scholarly journals The Role of Vitamin K and Its Related Compounds in Mendelian and Acquired Ectopic Mineralization Disorders

2019 ◽  
Vol 20 (9) ◽  
pp. 2142
Author(s):  
Lukas Nollet ◽  
Matthias Van Gils ◽  
Shana Verschuere ◽  
Olivier Vanakker
Keyword(s):  
Vitamin K ◽  
Current Knowledge ◽  
Pseudoxanthoma Elasticum ◽  
Ectopic Calcification ◽  
Multifactorial Diseases ◽  
Multiple Organs ◽  
Keutel Syndrome ◽  
Ectopic Mineralization ◽  
Related Compounds

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.

scholarly journals Disruption of Abcc6 Transporter in Zebrafish Causes Ocular Calcification and Cardiac Fibrosis

2020 ◽  
Vol 22 (1) ◽  
pp. 278
Author(s):  
Jianjian Sun ◽  
Peilu She ◽  
Xu Liu ◽  
Bangjun Gao ◽  
Daqin Jin ◽  
...  
Keyword(s):  
Vitamin K ◽  
Cardiac Fibrosis ◽  
Clinical Manifestations ◽  
Pseudoxanthoma Elasticum ◽  
Matrix Gla Protein ◽  
Ectopic Calcification ◽  
Transcription Activator ◽  
Multisystem Disorder ◽  
Ectopic Mineralization ◽  
Extensive Calcification

Pseudoxanthoma elasticum (PXE), caused by ABCC6/MRP6 mutation, is a heritable multisystem disorder in humans. The progressive clinical manifestations of PXE are accompanied by ectopic mineralization in various connective tissues. However, the pathomechanisms underlying the PXE multisystem disorder remains obscure, and effective treatment is currently available. In this study, we generated zebrafish abcc6a mutants using the transcription activator-like effector nuclease (TALEN) technique. In young adult zebrafish, abcc6a is expressed in the eyes, heart, intestine, and other tissues. abcc6a mutants exhibit extensive calcification in the ocular sclera and Bruch’s membrane, recapitulating part of the PXE manifestations. Mutations in abcc6a upregulate extracellular matrix (ECM) genes, leading to fibrotic heart with reduced cardiomyocyte number. We found that abcc6a mutation reduced levels of both vitamin K and pyrophosphate (PPi) in the serum and diverse tissues. Vitamin K administration increased the gamma-glutamyl carboxylated form of matrix gla protein (cMGP), alleviating ectopic calcification and fibrosis in vertebrae, eyes, and hearts. Our findings contribute to a comprehensive understanding of PXE pathophysiology from zebrafish models.

scholarly journals Dysregulation of gene expression in ABCC6 knockdown HepG2 cells

2014 ◽  
Vol 19 (4) ◽  
Author(s):  
Rocchina Miglionico ◽  
Maria Armentano ◽  
Monica Carmosino ◽  
Antonella Salvia ◽  
Flavia Cuviello ◽  
...  
Keyword(s):  
Hepg2 Cells ◽  
Autosomal Recessive ◽  
Pseudoxanthoma Elasticum ◽  
Arterial Calcification ◽  
Elastic Fibers ◽  
Ectopic Calcification ◽  
Ectopic Mineralization ◽  
Abcc6 Gene ◽  
Basolateral Plasma Membrane

AbstractABCC6 protein is an ATP-dependent transporter that is mainly found in the basolateral plasma membrane of hepatocytes. ABCC6 deficiency is the primary cause of several forms of ectopic mineralization syndrome. Mutations in the human ABCC6 gene cause pseudoxanthoma elasticum (PXE), an autosomal recessive disease characterized by ectopic calcification of the elastic fibers in dermal, ocular and vascular tissues. Mutations in the mouse ABCC6 gene were also associated with dystrophic cardiac calcification. Reduced levels of ABCC6 protein were found in a β-thalassemic mouse model. Moreover, some cases of generalized arterial calcification in infancy are due to ABCC6 mutations. In order to study the role of ABCC6 in the pathogenesis of ectopic mineralization, the expressions of genes involved in this process were evaluated in HepG2 cells upon stable knockdown of ABCC6 by small hairpin RNA (shRNA) technology. ABCC6 knockdown in HepG2 cells causes a significant upregulation of the genes promoting mineralization, such as TNAP, and a parallel downregulation of genes with anti-mineralization activity, such as NT5E, Fetuin A and Osteopontin. Although the absence of ABCC6 has been already associated with ectopic mineralization syndromes, this study is the first to show a direct relationship between reduced ABCC6 levels and the expression of pro-mineralization genes in hepatocytes.

