Overexpression of Fetuin-A Counteracts Ectopic Mineralization in a Mouse Model of Pseudoxanthoma Elasticum (Abcc6−/−)
| Autor: | Qiujie Jiang, Michael D. Lee, Florian Dibra, Jouni Uitto, Reid Oldenburg |
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| Rok vydání: | 2010 |
| Předmět: |
Male
alpha-2-HS-Glycoprotein Genetic enhancement Mutant Gene Expression ABCC6 Dermatology Biology Transfection Biochemistry Article Mice 030207 dermatology & venereal diseases 03 medical and health sciences 0302 clinical medicine Complementary DNA medicine Animals Pseudoxanthoma Elasticum Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences Gene Transfer Techniques Calcinosis Blood Proteins Genetic Therapy Cell Biology Pseudoxanthoma elasticum medicine.disease Molecular biology Fetuin Mice Mutant Strains Disease Models Animal Lac Operon Liver chemistry Connective Tissue Vibrissae Circulatory system biology.protein ATP-Binding Cassette Transporters Female Multidrug Resistance-Associated Proteins Glycoprotein |
| Zdroj: | Journal of Investigative Dermatology. 130:1288-1296 |
| ISSN: | 0022-202X |
| DOI: | 10.1038/jid.2009.423 |
| Popis: | The pathologic hallmark of pseudoxanthoma elasticum (PXE) is ectopic mineralization of soft connective tissues. Recent studies have suggested that PXE is a metabolic disease, and perturbations in a number of circulatory factors have been postulated. One of them is fetuin-A, a 60-kDa glycoprotein synthesized in the liver and secreted into blood. Observations in targeted mutant mice (Ahsg(-/-)) and in cell culture model systems have shown that fetuin-A is a powerful anti-mineralization factor in circulation, and the serum levels of fetuin-A in patients with PXE as well as in a mouse model of PXE (Abcc6(-/-)) have been shown to be reduced by up to 30%. In this study, we tested the hypothesis that overexpression of fetuin-A in Abcc6(-/-) mice counteracts the ectopic mineralization. Delivery of an expression construct containing full-length mouse fetuin-A complementary DNA (cDNA), linked to a His-tag, to the liver of these mice resulted in elevated serum levels of this protein. As a consequence, soft tissue mineralization, which is a characteristic of Abcc6(-/-) mice, was reduced by approximately 70% at 12 weeks of age, but the effect was transient when examined 4 weeks later. The results suggest that normalization of serum fetuin-A, either through gene therapy approaches or by direct protein delivery to the circulation, may offer strategies for treating PXE and perhaps other heritable disorders of soft tissue mineralization. |
| Databáze: | OpenAIRE |
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