Matrix metalloproteinase dysregulation in the stria vascularis of mice with Alport syndrome: Implications for capillary basement membrane pathology

Michael Anne Gratton, Velidi H. Rao, Daniel T. Meehan, Charles Askew, Dominic E Cosgrove

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Alport syndrome results from mutations in genes encoding collagen α3(IV), α4(IV), or α5(IV) and is characterized by progressive glomerular disease associated with a high-frequency sensorineural hearing loss. Earlier studies of a gene knockout mouse model for Alport syndrome noted thickening of strial capillary basement membranes in the cochlea, suggesting that the stria vascularis is the primary site of cochlear pathogenesis. Here we combine a novel cochlear mi-crodissection technique with molecular analyses to illustrate significant quantitative alterations in strial expression of mRNAs encoding matrix metalloproteinases-2, -9, -12, and -14. Gelatin zymography of extracts from the stria vascularis confirmed these findings. Treatment of Alport mice with a small molecule inhibitor of these matrix metalloproteinases exacerbated strial capillary basement membrane thickening, demonstrating that alterations in basement membrane metabolism result in matrix accumulation in the strial capillary basement membranes. This is the first demonstration of true quantitative analysis of specific mRNAs for matrix metalloproteinases in a cochlear microcompartment. Further, these data suggest that the altered basement membrane composition in Alport stria influences the expression of genes involved in basement membrane metabolism.

Original languageEnglish (US)
Pages (from-to)1465-1474
Number of pages10
JournalAmerican Journal of Pathology
Volume166
Issue number5
DOIs
StatePublished - May 2005

Fingerprint

Hereditary Nephritis
Stria Vascularis
Matrix Metalloproteinases
Basement Membrane
Cochlea
Pathology
High-Frequency Hearing Loss
Messenger RNA
Gene Knockout Techniques
Matrix Metalloproteinase Inhibitors
Sensorineural Hearing Loss
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Gelatin
Knockout Mice
Collagen
Gene Expression
Mutation
Genes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Matrix metalloproteinase dysregulation in the stria vascularis of mice with Alport syndrome : Implications for capillary basement membrane pathology. / Gratton, Michael Anne; Rao, Velidi H.; Meehan, Daniel T.; Askew, Charles; Cosgrove, Dominic E.

In: American Journal of Pathology, Vol. 166, No. 5, 05.2005, p. 1465-1474.

Research output: Contribution to journalArticle

@article{eb46f2dfcd054214821ffea0d06627dd,
title = "Matrix metalloproteinase dysregulation in the stria vascularis of mice with Alport syndrome: Implications for capillary basement membrane pathology",
abstract = "Alport syndrome results from mutations in genes encoding collagen α3(IV), α4(IV), or α5(IV) and is characterized by progressive glomerular disease associated with a high-frequency sensorineural hearing loss. Earlier studies of a gene knockout mouse model for Alport syndrome noted thickening of strial capillary basement membranes in the cochlea, suggesting that the stria vascularis is the primary site of cochlear pathogenesis. Here we combine a novel cochlear mi-crodissection technique with molecular analyses to illustrate significant quantitative alterations in strial expression of mRNAs encoding matrix metalloproteinases-2, -9, -12, and -14. Gelatin zymography of extracts from the stria vascularis confirmed these findings. Treatment of Alport mice with a small molecule inhibitor of these matrix metalloproteinases exacerbated strial capillary basement membrane thickening, demonstrating that alterations in basement membrane metabolism result in matrix accumulation in the strial capillary basement membranes. This is the first demonstration of true quantitative analysis of specific mRNAs for matrix metalloproteinases in a cochlear microcompartment. Further, these data suggest that the altered basement membrane composition in Alport stria influences the expression of genes involved in basement membrane metabolism.",
author = "Gratton, {Michael Anne} and Rao, {Velidi H.} and Meehan, {Daniel T.} and Charles Askew and Cosgrove, {Dominic E}",
year = "2005",
month = "5",
doi = "10.1016/S0002-9440(10)62363-2",
language = "English (US)",
volume = "166",
pages = "1465--1474",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "5",

}

TY - JOUR

T1 - Matrix metalloproteinase dysregulation in the stria vascularis of mice with Alport syndrome

T2 - Implications for capillary basement membrane pathology

AU - Gratton, Michael Anne

AU - Rao, Velidi H.

AU - Meehan, Daniel T.

AU - Askew, Charles

AU - Cosgrove, Dominic E

PY - 2005/5

Y1 - 2005/5

N2 - Alport syndrome results from mutations in genes encoding collagen α3(IV), α4(IV), or α5(IV) and is characterized by progressive glomerular disease associated with a high-frequency sensorineural hearing loss. Earlier studies of a gene knockout mouse model for Alport syndrome noted thickening of strial capillary basement membranes in the cochlea, suggesting that the stria vascularis is the primary site of cochlear pathogenesis. Here we combine a novel cochlear mi-crodissection technique with molecular analyses to illustrate significant quantitative alterations in strial expression of mRNAs encoding matrix metalloproteinases-2, -9, -12, and -14. Gelatin zymography of extracts from the stria vascularis confirmed these findings. Treatment of Alport mice with a small molecule inhibitor of these matrix metalloproteinases exacerbated strial capillary basement membrane thickening, demonstrating that alterations in basement membrane metabolism result in matrix accumulation in the strial capillary basement membranes. This is the first demonstration of true quantitative analysis of specific mRNAs for matrix metalloproteinases in a cochlear microcompartment. Further, these data suggest that the altered basement membrane composition in Alport stria influences the expression of genes involved in basement membrane metabolism.

AB - Alport syndrome results from mutations in genes encoding collagen α3(IV), α4(IV), or α5(IV) and is characterized by progressive glomerular disease associated with a high-frequency sensorineural hearing loss. Earlier studies of a gene knockout mouse model for Alport syndrome noted thickening of strial capillary basement membranes in the cochlea, suggesting that the stria vascularis is the primary site of cochlear pathogenesis. Here we combine a novel cochlear mi-crodissection technique with molecular analyses to illustrate significant quantitative alterations in strial expression of mRNAs encoding matrix metalloproteinases-2, -9, -12, and -14. Gelatin zymography of extracts from the stria vascularis confirmed these findings. Treatment of Alport mice with a small molecule inhibitor of these matrix metalloproteinases exacerbated strial capillary basement membrane thickening, demonstrating that alterations in basement membrane metabolism result in matrix accumulation in the strial capillary basement membranes. This is the first demonstration of true quantitative analysis of specific mRNAs for matrix metalloproteinases in a cochlear microcompartment. Further, these data suggest that the altered basement membrane composition in Alport stria influences the expression of genes involved in basement membrane metabolism.

UR - http://www.scopus.com/inward/record.url?scp=17844408713&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=17844408713&partnerID=8YFLogxK

U2 - 10.1016/S0002-9440(10)62363-2

DO - 10.1016/S0002-9440(10)62363-2

M3 - Article

C2 - 15855646

AN - SCOPUS:17844408713

VL - 166

SP - 1465

EP - 1474

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 5

ER -