scholarly journals ABCC6, Pyrophosphate and Ectopic Calcification: Therapeutic Solutions

2021 ◽  
Vol 22 (9) ◽  
pp. 4555
Author(s):  
Briana K. Shimada ◽  
Viola Pomozi ◽  
Janna Zoll ◽  
Sheree Kuo ◽  
Ludovic Martin ◽  
...  
Keyword(s):  
Soft Tissues ◽  
Genetic Disorders ◽  
Pseudoxanthoma Elasticum ◽  
Arterial Calcification ◽  
Ectopic Calcification ◽  
Direct Inhibition ◽  
Inorganic Pyrophosphate ◽  
Cardiovascular Tissues ◽  
Ectopic Mineralization

Pathological (ectopic) mineralization of soft tissues occurs during aging, in several common conditions such as diabetes, hypercholesterolemia, and renal failure and in certain genetic disorders. Pseudoxanthoma elasticum (PXE), a multi-organ disease affecting dermal, ocular, and cardiovascular tissues, is a model for ectopic mineralization disorders. ABCC6 dysfunction is the primary cause of PXE, but also some cases of generalized arterial calcification of infancy (GACI). ABCC6 deficiency in mice underlies an inducible dystrophic cardiac calcification phenotype (DCC). These calcification diseases are part of a spectrum of mineralization disorders that also includes Calcification of Joints and Arteries (CALJA). Since the identification of ABCC6 as the “PXE gene” and the development of several animal models (mice, rat, and zebrafish), there has been significant progress in our understanding of the molecular genetics, the clinical phenotypes, and pathogenesis of these diseases, which share similarities with more common conditions with abnormal calcification. ABCC6 facilitates the cellular efflux of ATP, which is rapidly converted into inorganic pyrophosphate (PPi) and adenosine by the ectonucleotidases NPP1 and CD73 (NT5E). PPi is a potent endogenous inhibitor of calcification, whereas adenosine indirectly contributes to calcification inhibition by suppressing the synthesis of tissue non-specific alkaline phosphatase (TNAP). At present, therapies only exist to alleviate symptoms for both PXE and GACI; however, extensive studies have resulted in several novel approaches to treating PXE and GACI. This review seeks to summarize the role of ABCC6 in ectopic calcification in PXE and other calcification disorders, and discuss therapeutic strategies targeting various proteins in the pathway (ABCC6, NPP1, and TNAP) and direct inhibition of calcification via supplementation by various compounds.

scholarly journals The role of menaquinones (vitamin K2) in human health

2013 ◽  
Vol 110 (8) ◽  
pp. 1357-1368 ◽  
Author(s):  
Joline W. J. Beulens ◽  
Sarah L. Booth ◽  
Ellen G. H. M. van den Heuvel ◽  
Elisabeth Stoecklin ◽  
Athanasia Baka ◽  
...  
Keyword(s):  
Dietary Intake ◽  
Human Health ◽  
Vitamin K ◽  
Chemical Structure ◽  
Current Knowledge ◽  
Coagulation Factors ◽  
Biological Functions ◽  
Potential Health ◽  
Dietary Reference Values

