title: Parabiotic heterogenetic pairing of Abcc6-/-/Rag1-/- mice and their wild-type counterparts halts ectopic mineralization in a murine model of pseudoxanthoma elasticum.
abstract: Pseudoxanthoma elasticum (PXE), a pleiotropic heritable disorder, is characterized by ectopic mineralization of the connective tissues. This disease is caused by mutations in the ABCC6 gene, which is expressed primarily in the baso-lateral surface of hepatocytes, and Abcc6(-/-) mice develop progressive mineralization mimicking human PXE. To investigate the hypothesis that PXE is a metabolic disorder, potentially caused by the absence of antimineralization factor(s) in circulation, we used parabiotic pairing, ie, surgical joining of two mice, to create a shared circulation between various Abcc6 genotypic mice. To prevent immune reaction between the parabiotic animals, all mice were bred to be Rag1(-/-). Shared circulation between the parabiotic animals was confirmed by Evans blue dye injection and by quantitative PCR of blood cell genotypes. Pairing of Abcc6(-/-) mice with their wild-type counterparts halted the connective tissue mineralization in the knockout mice. Homogenetic wild-type and heterozygous pairings serving as controls were phenotypically unaffected by parabiosis. Consequently, the observations on the parabiotic mice support the notion that PXE is a metabolic disease, potentially due to absence of systemic antimineralization factor(s). These observations suggest that reintroduction of the critical antimineralization factors into circulation could provide a potential treatment for this, currently intractable, disease.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Philadelphia, PA 19107, USA.
authors.forename: Qiujie
authors.initials: Q
authors.lastname: Jiang
authors.forename: Reid
authors.initials: R
authors.lastname: Oldenburg
authors.forename: Satoru
authors.initials: S
authors.lastname: Otsuru
authors.forename: Alix E
authors.initials: AE
authors.lastname: Grand-Pierre
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Horwitz
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D002114:Calcinosis / Q000378:metabolism*; D003238:Connective Tissue / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009154:Mutation; D011561:Pseudoxanthoma Elasticum / Q000235:genetics*
chemical_list: D018528:ATP-Binding Cassette Transporters; D018398:Homeodomain Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C504743:Abcc6 protein, mouse; C064658:RAG-1 protein