix metalloproteinases 2 and 9 in the cochlea: expression and activity after aminoglycoside exposition

Setz, Cristian; Brand, Yves; Radojević, Vesna; Hanusek, Claudia; Mullen, Peter; Levano, Soledad; Listyo, Alwin; Bodmer, Daniel

doi:10.1016/j.neuroscience.2011.02.043

Cited by 17 publications

(16 citation statements)

References 33 publications

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“…The maintenance of ECM homeostasis has been shown to be important for inner ear development (Szabova et al; Davies et al, 2007), and the dysregulation of this structure leads to sensorineural hearing loss (Gratton et al, 2005; Kundu et al, 2009; Nam et al, 2011; Setz et al, 2011). In noise-traumatized cochleae, morphological changes in ECM structures have been documented (Canlon, 1987, 1988).…”

Section: Introductionmentioning

confidence: 99%

Metalloproteinases and Their Associated Genes Contribute to the Functional Integrity and Noise-Induced Damage in the Cochlear Sensory Epithelium

Cai

et al. 2012

J. Neurosci.

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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.

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Section: Introductionmentioning

confidence: 99%

Metalloproteinases and Their Associated Genes Contribute to the Functional Integrity and Noise-Induced Damage in the Cochlear Sensory Epithelium

Cai

et al. 2012

J. Neurosci.

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“…However, Hu et al (2012) focused on the sensory epithelium of the cochlea and not on SGNs. Recently, our group demonstrated that general inhibition of MMPs resulted in auditory HC loss in vitro (Setz et al 2011). The data of the present study indicates that MMP inhibition not only affects the auditory HCs, but also has a negative influence on SGNs.…”

Section: Discussionmentioning

confidence: 99%

“…However, hearing tests in these mice have not been performed. We previously found that inhibition of MMP activity resulted in auditory HC loss in vitro (Setz et al 2011). However, the effect of MMP inhibition has not been investigated in SGNs.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of MMP-2 but not MMP-9 Influences Inner Ear Spiral Ganglion Neurons In Vitro

et al. 2014

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Matrix metalloproteinases (MMPs) play an important role in modeling of the extracellular matrix. There is increasing evidence that these proteases are important in neurite elongation and axonal guidance during development in the central nervous system and retina. Moreover, they are also expressed after acute injury and can be the key mediators of pathogenesis. However, the role of MMPs in the inner ear is largely unknown. Our group recently demonstrated that general inhibition of MMPs resulted in auditory hair cell loss in vitro. In the present study, we investigated the role of MMPs in inner ear spiral ganglion neuron (SGN) survival, neuritogenesis and neurite extension by blocking MMPs known to be involved in axonal guidance, neurite elongation, and apoptosis in other neuronal systems. Spiral ganglion (SG) explants from 5-day-old Wistar rats were treated with different concentrations of the general MMP inhibitor GM6001, a specific MMP-2 inhibitor, and a specific MMP-9 inhibitor, in vitro. The general inhibitor of MMPs and the specific inhibition of MMP-2 significantly reduced both the number of neurites that extended from SG explants, as well as the length of individual neurites. However, neither the general inhibitor of MMPs nor the specific inhibition of MMP-2 influenced SGN survival. Inhibition of MMP-9 had no influence on SGNs. The data suggest that MMPs, and more specifically MMP-2, influence the growth of developing afferent neurites in the mammalian inner ear in vivo.

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“…Setz et al demonstrated that exposure of the organ of corti to gentamycin increased the expression of MMP-2 and MMP-9 and exposure to MMP inhibitors resulted in hair cell death in wild type mice. This indicated that optimum concentrations of MMP-2 and MMP-9 are required for the normal functioning of the organ of corti hair cells [19].…”

Section: Homocysteine the Cochlea And Hearingmentioning

confidence: 97%

Hyperhomocysteinemia, MMPs and Cochlear Function: A Short Review

Bhargava

et al. 2015

Ind J Clin Biochem

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Hyperhomocysteinemia (HHCY) has been demonstrated to affect cochlear microvasculature as well as cochlear epithelial cells directly, with a resultant alteration of the expression of matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). Hence, ascertaining the optimum concentration of MMPs and TIMPs in the cochlea could help to inhibit hearing loss due to HHCY by the administration of appropriate MMP inhibitors, Since infections/inflammations as well as ototoxic antibiotics have a similar mechanism of otic pathology, the cochlear damage they cause could also be similarly prevented.

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Matrix metalloproteinases 2 and 9 in the cochlea: expression and activity after aminoglycoside exposition

Cited by 17 publications

References 33 publications

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

Inhibition of MMP-2 but not MMP-9 Influences Inner Ear Spiral Ganglion Neurons In Vitro

Hyperhomocysteinemia, MMPs and Cochlear Function: A Short Review

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