Abstract
Mineralization of elastic fibers in pseudoxanthoma elasticum (PXE) has been associated with low levels of carboxylated matrix gla protein (MGP), most likely as a consequence of reduced vitamin K (vit K) availability. Unexpectedly, vit K supplementation does not exert beneficial effects on soft connective tissue mineralization in the PXE animal model. To understand the effects of vit K supplementation and in the attempt to interfere with pathways leading to the accumulation of calcium and phosphate within PXE-mineralized soft connective tissues, we have conducted in vitro studies on dermal fibroblasts isolated from control subjects and from PXE patients. Cells were cultured in standard conditions and in calcifying medium (CM) in the presence of vit K1 and K2, or levamisole, an alkaline phosphatase (ALP) inhibitor. Control and PXE fibroblasts were characterized by a similar dose-dependent uptake of both vit K1 and vit K2, thus promoting a significant increase of total protein carboxylation in all cell lines. Nevertheless, MGP carboxylation remained much less in PXE fibroblasts. Interestingly, PXE fibroblasts exhibited a significantly higher ALP activity. Consistently, the mineralization process induced in vitro by a long-term culture in CM appeared unaffected by vit K, whereas it was abolished by levamisole.
Highlights
Pseudoxanthoma elasticum (PXE) is a genetic disorder associated with mutations in the ABCC6 gene (Le Saux et al, 2000) and characterized by progressive mineralization of elastic fibers affecting skin, eyes, and the cardiovascular system (Quaglino et al, 2011)
We have investigated in 79 pseudoxanthoma elasticum (PXE) patients the levels of a number of circulating parameters known to be related to the development of ectopic calcifications, and compared the values with reference values in control individuals (Table 1)
Despite the well-known limits provided by the simplifications usually associated with in vitro models, studies on cultured human dermal fibroblasts that, isolated from healthy subjects as well as from PXE patient’s, maintain in vitro several characteristics related to their pathologic www.jidonline.org 951
Summary
Pseudoxanthoma elasticum (PXE) is a genetic disorder associated with mutations in the ABCC6 gene (Le Saux et al, 2000) and characterized by progressive mineralization of elastic fibers affecting skin, eyes, and the cardiovascular system (Quaglino et al, 2011). The low vit K concentrations measured in the circulation of PXE patients (Vanakker et al, 2010) were not associated by an impairment of their blood coagulation system, indicating that the vitamin can reach the liver to be metabolized and used for the activation of coagulation factors, whereas it seems to be extruded or transported less efficiently from hepatocytes to the periphery (Borst et al, 2008; Brampton et al, 2011), affecting connective tissues In this scenario, it has been suggested that vit K supplementation might be capable of restoring MGP carboxylation and to inhibit ectopic calcifications (Borst et al, 2008). Key question is whether PXE fibroblasts are able to utilize vit K and restore an adequate MGP carboxylation
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