4.6 Article

Parabiotic Heterogenetic Pairing of Abcc6-/-/Ragl-/- Mice and Their Wild-Type Counterparts Halts Ectopic Mineralization in a Murine Model of Pseudoxanthoma Elasticum

Journal

AMERICAN JOURNAL OF PATHOLOGY
Volume 176, Issue 4, Pages 1855-1862

Publisher

ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2010.090983

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Funding

  1. National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR28450, R01 AR55225]
  2. Dermatology Foundation

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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. (Am J Pathol 2010, 176-1855-1862; DOL. 10.2353/ajpath.2010.090983)

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