Dietary Pyrophosphate Modulates Calcification in a Mouse Model of Pseudoxanthoma Elasticum: Implication for Treatment of Patients

Pomozi, Viola; Julian, Charnelle B.; Zoll, Janna; Pham, Kevin; Kuo, Sheree; Tõkési, Natália; Martin, Ludovic; Váradi, András; Saux, Olivier Le

doi:10.1016/j.jid.2018.10.040

Cited by 27 publications

(30 citation statements)

References 55 publications

(96 reference statements)

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“…animal model used to study human diseases, the biology of rodents can be noticeably divergent 53 . Abcc6 −/− mice, despite the known differences with the human phenotype 54 , have been extraordinarily useful for the study of PXE 55,56 and the development of therapeutic approaches 49,[57][58][59][60] . However, mice present singular differences in lipoproteins and atherosclerosis development 61 .…”

Section: Discussionmentioning

confidence: 99%

ABCC6 deficiency promotes dyslipidemia and atherosclerosis

Brampton

Pomozi

Chen

et al. 2021

Sci Rep

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ABCC6 deficiency promotes ectopic calcification; however, circumstantial evidence suggested that ABCC6 may also influence atherosclerosis. The present study addressed the role of ABCC6 in atherosclerosis using Ldlr−/− mice and pseudoxanthoma elasticum (PXE) patients. Mice lacking the Abcc6 and Ldlr genes were fed an atherogenic diet for 16 weeks before intimal calcification, aortic plaque formation and lipoprotein profile were evaluated. Cholesterol efflux and the expression of several inflammation, atherosclerosis and cholesterol homeostasis-related genes were also determined in murine liver and bone marrow-derived macrophages. Furthermore, we examined plasma lipoproteins, vascular calcification, carotid intima-media thickness and atherosclerosis in a cohort of PXE patients with ABCC6 mutations and compared results to dysmetabolic subjects with increased cardiovascular risk. We found that ABCC6 deficiency causes changes in lipoproteins, with decreased HDL cholesterol in both mice and humans, and induces atherosclerosis. However, we found that the absence of ABCC6 does not influence overall vascular mineralization induced with atherosclerosis. Decreased cholesterol efflux from macrophage cells and other molecular changes such as increased pro-inflammation seen in both humans and mice are likely contributors for the phenotype. However, it is likely that other cellular and/or molecular mechanisms are involved. Our study showed a novel physiological role for ABCC6, influencing plasma lipoproteins and atherosclerosis in a haploinsufficient manner, with significant penetrance.

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Section: Discussionmentioning

confidence: 99%

ABCC6 deficiency promotes dyslipidemia and atherosclerosis

Brampton

Pomozi

Chen

et al. 2021

Sci Rep

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“…PPi might therefore be an important biomarker for the severity or predict the progression of PXE. Intraperitoneal PPi supplementation halted calcification in mice and oral PPi increased plasma PPi levels in healthy volunteers [9,31]. In addition, several other therapies that interfere in the PPi homeostasis or ectopic calcification are being developed for PXE and related disorders [32].…”

Section: Discussionmentioning

confidence: 99%

Genotype-phenotype correlation in pseudoxanthoma elasticum

et al. 2021

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Background and aims: Pseudoxanthoma elasticum (PXE) is caused by variants in the ABCC6 gene. It results in calcification in the skin, peripheral arteries and the eyes, but has considerable phenotypic variability. We investigated the association between the ABCC6 genotype and calcification and clinical phenotypes in these different organs. Methods: ABCC6 sequencing was performed in 289 PXE patients. Genotypes were grouped as two truncating, mixed, or two non-truncating variants. Arterial calcification mass was quantified on whole body, low dose CT scans; and peripheral arterial disease was measured with the ankle brachial index after treadmill test. The presence of pseudoxanthoma in the skin was systematically scored. Ophthalmological phenotypes were the length of angioid streaks as a measure of Bruchs membrane calcification, the presence of choroidal neovascularizations, severity of macular atrophy and visual acuity. Regression models were built to test the age and sex adjusted genotype-phenotype association. Results: 158 patients (median age 51 years) had two truncating variants, 96 (median age 54 years) a mixed genotype, 18 (median age 47 years) had two non-truncating variants. The mixed genotype was associated with lower peripheral (β: 0.39, 95%CI:-0.62;-0.17) and total (β: 0.28, 95%CI:-0.47;-0.10) arterial calcification mass scores, and lower prevalence of choroidal neovascularizations (OR: 0.41 95%CI:0.20; 0.83) compared to two truncating variants. No association with pseudoxanthomas was found. Conclusions: PXE patients with a mixed genotype have less severe arterial and ophthalmological phenotypes than patients with two truncating variants in the ABCC6 gene. Research into environmental and genetic modifiers might provide further insights into the unexplained phenotypic variability.

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“…Patients with PXE and GACI as well as Abcc6 −/− and Enpp1 mutant (tiptoe walking: ttw/ttw) mice have a reduced plasma PPi level, explaining, at least in part, their mineralization disorder [22]. Of note, PPi treatment is sufficient to prevent ectopic mineralization in both Abcc6 −/− and Enpp1 ttw/ttw murine models [33][34][35].…”

Section: Pathophysiology Of Pxe Gaci and Acdc: Pyrophosphate Deficiencymentioning

confidence: 99%

“…Abcc6 −/− mice expressing a functional human ABCC6 protein in the liver or supplemented with PPi were protected against kidney calcification [33,34]. It has been shown that oral PPi is partly absorbed in human subjects and increases serum PPi circulating levels.…”

Section: The Abcc6 −/− Murine Model: a Tool To Identify Randall's Plamentioning

confidence: 99%

Pseudoxanthoma Elasticum, Kidney Stones and Pyrophosphate: From a Rare Disease to Urolithiasis and Vascular Calcifications

Letavernier

Bouderlique

Martin

et al. 2019

IJMS

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Pseudoxanthoma elasticum is a rare disease mainly due to ABCC6 gene mutations and characterized by ectopic biomineralization and fragmentation of elastic fibers resulting in skin, cardiovascular and retinal calcifications. It has been recently described that pyrophosphate (a calcification inhibitor) deficiency could be the main cause of ectopic calcifications in this disease and in other genetic disorders associated to mutations of ENPP1 or CD73. Patients affected by Pseudoxanthoma Elasticum seem also prone to develop kidney stones originating from papillary calcifications named Randall’s plaque, and to a lesser extent may be affected by nephrocalcinosis. In this narrative review, we summarize some recent discoveries relative to the pathophysiology of this mendelian disease responsible for both cardiovascular and renal papillary calcifications, and we discuss the potential implications of pyrophosphate deficiency as a promoter of vascular calcifications in kidney stone formers and in patients affected by chronic kidney disease.

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Dietary Pyrophosphate Modulates Calcification in a Mouse Model of Pseudoxanthoma Elasticum: Implication for Treatment of Patients

Cited by 27 publications

References 55 publications

ABCC6 deficiency promotes dyslipidemia and atherosclerosis

ABCC6 deficiency promotes dyslipidemia and atherosclerosis

Genotype-phenotype correlation in pseudoxanthoma elasticum

Pseudoxanthoma Elasticum, Kidney Stones and Pyrophosphate: From a Rare Disease to Urolithiasis and Vascular Calcifications

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