{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T02:12:57Z","timestamp":1790475177411,"version":"4.1.0"},"reference-count":120,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2017,9,11]],"date-time":"2017-09-11T00:00:00Z","timestamp":1505088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pseudoxanthoma elasticum (PXE) is an inherited metabolic disease with autosomal recessive inheritance caused by mutations in the ABCC6 gene. Since the first description of the disease in 1896, alleging a disease involving the elastic fibers, the concept evolved with the further discoveries of the pivotal role of ectopic mineralization that is preponderant in the elastin-rich tissues of the skin, eyes and blood vessel walls. After discovery of the causative gene of the disease in 2000, the function of the ABCC6 protein remains elusive. More than 300 mutations have been now reported and the concept of a dermal disease has progressively evolved toward a metabolic disorder resulting from the remote effects caused by lack of a circulating anti-mineralization factor. Very recently, evidence has accumulated that this anti-mineralizing factor is inorganic pyrophosphate (PPi). This leads to decreased PPi\/Pi (inorganic phosphate) ratio that results from the lack of extracellular ATP release by hepatocytes and probably renal cells harboring the mutant ABCC6 protein. However, the mechanism by which ABCC6 dysfunction causes diminished ATP release remains an enigma. Studies of other ABC transporters, such as ABCC7 or ABCC1 could help our understanding of what ABCC6 exact function is. Data and a hypothesis on the possible roles of ABCC6 in acquired metabolic diseases are also discussed.<\/jats:p>","DOI":"10.3390\/ijms18091941","type":"journal-article","created":{"date-parts":[[2017,9,11]],"date-time":"2017-09-11T10:28:46Z","timestamp":1505125726000},"page":"1941","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["The ABCC6 Transporter: A New Player in Biomineralization"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1069-4344","authenticated-orcid":false,"given":"Guillaume","family":"Favre","sequence":"first","affiliation":[{"name":"FINSERM, U 1081, Aging and Diabetes Team, Institute for Research on Cancer and Aging of Nice (IRCAN), 06107 Nice, France"},{"name":"CNRS, UMR7284, Institute for Research on Cancer and Aging of Nice (IRCAN), 06107 Nice, France"},{"name":"Faculty of Medicine, University of Nice-Sophia Antipolis, 06107 Nice, France"},{"name":"Nephrology Department, University Hospital, 06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Laurain","sequence":"additional","affiliation":[{"name":"Nephrology Department, University Hospital, 06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamas","family":"Aranyi","sequence":"additional","affiliation":[{"name":"Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flora","family":"Szeri","sequence":"additional","affiliation":[{"name":"Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisztina","family":"Fulop","sequence":"additional","affiliation":[{"name":"Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5605-3617","authenticated-orcid":false,"given":"Olivier","family":"Le Saux","sequence":"additional","affiliation":[{"name":"Department Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96813, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Duranton","sequence":"additional","affiliation":[{"name":"Laboratory of Physiology and Molecular Medicine (LP2M) UMR CNRS 7073, 06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4994-8305","authenticated-orcid":false,"given":"Gilles","family":"Kauffenstein","sequence":"additional","affiliation":[{"name":"UMR CNRS 6015-Inserm 1083, School of Medicine, Bretagne Loire University, 49045 Angers, France"},{"name":"PXE Health and Research Center, University Hospital of Angers, 49045 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludovic","family":"Martin","sequence":"additional","affiliation":[{"name":"UMR CNRS 6015-Inserm 1083, School of Medicine, Bretagne Loire University, 49045 Angers, France"},{"name":"PXE Health and Research Center, University Hospital of Angers, 49045 Angers, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georges","family":"Lefth\u00e9riotis","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Nice-Sophia Antipolis, 06107 Nice, France"},{"name":"Laboratory of Physiology and Molecular Medicine (LP2M) UMR CNRS 7073, 06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,9,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1080\/01913120390248584","article-title":"Extracutaneous ultrastructural alterations in pseudoxanthoma elasticum","volume":"27","author":"Gheduzzi","year":"2003","journal-title":"Ultrastruct. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1007\/s00795-007-0368-5","article-title":"An autopsy case of pseudoxanthoma elasticum: Histochemical characteristics","volume":"40","author":"Miki","year":"2007","journal-title":"Med. Mol. Morphol."