title: Upregulation of elastase activity in aorta in mucopolysaccharidosis I and VII dogs may be due to increased cytokine expression.
abstract: Mucopolysaccharidosis I (MPS I) and MPS VII are due to loss-of-function mutations within the genes that encode the lysosomal enzymes alpha-l-iduronidase and beta-glucuronidase, respectively, and result in accumulation of glycosaminoglycans and multisystemic disease. Both disorders are associated with elastin fragmentation and dilatation of the aorta. Here, the pathogenesis and effect of gene therapy on aortic disease in canine models of MPS was evaluated. We found that cathepsin S is upregulated at the mRNA and enzyme activity level, while matrix metalloproteinase 12 (MMP-12) is upregulated at the mRNA level, in aortas from untreated MPS I and MPS VII dogs. Both of these proteases can degrade elastin. In addition, mRNA levels for the interleukin 6-like cytokine oncostatin M were increased in MPS I and MPS VII dog aortas, while mRNA for tumor necrosis factor alpha and toll-like receptor 4 were increased in MPS VII dog aortas. These cytokines could contribute to upregulation of the elastases. Neonatal intravenous injection of a retroviral vector expressing beta-glucuronidase to MPS VII dogs reduced RNA levels of cathepsin S and MMP-12 and aortic dilatation was delayed, albeit dilatation developed at late times after gene therapy. A post-mortem aorta from a patient with MPS VII also exhibited elastin fragmentation. We conclude that aortic dilatation in MPS I and MPS VII dogs is likely due to degradation of elastin by cathepsin S and/or MMP-12. Inhibitors of these enzymes or these cytokine-induced signal transduction pathways might reduce aortic disease in patients with MPS.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Metcalf
authors.forename: Bruce
authors.initials: B
authors.lastname: Linders
authors.forename: Susan
authors.initials: S
authors.lastname: Wu
authors.forename: Paul
authors.initials: P
authors.lastname: Bigg
authors.forename: Patricia
authors.initials: P
authors.lastname: O'Donnell
authors.forename: Meg M
authors.initials: MM
authors.lastname: Sleeper
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
authors.forename: Mark
authors.initials: M
authors.lastname: Haskins
authors.forename: Katherine P
authors.initials: KP
authors.lastname: Ponder
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology*; D001018:Aortic Diseases / Q000150:complications; D002403:Cathepsins / Q000378:metabolism; D004283:Dog Diseases / Q000201:enzymology*; D004285:Dogs; D004549:Elastin / Q000378:metabolism; D006801:Humans; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism; D008059:Mucopolysaccharidosis I / Q000201:enzymology* / Q000662:veterinary*; D016538:Mucopolysaccharidosis VII / Q000201:enzymology* / Q000662:veterinary; D010196:Pancreatic Elastase / Q000378:metabolism*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D004549:Elastin; D002403:Cathepsins; D010196:Pancreatic Elastase; C028217:cathepsin S; D053508:Matrix Metalloproteinase 12