Recent reports have attributed the potential health benefits of vitamin K beyond its function to activate hepatic coagulation factors. Moreover, several studies have suggested that menaquinones, also known as vitamin K2, may be more effective in activating extra-hepatic vitamin K-dependent proteins than phylloquinone, also known as vitamin K1. Nevertheless, present dietary reference values (DRV) for vitamin K are exclusively based on phylloquinone, and its function in coagulation. The present review describes the current knowledge on menaquinones based on the following criteria for setting DRV: optimal dietary intake; nutrient amount required to prevent deficiency, maintain optimal body stores and/or prevent chronic disease; factors influencing requirements such as absorption, metabolism, age and sex. Dietary intake of menaquinones accounts for up to 25 % of total vitamin K intake and contributes to the biological functions of vitamin K. However, menaquinones are different from phylloquinone with respect to their chemical structure and pharmacokinetics, which affects bioavailability, metabolism and perhaps impact on health outcomes. There are significant gaps in the current knowledge on menaquinones based on the criteria for setting DRV. Therefore, we conclude that further investigations are needed to establish how differences among the vitamin K forms may influence tissue specificities and their role in human health. However, there is merit for considering both menaquinones and phylloquinone when developing future recommendations for vitamin K intake.

scholarly journals Matrix Gla protein in tumoral pathology

2016 ◽  
Vol 89 (3) ◽  
pp. 319-321 ◽  
Author(s):  
Simona Roxana Gheorghe ◽  
Alexandra Mărioara Crăciun
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle Cells ◽  
Vitamin K ◽  
Matrix Gla Protein ◽  
Ectopic Calcification ◽  
Clinical Implications ◽  
Pathological Angiogenesis ◽  
Different Types ◽  
Dependent Protein

Matrix Gla protein is a vitamin K-dependent protein secreted by chondrocytes and vascular smooth muscle cells. The presence of matrix Gla protein was reported in arterial and venous walls, lungs, kidney, uterus, heart, tooth cementum and eyes. Several studies identified matrix Gla protein in tumoral pathology.Until recently, it was thought to only have an inhibitory role of physiological and ectopic calcification. New studies demonstrated that it also has a role in physiological and pathological angiogenesis, as well as in tumorigenesis.The aim of this review is to report the latest findings related to the expression and clinical implications of matrix Gla protein in different types of cancer with an emphasis on cerebral tumors.

scholarly journals Administration of vitamin K does not counteract the ectopic mineralization of connective tissues inAbcc6-/-mice, a model for pseudoxanthoma elasticum

Cell Cycle ◽  
2011 ◽  
Vol 10 (4) ◽  
pp. 701-707 ◽  
Author(s):  
Qiujie Jiang ◽  
Qiaoli Li ◽  
Alix E. Grand-Pierre ◽  
Leon J. Schurgers ◽  
Jouni Uitto
Keyword(s):  
Vitamin K ◽  
Pseudoxanthoma Elasticum ◽  
Connective Tissues ◽  
Ectopic Mineralization

scholarly journals Molecular Regulation of Cell Fate in Cerebral Ischemia: Role of the Inflammasome and Connected Pathways

2014 ◽  
Vol 34 (12) ◽  
pp. 1857-1867 ◽  
Author(s):  
George Trendelenburg
Keyword(s):  
Cell Fate ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Sterile Inflammation ◽  
Inflammasome Activation ◽  
Stroke Incidence ◽  
Multifactorial Diseases ◽  
Relevant Role ◽  
Metabolic Conditions

Analogous to Toll-like receptors, NOD-like receptors represent a class of pattern recognition receptors, which are cytosolic and constitute part of different inflammasomes. These large protein complexes are activated not only by different pathogens, but also by sterile inflammation or by specific metabolic conditions. Mutations can cause hereditary autoinflammatory systemic diseases, and inflammasome activation has been linked to many multifactorial diseases, such as diabetes or cardiovascular diseases. Increasing data also support an important role in different central nervous diseases such as stroke. Thus, the current knowledge of the functional role of this intracellular ‘master switch’ of inflammation is discussed with a focus on its role in ischemic stroke, neurodegeneration, and also with regard to the recent data which argues for a relevant role in other organs or biologic systems which influence stroke incidence or prognosis.

