title: Overexpression of fetuin-a counteracts ectopic mineralization in a mouse model of pseudoxanthoma elasticum (abcc6(-/-)).
abstract: 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.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Qiujie
authors.initials: Q
authors.lastname: Jiang
authors.forename: Florian
authors.initials: F
authors.lastname: Dibra
authors.forename: Michael D
authors.initials: MD
authors.lastname: Lee
authors.forename: Reid
authors.initials: R
authors.lastname: Oldenburg
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001798:Blood Proteins / Q000235:genetics* / Q000378:metabolism; D002114:Calcinosis / Q000503:physiopathology*; D003238:Connective Tissue / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000502:physiology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007763:Lac Operon; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011561:Pseudoxanthoma Elasticum / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D014162:Transfection; D014738:Vibrissae / Q000473:pathology / Q000502:physiology; D060749:alpha-2-HS-Glycoprotein
chemical_list: D018528:ATP-Binding Cassette Transporters; D001798:Blood Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D060749:alpha-2-HS-Glycoprotein; C504743:Abcc6 protein, mouse; C556357:Ahsg protein, mouse