title: Aberrant mineralization of connective tissues in a mouse model of pseudoxanthoma elasticum: systemic and local regulatory factors.
abstract: Pseudoxanthoma elasticum (PXE) is caused by mutations in the ABCC6 gene, but the cellular and molecular events leading to aberrant mineralization of soft tissues are unknown. To characterize the mineralization process, we examined a PXE animal model, the Abcc6-/- mouse, with respect to specific proteins serving as inhibitors of mineralization. The levels of calcium and phosphate in serum of these mice were normal, but the Abcc6-/- serum had less ability to prevent the mineral deposition induced by inorganic phosphate in a cell culture system. Addition of fetuin-A to the culture system prevented the mineralization. The calcium x phosphate product was markedly elevated in the mineralized vibrissae of Abcc6-/- mice, an early biomarker of the mineralization process, consistent with histopathologic findings. Levels of fetuin-A were slightly decreased in Abcc6-/- serum, and positive immunostaining for matrix-gla-protein (MGP), fetuin-A, and ankylosis protein (Ank) as well as alkaline phosphatase activity were strongly associated with the mineralization process. In situ hybridization demonstrated that the genes for MGP and Ank were expressed locally in vibrissae, whereas fetuin-A was expressed highly in the liver. These data suggest that the deposition of the bone-associated proteins spatially coincides with mineralization and actively regulates this process locally and systemically.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Qiujie
authors.initials: Q
authors.lastname: Jiang
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Li
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism; D002114:Calcinosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003238:Connective Tissue / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008099:Liver / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D028061:Phosphate Transport Proteins; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011561:Pseudoxanthoma Elasticum / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D014738:Vibrissae / Q000473:pathology; D060749:alpha-2-HS-Glycoprotein
chemical_list: D018528:ATP-Binding Cassette Transporters; D000469:Alkaline Phosphatase; D015415:Biomarkers; D001798:Blood Proteins; D024042:Collagen Type I; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D028061:Phosphate Transport Proteins; D011506:Proteins; D060749:alpha-2-HS-Glycoprotein; C556354:AHSG protein, human; C504743:Abcc6 protein, mouse; C556357:Ahsg protein, mouse; C410982:ank protein, mouse; C039391:granuloma protein, mouse