},{"key":"ref_3","first-page":"65","article-title":"Recherches sur les caract\u00e8res anatomiques du xanthelasma","volume":"4","author":"Balzer","year":"1884","journal-title":"Arch. Physiol."},{"key":"ref_4","first-page":"412","article-title":"Xanth\u00e9lasma diss\u00e9min\u00e9 et sym\u00e9trique et sans insuffisance h\u00e9patique","volume":"6","author":"Chauffard","year":"1889","journal-title":"Bull. Soc. Med. Paris"},{"key":"ref_5","first-page":"491","article-title":"Observation pour servir \u00e0 l\u2019histoire de la ch\u00e9loide diffuse xanth\u00e9lasmique","volume":"2","author":"Rigal","year":"1881","journal-title":"Ann. Dermatol. Syphilol."},{"key":"ref_6","first-page":"289","article-title":"Pseudo-xanthome \u00e9lastique","volume":"23","author":"Darier","year":"1896","journal-title":"III \u00e8me congr\u00e8s Intern. de Dermat de Londres"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1007\/BF01936164","article-title":"Uber pseudoxanthoma elasticum","volume":"69","author":"Werther","year":"1904","journal-title":"Arch. Dermatol. Syph."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0190-9622(08)81894-4","article-title":"Classification of pseudoxanthoma elasticum: Report of a consensus conference","volume":"30","author":"Lebwohl","year":"1994","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3389\/fgene.2013.00004","article-title":"The vascular phenotype in Pseudoxanthoma elasticum and related disorders: Contribution of a genetic disease to the understanding of vascular calcification","volume":"4","author":"Leftheriotis","year":"2013","journal-title":"Front. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.atherosclerosis.2016.11.012","article-title":"Prevalence and severity of arterial calcifications in pseudoxanthoma elasticum (PXE) compared to hospital controls. Novel insights into the vascular phenotype of PXE","volume":"256","author":"Kranenburg","year":"2017","journal-title":"Atherosclerosis"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1016\/j.jvs.2011.04.041","article-title":"Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum","volume":"54","author":"Leftheriotis","year":"2011","journal-title":"J. Vasc. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1038\/sj.jid.5700201","article-title":"Serum factors from pseudoxanthoma elasticum patients alter elastic fiber formation in vitro","volume":"126","author":"Bunda","year":"2006","journal-title":"J. Investig. Dermatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1161\/hy1101.096108","article-title":"Compressibility of the carotid artery in patients with pseudoxanthoma elasticum","volume":"38","author":"Boutouyrie","year":"2001","journal-title":"Hypertension"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1159\/000016076","article-title":"Prevalence of symptomatic intracranial aneurysm and ischaemic stroke in pseudoxanthoma elasticum","volume":"10","author":"Hennekam","year":"2000","journal-title":"Cerebrovasc. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1161\/ATVBAHA.113.302943","article-title":"Disseminated arterial calcification and enhanced myogenic response are associated with abcc6 deficiency in a mouse model of pseudoxanthoma elasticum","volume":"34","author":"Kauffenstein","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.bone.2017.06.017","article-title":"Early arterial calcification does not correlate with bone loss in pseudoxanthoma elasticum","volume":"103","author":"Martin","year":"2017","journal-title":"Bone"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.molmed.2009.07.001","article-title":"Vascular calcification and bone disease: The calcification paradox","volume":"15","author":"Persy","year":"2009","journal-title":"Trends Mol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1097\/GIM.0b013e3181c00a96","article-title":"Pseudoxanthoma elasticum: Wide phenotypic variation in homozygotes and no signs in heterozygotes for the c.3775delT mutation in ABCC6","volume":"11","author":"Plomp","year":"2009","journal-title":"Genet. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.survophthal.2008.12.006","article-title":"Pseudoxanthoma elasticum: Genetics, clinical manifestations and therapeutic approaches","volume":"54","author":"Finger","year":"2009","journal-title":"Surv. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Prunier, F., Terrien, G., Le Corre, Y., Apana, A.L., Biere, L., Kauffenstein, G., Furber, A., Bergen, A.A., Gorgels, T.G., and Le Saux, O. (2013). Pseudoxanthoma elasticum: Cardiac findings in patients and Abcc6-deficient mouse model. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0068700"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8299","DOI":"10.1128\/MCB.25.18.8299-8310.2005","article-title":"Targeted ablation of the abcc6 gene results in ectopic mineralization of connective tissues","volume":"25","author":"Klement","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1093\/hmg\/ddi183","article-title":"Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum","volume":"14","author":"Gorgels","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2208","DOI":"10.1016\/j.ajpath.2012.02.007","article-title":"Quantification of the calcification phenotype of Abcc6-deficient mice with microcomputed tomography","volume":"180","author":"Froeliger","year":"2012","journal-title":"Am. J. