Abstract
Ectopic mineralization disorders comprise a broad spectrum of inherited or acquired diseases characterized by aberrant deposition of calcium crystals in multiple organs, such as the skin, eyes, kidneys, and blood vessels. Although the precise mechanisms leading to ectopic calcification are still incompletely known to date, various molecular targets leading to a disturbed balance between pro- and anti-mineralizing pathways have been identified in recent years. Vitamin K and its related compounds, mainly those post-translationally activated by vitamin K-dependent carboxylation, may play an important role in the pathogenesis of ectopic mineralization as has been demonstrated in studies on rare Mendelian diseases, but also on highly prevalent disorders, like vascular calcification. This narrative review compiles and summarizes the current knowledge regarding the role of vitamin K, its metabolism, and associated compounds in the pathophysiology of both monogenic ectopic mineralization disorders, like pseudoxanthoma elasticum or Keutel syndrome, as well as acquired multifactorial diseases, like chronic kidney disease. Clinical and molecular aspects of the various disorders are discussed according to the state-of-the-art, followed by a comprehensive literature review regarding the role of vitamin K in molecular pathophysiology and as a therapeutic target in both human and animal models of ectopic mineralization disorders.
Highlights
Ectopic mineralization disorders are characterized by abnormal mineral deposition in soft tissues, such as the skin, kidneys, blood vessels, and cardiac valves [1]
Similar serum levels of PIVKA-II were measured in pseudoxanthoma elasticum (PXE) patients compared to controls, confirming that the vitamin K-dependent coagulation factors are not affected in PXE, contrary to PXE-like syndrome [55]
A recently published large scale systematic review and meta-analysis by Lees et al [88] found that vitamin K supplementation was associated with a significant reduction in calcification and dp-ucMGP concentrations compared to controls, while longitudinal studies could even demonstrate an association between vitamin K-dependent proteins (VKDPs) serum levels and cardiovascular disease and mortality
Summary
Ectopic mineralization disorders are characterized by abnormal mineral deposition in soft tissues, such as the skin, kidneys, blood vessels, and cardiac valves [1]. Ectopic mineralization occurs in multiple rare Mendelian disorders as well as in some of the most prevalent diseases in humans, such as diabetes mellitus, chronic kidney disease (CKD), and ischemic stroke [4]. Monogenic orphan diseases, such as pseudoxanthoma elasticum (PXE)—in which abnormal connective tissue calcification is a hallmark finding—are considered excellent research models to investigate the molecular and cellular signaling pathways involved in ectopic mineralization [4]. High quality fundamental research into these intricate genetic disorders is needed to gain further knowledge about the molecular etiopathogenesis of these diseases, identify novel therapeutic targets, and develop future drugs, which may prove to be beneficial to those patients carrying the burden of a rare heritable ectopic mineralization disorder, and to the millions of people worldwide suffering from acquired, mostly cardiovascular, calcification disorders, causing significant morbidity, mortality, and associated healthcare costs both on an individual and population level
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