Magnesium carbonate-containing phosphate binder prevents connective tissue mineralization in Abcc6(-/-) mice-potential for treatment of pseudoxanthoma elasticum.
Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by ectopic mineralization of connective tissues primarily in the skin, eyes, and the cardiovascular system. PXE is caused by mutations in the ABCC6 gene. While PXE is associated with considerable morbidity and mortality, there is currently no effective or specific treatment. In this study, we tested oral phosphate binders for treatment of a mouse model of PXE which we have developed by targeted ablation of the corresponding mouse gene (Abcc6(-/-)). This "knock-out" (KO) mouse model recapitulates features of PXE and demonstrates mineralization of a number of tissues, including the connective tissue capsule surrounding vibrissae in the muzzle skin which serves as an early biomarker of the mineralization process. Treatment of these mice with a magnesium carbonate-enriched diet (magnesium concentration being 5-fold higher than in the control diet) completely prevented mineralization of the vibrissae up to 6 months of age, as demonstrated by computerized morphometric analysis of histopathology as well as by calcium and phosphate chemical assays. The magnesium carbonate-enriched diet also prevented the progression of mineralization when the mice were placed on that experimental diet at 3 months of age and followed up to 6 months of age. Treatment with magnesium carbonate was associated with a slight increase in the serum concentration of magnesium, with no effect on serum calcium and phosphorus levels. In contrast, concentration of calcium in the urine was increased over 10-fold while the concentration of phosphorus was markedly decreased, being essentially undetectable after long-term (> 4 month) treatment. No significant changes were noted in the serum parathyroid hormone levels. Computerized axial tomography scan of bones in mice placed on magnesium carbonate-enriched diet showed no differences in the bone density compared to mice on the control diet, and chemical assays showed a small increase in the calcium and phosphate content of the femurs by chemical assay, in comparison to mice on control diet. Similar experiments with another experimental diet supplemented with lanthanum carbonate did not interfere with the mineralization process in Abcc6(-/-) mice. These results suggest that magnesium carbonate may offer a potential treatment modality for PXE, a currently intractable disease, as well as for other conditions characterized by ectopic mineralization of connective tissues.
Li
Qiaoli
Q
Department of Dermatology and Cutaneous Biology, Jefferson Medical College, and Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Larusso
Jennifer
J
Grand-Pierre
Alix E
AE
Uitto
Jouni
J
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D002113:Calcification, Physiologic / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D003238:Connective Tissue / Q000187:drug effects* / Q000473:pathology; D004032:Diet; D005269:Femur / Q000000981:diagnostic imaging / Q000378:metabolism; D007811:Lanthanum / Q000494:pharmacology / Q000627:therapeutic use; D008274:Magnesium / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008903:Minerals / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010710:Phosphates / Q000627:therapeutic use*; D010758:Phosphorus / Q000378:metabolism; D011561:Pseudoxanthoma Elasticum / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D014057:Tomography, X-Ray Computed; D014738:Vibrissae / Q000187:drug effects / Q000473:pathology
D018528:ATP-Binding Cassette Transporters; D002118:Calcium; D007811:Lanthanum; D008274:Magnesium; D008903:Minerals; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010710:Phosphates; D010758:Phosphorus; C504743:Abcc6 protein, mouse; C005479:magnesium carbonate; C119467:lanthanum carbonate