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1111\/cts.12057","article-title":"Rate of change of carotid intima-media thickness with magnesium administration in Abcc6(-)\/(-) mice","volume":"6","author":"Kupetsky","year":"2013","journal-title":"Clin. Transl. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"7608","DOI":"10.1074\/jbc.M708290200","article-title":"An alternative splice variant in Abcc6, the gene causing dystrophic calcification, leads to protein deficiency in C3H\/He mice","volume":"283","author":"Aherrahrou","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.aanat.2006.01.013","article-title":"Arterial calcification in mice after freeze-thaw injury","volume":"188","author":"Doehring","year":"2006","journal-title":"Ann. Anat."},{"key":"ref_27","first-page":"173","article-title":"Dystrophic cardiac calcinosis in mice: Genetic, hormonal, and dietary influences","volume":"90","author":"Eaton","year":"1978","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4530","DOI":"10.1073\/pnas.0607620104","article-title":"Identification of Abcc6 as the major causal gene for dystrophic cardiac calcification in mice through integrative genomics","volume":"104","author":"Meng","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1177\/030098588802500202","article-title":"High mortality with severe dystrophic cardiac calcinosis in C3H\/OUJ mice fed high fat purified diets","volume":"25","author":"Everitt","year":"1988","journal-title":"Vet. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1016\/S0002-9440(10)63224-5","article-title":"A locus on chromosome 7 determines dramatic up-regulation of osteopontin in dystrophic cardiac calcification in mice","volume":"164","author":"Aherrahrou","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1152\/physiolgenomics.2001.6.3.137","article-title":"New Dyscalc loci for myocardial cell necrosis and calcification (dystrophic cardiac calcinosis) in mice","volume":"6","author":"Ivandic","year":"2001","journal-title":"Physiol. Genom."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1152\/physiolgenomics.00010.2006","article-title":"Fine mapping of Dyscalc1, the major genetic determinant of dystrophic cardiac calcification in mice","volume":"25","author":"Korff","year":"2006","journal-title":"Physiol. Genom."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/j.jid.2016.11.042","article-title":"Abcc6 Knockout Rat Model Highlights the Role of Liver in PPi Homeostasis in Pseudoxanthoma Elasticum","volume":"137","author":"Li","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1038\/jid.2010.174","article-title":"The abcc6a gene expression is required for normal zebrafish development","volume":"130","author":"Li","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/76102","article-title":"Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum","volume":"25","author":"Urban","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1038\/jid.2009.411","article-title":"Pseudoxanthoma elasticum: Molecular genetics and putative pathomechanisms","volume":"130","author":"Uitto","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.1093\/molbev\/msn202","article-title":"How segmental duplications shape our genome: Recent evolution of ABCC6 and PKD1 Mendelian disease genes","volume":"25","author":"Symmons","year":"2008","journal-title":"Mol. Biol. Evol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1007\/s004390100582","article-title":"Identification of ABCC6 pseudogenes on human chromosome 16p: Implications for mutation detection in pseudoxanthoma elasticum","volume":"109","author":"Pulkkinen","year":"2001","journal-title":"Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"18643","DOI":"10.1074\/jbc.M501139200","article-title":"Identification of a DNA methylation-dependent activator sequence in the pseudoxanthoma elasticum gene, ABCC6","volume":"280","author":"Aranyi","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"22800","DOI":"10.1074\/jbc.M110.105593","article-title":"The ERK1\/2-hepatocyte nuclear factor 4alpha axis regulates human ABCC6 gene expression in hepatocytes","volume":"285","author":"Ratajewski","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.bbaexp.2006.08.002","article-title":"HNF4alpha and NF-E2 are key transcriptional regulators of the murine Abcc6 gene expression","volume":"1759","author":"Douet","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2709","DOI":"10.1038\/jid.2012.218","article-title":"ABCC6 Expression Is Regulated by CCAAT\/Enhancer-Binding Protein Activating a Primate-Specific Sequence Located in the First Intron of the