Deficiency in Matrix Metalloproteinase Gelatinase B (MMP-9) Protects against Retinal Ganglion Cell Death after Optic Nerve Ligation

Loss of retinal ganglion cells is the final end point in blinding diseases of the optic nerve such as glaucoma. To enable the use of mouse genetics to investigate mechanisms underlying ganglion cell loss, we adapted an experimental model of optic nerve ligation to the mouse and further characterized...

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Bibliographic Details
Published in:The Journal of biological chemistry 2002-12, Vol.277 (49), p.47461-47468
Main Authors: Chintala, Shravan K., Zhang, Xu, Austin, Jeffrey S., Fini, M. Elizabeth
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Blotting, Western
Cell Death
Ganglia - cytology
Ganglia - pathology
Immunohistochemistry
In Situ Nick-End Labeling
Laminin - metabolism
Matrix Metalloproteinase 9 - deficiency
Matrix Metalloproteinase 9 - physiology
Mice
Mice, Transgenic
Microscopy, Fluorescence
Optic Nerve - metabolism
Optic Nerve - surgery
Phenotype
Protein Binding
Retina - cytology
Retina - pathology
Time Factors
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Summary:Loss of retinal ganglion cells is the final end point in blinding diseases of the optic nerve such as glaucoma. To enable the use of mouse genetics to investigate mechanisms underlying ganglion cell loss, we adapted an experimental model of optic nerve ligation to the mouse and further characterized post-surgical outcome. We made the novel finding that apoptosis of retinal ganglion cells correlates with specific degradation of laminin from the underlying inner limiting membrane and an increase in gelatinolytic metalloproteinase activity. These changes co-localize with a specific increase in levels of the matrix metalloproteinase, gelatinase B (GelB; MMP-9). Using a transgenic mouse line harboring a reporter gene driven by the GelB promoter, we further show that increased GelB is controlled by activation of the GelB promoter. These findings led us to hypothesize that GelB activity plays a role in ganglion cell death and degradation of laminin. Applying the genetic approach, we demonstrate that GelB-deficient mice are protected against these pathological changes. This is the first report demonstrating a causal connection between GelB activity and pathological changes to the inner retina after optic nerve ligation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M204824200