An inducible model for medial calcification based on matrix Gla protein deficiency

Abstract

Calcific deposits in the arterial media have been associated with a number of metabolic and genetic disorders including diabetes, chronic kidney disease and generalized arterial calcification of infancy. The loss of matrix Gla protein (MGP) leads to medial elastic lamina calcification (elastocalcinosis) in both humans and animal models. While MGP-deficient (Mgp^-/-) mice have been used as a reliable model to study medial elastocalcinosis, these mice are difficult to maintain because of their fragility. Also, these mice are unsuitable for long-term calcification studies in relation to age and sex as most often they die prematurely. In order to circumvent these problems we generated Mgp^-/-;ApoE-FGF23 mice, which in addition to the ablation of Mgp alleles, carries a transgene expressing the phosphaturic hormone FGF23. Increased FGF23 levels in the circulation and ensuing hypophosphatemia in these mice lead to a complete prevention of medial calcification until late adulthood. Interestingly, upon feeding a high phosphorus diet for 10 days, we were able to induce medial calcification in 3-week-old Mgp^-/-;ApoE-FGF23 mice. Our mineral analyses showed that the Ca/P% in the calcific deposits in these mice were comparable to that of 5-week-old Mgp^-/- mice although the level of crystallinity differed. The aorta explants from Mgp^-/-;ApoE-FGF23 mice resulted in elastocalcinosis in the presence of 2 mM phosphate in the culture medium which was completely prevented by pyrophosphate analogue alendronate. Mgp^-/-;ApoE-FGF23 mice will be suitable for future in vivo or ex vivo studies examining the effects of age, sex and mineralization inhibitors on medial elastocalcinosis.