Gene","volume":"131","author":"Ratajewski","year":"2012","journal-title":"J. Investig. Dermatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/sj.jid.5700065","article-title":"Transcriptional regulation and characterization of the promoter region of the human ABCC6 gene","volume":"126","author":"Jiang","year":"2006","journal-title":"J. Investig. Dermatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.ajpath.2010.10.004","article-title":"A mouse model of beta-thalassemia shows a liver-specific down-regulation of Abcc6 expression","volume":"178","author":"Martin","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7","DOI":"10.5070\/D31CW031GJ","article-title":"Pseudoxanthoma-elasticum-like syndrome and thalassemia: An update","volume":"15","author":"Fabbri","year":"2009","journal-title":"Dermatol. Online J."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Veto, B., Bojcsuk, D., Bacquet, C., Kiss, J., Sipeki, S., Martin, L., Buday, L., Balint, B.L., and Aranyi, T. (2017). The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1\/2. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0172020"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"16860","DOI":"10.1074\/jbc.M110918200","article-title":"Loss of ATP-dependent transport activity in pseudoxanthoma elasticum-associated mutants of human ABCC6 (MRP6)","volume":"277","author":"Ilias","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1038\/jid.2013.482","article-title":"Analysis of pseudoxanthoma elasticum-causing missense mutants of ABCC6 in vivo; pharmacological correction of the mislocalized proteins","volume":"134","author":"Pomozi","year":"2014","journal-title":"J. Investig. Dermatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.jid.2016.10.035","article-title":"Functional Rescue of ABCC6 Deficiency by 4-Phenylbutyrate Therapy Reduces Dystrophic Calcification in Abcc6\u2212\/\u2212 Mice","volume":"137","author":"Pomozi","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Le Saux, O., Fulop, K., Yamaguchi, Y., Ilias, A., Szabo, Z., Brampton, C.N., Pomozi, V., Huszar, K., Aranyi, T., and Varadi, A. (2011). Expression and in vivo rescue of human ABCC6 disease-causing mutants in mouse liver. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024738"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1124\/mol.57.3.634","article-title":"Transport function and hepatocellular localization of mrp6 in rat liver","volume":"57","author":"Madon","year":"2000","journal-title":"Mol. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1007\/s00418-004-0744-3","article-title":"Analysis of ABCC6 (MRP6) in normal human tissues","volume":"123","author":"Beck","year":"2005","journal-title":"Histochem. Cell Biol."},{"key":"ref_53","first-page":"175","article-title":"Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells","volume":"59","author":"Kool","year":"1999","journal-title":"Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1016\/j.lfs.2005.09.016","article-title":"Tissue distribution and induction of the rat multidrug resistance-associated proteins 5 and 6","volume":"78","author":"Maher","year":"2006","journal-title":"Life Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1124\/dmd.105.003780","article-title":"Tissue distribution and hepatic and renal ontogeny of the multidrug resistance-associated protein (Mrp) family in mice","volume":"33","author":"Maher","year":"2005","journal-title":"Drug Metab. Dispos."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1111\/j.0022-202X.2005.23897.x","article-title":"Tissue-specific expression of the ABCC6 gene","volume":"125","author":"Matsuzaki","year":"2005","journal-title":"J. Investig. Dermatol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e148","DOI":"10.1161\/CIRCRESAHA.111.300194","article-title":"ABCC6 is a basolateral plasma membrane protein","volume":"112","author":"Pomozi","year":"2013","journal-title":"Circ. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1177\/002215540305100704","article-title":"The distribution of Abcc6 in normal mouse tissues suggests multiple functions for this ABC transporter","volume":"51","author":"Beck","year":"2003","journal-title":"J. Histochem. Cytochem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1038\/sj.bjc.6690527","article-title":"MOAT-E (ARA) is a full-length MRP\/cMOAT subfamily transporter expressed in kidney and liver","volume":"80","author":"Belinsky","year":"1999","journal-title":"Bri. J. Cancer"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/labinvest.3780444","article-title":"MRP6 (ABCC6) detection in normal human tissues and tumors","volume":"82","author":"Scheffer","year":"2002","journal-title":"Lab. Investig."