Molecular Nature and Physiological Role of the Mitochondrial Calcium Uniporter Channel

2020 ◽  
Author(s):  
B. Rita Alevriadou ◽  
Akshar Patel ◽  
Megan Noble ◽  
Sagnika Ghosh ◽  
Vishal M. Gohil ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cell Function ◽  
Current Knowledge ◽  
Physiological Role ◽  
Mitochondrial Pathway ◽  
Dominant Negative ◽  
Multiple Organs ◽  
Calcium Uniporter ◽  
Intracellular Ca

Calcium (Ca2+) signaling is critical for cell function and cell survival. Mitochondria play a major role in regulating the intracellular Ca2+ concentration ([Ca2+]i). Mitochondrial Ca2+ uptake is an important determinant of cell fate and governs respiration, mitophagy/autophagy, and mitochondrial pathway of apoptosis. Mitochondrial Ca2+ uptake occurs via the mitochondrial Ca2+ uniporter (MCU) complex. This review summarizes the current knowledge on the function of MCU complex, regulation of MCU channel, and the role of MCU in Ca2+ homeostasis and human disease pathogenesis. The channel core consists of four MCU subunits and EMRE. Regulatory proteins that interact with them include mitochondrial Ca2+ uptake 1/2 (MICU1/2), MCU dominant negative beta subunit (MCUb), MCU regu­lator 1 (MCUR1) and solute carrier 25A23 (SLC25A23). In addition to these proteins, cardiolipin, a mito­chondrial mem­brane-specific phospholipid, has been shown to interact with the channel core. The dynamic interplay between the core and regu­latory proteins modulates MCU channel activity after sensing local changes in [Ca2+]i, reactive oxygen species, and other environmental factors. Here, we highlight the structural details of the human MCU heteromeric assemblies and their known roles in regulating mitochondrial Ca2+ homeostasis. MCU dysfunction has been shown to alter mitochondrial Ca2+ dynamics, in turn eliciting cell apoptosis. Changes in mitochondrial Ca2+ uptake have been implicated in pathological con­ditions af­fecting multiple organs, including the heart, skeletal muscle, and brain. However, our structural and functional knowledge of this vital protein complex remains incomplete and under­standing the precise role for MCU-mediated mito­chondrial Ca2+ signaling in disease requires further research ef­forts.

Fibroblast protein profile analysis highlights the role of oxidative stress and vitamin K recycling in the pathogenesis of pseudoxanthoma elasticum

2009 ◽  
Vol 3 (9) ◽  
pp. 1084-1098 ◽  
Author(s):  
Federica Boraldi ◽  
Giulia Annovi ◽  
Deanna Guerra ◽  
Chiara Paolinelli DeVincenzi ◽  
Maria Inmaculada Garcia-Fernandez ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Vitamin K ◽  
Profile Analysis ◽  
Protein Profile ◽  
Pseudoxanthoma Elasticum

scholarly journals The ABCC6 Transporter as a Paradigm for Networking from an Orphan Disease to Complex Disorders

2015 ◽  
Vol 2015 ◽  
pp. 1-18 ◽  
Author(s):  
Eva Y. G. De Vilder ◽  
Mohammad Jakir Hosen ◽  
Olivier M. Vanakker
Keyword(s):  
Pseudoxanthoma Elasticum ◽  
Integrated System ◽  
Orphan Disease ◽  
Complex Disorders ◽  
Monogenic Disorders ◽  
Ectopic Mineralization ◽  
Monogenic Diseases ◽  
Network Approaches ◽  
Generation Sequencing

The knowledge on the genetic etiology of complex disorders largely results from the study of rare monogenic disorders. Often these common and rare diseases show phenotypic overlap, though monogenic diseases generally have a more extreme symptomatology.ABCC6, the gene responsible for pseudoxanthoma elasticum, an autosomal recessive ectopic mineralization disorder, can be considered a paradigm gene with relevance that reaches far beyond this enigmatic orphan disease. Indeed, common traits such as chronic kidney disease or cardiovascular disorders have been linked to theABCC6gene. While during the last decade the awareness of the wide ramifications ofABCC6has increased significantly, the gene itself and the transmembrane transporter it encodes have not unveiled all of the mysteries that surround them. To gain more insights, multiple approaches are being used including next-generation sequencing, computational methods, and various “omics” technologies. Much effort is made to place the vast amount of data that is gathered in an integrated system-biological network; the involvement ofABCC6in common disorders provides a good view on the wide implications and potential of such a network. In this review, we summarize the network approaches used to studyABCC6and the role of this gene in several complex diseases.

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