Magnesium Reduces Carotid Intima‐Media Thickness in a Mouse Model of Pseudoxanthoma Elasticum: A Novel Treatment Biomarker

Abstract

Pseudoxanthoma elasticum (PXE), which demonstrates progressive build-up of calcium phosphate and proteoglycan deposits in skin, eye, and arteries, has been associated with myocardial infarctions, stroke, and blindness. In a mouse model of PXE, a magnesium-enriched diet prevents mineralization of the vibrissae capsule, an early biomarker for PXE. However, biomarkers for therapeutic responses in PXE have not been identified in humans. Since PXE patients have an increased carotid intima-media thickness (CIMT), a risk factor for cardiovascular disease and stroke, we analyzed the feasibility of CIMT as a treatment endpoint before and after magnesium supplementation in a mouse model of PXE (Abcc6−/−). CIMT was measured in one year-old Abcc6−/− and Abcc6+/+ mice fed either standard rodent diet with or without magnesium oxide supplementation for two months. Baseline CIMT in Abcc6−/− vs. Abcc6+/+ mice was increased (p-value = 0.009), while CIMT in magnesium-treated vs. untreated Abcc6−/− mice was reduced (p-value = 0.024). CIMT is a novel treatment endpoint in this mouse model and may serve as a predictive biomarker of therapeutic response in PXE patients. In that context, magnesium oxide significantly reduced CIMT in PXE mice, and may be useful for disease prevention in PXE patients.

Magnesium: Novel Applications in Cardiovascular Disease – A Review of the Literature

“…The influence of magnesium on mineralization was recently tested in a mouse model with an autosomal recessive ectopic mineralizing disorder, pseudoxanthoma elasticum (PXE), a condition marked with vascular deposits of calcium phosphate [28,29]. This disease manifests clinically with HTN, intermittent claudication, myocardial infarction, stroke, loss of visual acuity, blindness and elevated CIMT (a biomarker for atherosclerosis) [30].…”

“…In humans, there is no effective treatment and no validated biomarker for PXE. When a knock-out mouse model for this disease (Abcc6 –/– ) , which also shows elevated CIMT, was administered with a 5-fold excess of magnesium oxide in its standard rodent chow for 2 months, the CIMT was significantly reduced by 26% (p = 0.02) [29]. Magnesium, calcium, vitamin D and parathyroid hormone levels in the blood were normal.…”

Dysmagnesemia in Hospitalized Patients: Prevalence and Prognostic Importance

“…Despite lacking outcome information, it has been suggested that increasing Mg intake and mild serum Mg elevation might be beneficial, 3,10-13 based in part on studies reporting a reduced carotid intima-media thickness and soft tissue calcification with Mg supplementation. [14][15][16][17][18][19][20] The aim of the current study was to comprehensively examine the prevalence and clinical outcomes of dysmagnesemia in all hospitalized patients in the current era.…”

Is classical pseudoxanthoma elasticum a consequence of hepatic ‘intoxication’ due to ABCC6 substrate accumulation in the liver?

“…Without knowing the substrate identity, new medicine may also be developed within a few years by identifying agents that inflict with the mineralization process in the blood. In this line, several studies have recently presented intriguing data showing that a magnesium-rich diet reduces the peripheral mineralization deposits and PXE pathology in the PXE mouse model [78][79][80][81][82].…”