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/jid.2008.212","article-title":"Pseudoxanthoma elasticum is a metabolic disease","volume":"129","author":"Jiang","year":"2009","journal-title":"J. Investig. Dermatol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.2353\/ajpath.2010.090983","article-title":"Parabiotic heterogenetic pairing of Abcc6\u2212\/\u2212\/Rag1\u2212\/\u2212 mice and their wild-type counterparts halts ectopic mineralization in a murine model of pseudoxanthoma elasticum","volume":"176","author":"Jiang","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/jid.2008.271","article-title":"Mutations in the GGCX and ABCC6 genes in a family with pseudoxanthoma elasticum-like phenotypes","volume":"129","author":"Li","year":"2009","journal-title":"J. Investig. Dermatol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/sj.jid.5700610","article-title":"Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity","volume":"127","author":"Vanakker","year":"2007","journal-title":"J. Investig. Dermatol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"701","DOI":"10.4161\/cc.10.4.14862","article-title":"Administration of vitamin K does not counteract the ectopic mineralization of connective tissues in Abcc6\u2212\/\u2212 mice, a model for pseudoxanthoma elasticum","volume":"10","author":"Jiang","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1810","DOI":"10.4161\/cc.10.11.15681","article-title":"Vitamin K does not prevent soft tissue mineralization in a mouse model of pseudoxanthoma elasticum","volume":"10","author":"Brampton","year":"2011","journal-title":"Cell Cycle"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1161\/ATVBAHA.114.304017","article-title":"ABCC6-mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report","volume":"34","author":"Jansen","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"20206","DOI":"10.1073\/pnas.1319582110","article-title":"ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release","volume":"110","author":"Jansen","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1073\/pnas.90.1.312","article-title":"The multidrug resistance (mdr1) gene product functions as an ATP channel","volume":"90","author":"Abraham","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1126\/science.7543697","article-title":"Regulation of ion channels by ABC transporters that secrete ATP","volume":"269","year":"1995","journal-title":"Science"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/ng1221","article-title":"Mutations in ENPP1 are associated with \u201cidiopathic\u201d infantile arterial calcification","volume":"34","author":"Rutsch","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1056\/NEJMoa0912923","article-title":"NT5E mutations and arterial calcifications","volume":"364","author":"Ziegler","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1038\/212901a0","article-title":"Effect of pyrophosphate on hydroxyapatite and its implications in calcium homeostasis","volume":"212","author":"Fleisch","year":"1966","journal-title":"Nature"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1038\/ki.2013.521","article-title":"Vascular calcification is dependent on plasma levels of pyrophosphate","volume":"85","author":"Lomashvili","year":"2014","journal-title":"Kidney Int."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Ziegler, S.G., Ferreira, C.R., MacFarlane, E.G., Riddle, R.C., Tomlinson, R.E., Chew, E.Y., Martin, L., Ma, C.T., Sergienko, E., and Pinkerton, A.B. (2017). Ectopic calcification in pseudoxanthoma elasticum responds to inhibition of tissue-nonspecific alkaline phosphatase. Sci. Transl. Med., 9.","DOI":"10.1126\/scitranslmed.aal1669"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Dedinszki, D., Szeri, F., Kozak, E., Pomozi, V., Tokesi, N., Mezei, T.R., Merczel, K., Letavernier, E., Tang, E., and Le Saux, O. (2017). Oral administration of pyrophosphate inhibits connective tissue calcification. EMBO Mol. Med.","DOI":"10.15252\/emmm.201707532"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Ho, A.M., Johnson, M.D., and Kingsley, D.M. (2000). Role of the Mouse ank Gene in Control of Tissue Calcification and Arthritis. Science, 289.","DOI":"10.1126\/science.289.5477.265"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1373\/clinchem.2006.076364","article-title":"Human plasma ATP concentration","volume":"53","author":"Gorman","year":"2007","journal-title":"Clin. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1113\/jphysiol.2010.203034","article-title":"Local release of ATP into the arterial inflow and venous drainage of human skeletal muscle: Insight from ATP determination with the intravascular microdialysis technique","volume":"589","author":"Mortensen","year":"2011","journal-title":"J. Physiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1093\/cvr\/cvs187","article-title":"Mechanisms of ATP release and signalling in the blood vessel wall","volume":"95","author":"Lohman","year":"2012","journal-title":"Cardiovasc. Res."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Zhao, J., Kingman, J., Sundberg, J.P., Uitto, J., and Li, Q. (2017). Plasma PPi Deficiency is the Major, But Not the Exclusive, Cause of Ectopic Mineralization in an Abcc6\u2212\/\u2212 Mouse Model of PXE. J. Investig. Dermatol., in press.","DOI":"10.1016\/j.jid.2017.06.006"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1046\/j.1523-1755.2000.00178.x","article-title":"Increased risk of hip fracture among patients with end-stage renal disease","volume":"58","author":"Alem","year":"2000","journal-title":"Kidney Int."