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 alpha3(IV), alpha4(IV), or alpha5(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 microdissection 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.
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Michael Anne
authors.initials: MA
authors.lastname: Gratton
authors.forename: Velidi H
authors.initials: VH
authors.lastname: Rao
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Meehan
authors.forename: Charles
authors.initials: C
authors.lastname: Askew
authors.forename: Dominic
authors.initials: D
authors.lastname: Cosgrove
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000473:pathology; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D003199:Computer Systems; D006877:Hydroxamic Acids / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009394:Nephritis, Hereditary / Q000201:enzymology* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013316:Stria Vascularis / Q000187:drug effects / Q000201:enzymology*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C097658:CGS 27023A; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011719:Pyrazines; D012333:RNA, Messenger; D013449:Sulfonamides; D020782:Matrix Metalloproteinases