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1111\/j.1523-1755.2000.00394.x","article-title":"Risk factors for hip fracture among patients with end-stage renal disease","volume":"58","author":"Sherrard","year":"2000","journal-title":"Kidney Int."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"4246","DOI":"10.1210\/jc.2003-030964","article-title":"Aortic calcification and the risk of osteoporosis and fractures","volume":"89","author":"Schulz","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/BF02390833","article-title":"Bone loss and the progression of abdominal aortic calcification over a 25 year period: The Framingham Heart Study","volume":"68","author":"Kiel","year":"2001","journal-title":"Calcif. Tissue Int."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/nrneph.2017.63","article-title":"Reducing the costs of chronic kidney disease while delivering quality health care: A call to action","volume":"13","author":"Vanholder","year":"2017","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1056\/NEJMoa041031","article-title":"Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization","volume":"351","author":"Go","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1111\/j.1365-2796.2010.02269.x","article-title":"Chronic kidney disease: A public health priority and harbinger of premature cardiovascular disease","volume":"268","author":"Stenvinkel","year":"2010","journal-title":"J. Intern. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/0735-1097(90)90282-T","article-title":"Quantification of coronary artery calcium using ultrafast computed tomography","volume":"15","author":"Agatston","year":"1990","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1016\/j.jacc.2006.10.079","article-title":"Long-term prognosis associated with coronary calcification: Observations from a registry of 25,253 patients","volume":"49","author":"Budoff","year":"2007","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/S0272-6386(96)90363-7","article-title":"Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients","volume":"27","author":"Braun","year":"1996","journal-title":"Am. J. Kidney Dis."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1681\/ASN.2011111115","article-title":"Cardiovascular disease in children with chronic kidney disease","volume":"23","author":"Mitsnefes","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1681\/ASN.2008020159","article-title":"Timing of onset of CKD-related metabolic complications","volume":"20","author":"Moranne","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1681\/ASN.2004080694","article-title":"Reduced plasma pyrophosphate levels in hemodialysis patients","volume":"16","author":"Lomashvili","year":"2005","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1093\/ndt\/gfp362","article-title":"Plasma pyrophosphate and vascular calcification in chronic kidney disease","volume":"25","author":"Sigrist","year":"2010","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1159\/000365014","article-title":"Chronic kidney disease results in deficiency of ABCC6, the novel inhibitor of vascular calcification","volume":"40","author":"Lau","year":"2014","journal-title":"Am. J. Nephrol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1038\/ki.2008.26","article-title":"Upregulation of alkaline phosphatase and pyrophosphate hydrolysis: Potential mechanism for uremic vascular calcification","volume":"73","author":"Lomashvili","year":"2008","journal-title":"Kidney Int."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nrneph.2017.60","article-title":"Alkaline phosphatase: A novel treatment target for cardiovascular disease in CKD","volume":"13","author":"Haarhaus","year":"2017","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1016\/j.jhep.2016.07.033","article-title":"NAFLD and liver transplantation: Current burden and expected challenges","volume":"65","author":"Pais","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1007\/s10620-009-0935-9","article-title":"Association between nonalcoholic fatty liver disease and coronary artery calcification","volume":"55","author":"Chen","year":"2010","journal-title":"Dig. Dis. Sci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1148\/radiol.09090769","article-title":"Presence of coronary plaques in patients with nonalcoholic fatty liver disease","volume":"254","author":"Assy","year":"2010","journal-title":"Radiology"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.atherosclerosis.2006.08.021","article-title":"Non-alcoholic fatty liver disease and increased risk of cardiovascular disease","volume":"191","author":"Targher","year":"2007","journal-title":"Atherosclerosis"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"d6891","DOI":"10.1136\/bmj.d6891","article-title":"Non-alcoholic fatty liver disease and mortality among US adults: Prospective cohort study","volume":"343","author":"Lazo","year":"2011","journal-title":"BMJ"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cgh.2011.12.039","article-title":"Independent association between nonalcoholic fatty liver disease and cardiovascular disease in the US population","volume":"10","author":"Stepanova","year":"2012","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1111\/hepr.12665","article-title":"Association of coronary artery calcification with liver fibrosis in Japanese patients with non-alcoholic fatty liver disease","volume":"46","author":"Ishiba","year":"2016","journal-title":"Hepatol. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1097\/MEG.0000000000000286","article-title":"Association between liver fibrosis and coronary heart disease risk in patients with nonalcoholic fatty liver disease","volume":"27","author":"Dogan","year":"2015","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1111\/jgh.12992","article-title":"Hepatic fibrosis assessed using transient elastography independently associated with coronary artery calcification","volume":"30","author":"You","year":"2015","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1002\/hep.26156","article-title":"Association between noninvasive fibrosis markers and mortality among adults with nonalcoholic fatty liver disease in the United States","volume":"57","author":"Kim","year":"2013","journal-title":"Hepatology"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1001\/jama.282.17.1659","article-title":"Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: A pilot study","volume":"282","author":"Chatham","year":"1999","journal-title":"JAMA"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.mce.2013.06.002","article-title":"Hepatic energy metabolism in human diabetes mellitus, obesity and non-alcoholic fatty liver disease","volume":"379","author":"Koliaki","year":"2013","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.jaad.2004.11.066","article-title":"Oral phosphate binders in the treatment of pseudoxanthoma elasticum","volume":"53","author":"Sherer","year":"2005","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.jaad.2010.05.023","article-title":"A randomized controlled trial of oral phosphate binders in the treatment of pseudoxanthoma elasticum","volume":"65","author":"Yoo","year":"2011","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1038\/jid.2008.391","article-title":"Elevated dietary magnesium prevents connective tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6\u2212\/\u2212)","volume":"129","author":"LaRusso","year":"2009","journal-title":"J. Investig. Dermatol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/j.ajpath.2017.02.009","article-title":"Pyrophosphate Supplementation Prevents Chronic and Acute Calcification in ABCC6-Deficient Mice","volume":"187","author":"Pomozi","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/ki.2010.461","article-title":"Treatment with pyrophosphate inhibits uremic vascular calcification","volume":"79","author":"Lomashvili","year":"2011","journal-title":"Kidney Int."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1126\/science.165.3899.1264","article-title":"Diphosphonates inhibit formation of calcium phosphate crystals in vitro and pathological calcification in vivo","volume":"165","author":"Francis","year":"1969","journal-title":"Science"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1080\/15384101.2015.1007809","article-title":"The effects of bisphosphonates on ectopic soft tissue mineralization caused by mutations in the ABCC6 gene","volume":"14","author":"Li","year":"2015","journal-title":"Cell Cycle"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"10006","DOI":"10.1038\/ncomms10006","article-title":"ENPP1-Fc prevents mortality and vascular calcifications in rodent model of generalized arterial calcification of infancy","volume":"6","author":"Albright","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/s007740170021","article-title":"Role of K vitamins in the regulation of tissue calcification","volume":"19","author":"Vermeer","year":"2001","journal-title":"J. Bone Miner. Metab."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1556\/APhysiol.97.2010.3.2","article-title":"Vitamin K and vascular calcifications","volume":"97","author":"Fodor","year":"2010","journal-title":"Acta Physiol. Hung."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/9\/1941\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:44:35Z","timestamp":1760208275000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/9\/1941"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,11]]},"references-count":120,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2017,9]]}},"alternative-id":["ijms18091941"],"URL":"https:\/\/doi.org\/10.3390\/ijms18091941","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,11]]}}}