pyrophosphate and Vascular-Diseases

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.

Topics: 5'-Nucleotidase; Animals; ATP-Binding Cassette Transporters; Calcification, Physiologic; Calcinosis; Diphosphates; GPI-Linked Proteins; Humans; Joint Diseases; Mice; Multidrug Resistance-Associated Proteins; Phosphoric Diester Hydrolases; Pseudoxanthoma Elasticum; Pyrophosphatases; Rats; Vascular Calcification; Vascular Diseases

Mineralization imparts important biomechanical and other functional properties to bones and teeth. Ectopic pathologic mineralization, however, occurring in soft tissues such as blood vessels, kidneys, articular cartilage and also in body fluids, including urine and synovial fluid, is generally debilitating, often painful and typically is destructive of compromised tissue. Here we review new findings on direct molecular determinants of mineralization operating locally at the level of the extracellular matrix, with a focus on bone and blood vessels.. Accumulating evidence indicates important key roles for secreted noncollagenous proteins in regulating mineralization, wherein they also contribute structurally to the scaffolding properties of the extracellular matrix. Mineral-binding proteins contain conserved acidic peptide domains (often highly phosphorylated), which bind strongly to calcium within the apatitic mineral phase of bone and calcified blood vessels to regulate crystal growth. Other recent work has underscored the importance of the small-molecule mineralization inhibitor pyrophosphate in inhibiting tissue mineralization - an inhibition released through its enzymatic cleavage by tissue-nonspecific alkaline phosphatase. Recent findings on mechanisms involved in matrix vesicle-mediated mineralization are also discussed.. Mechanistic details are emerging that describe a scenario wherein the combined actions of mineral-binding noncollagenous matrix peptides/proteins within a scaffolding of collagen (and also elastin in blood vessels), phosphatases and matrix vesicles all contribute importantly to promoting or limiting mineralization.

Topics: Animals; Blood Vessels; Calcification, Physiologic; Calcinosis; Diphosphates; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Phosphates; Vascular Diseases

Patients with chronic kidney disease have increased cardiovascular mortality from a combination of increased atherosclerotic disease, left ventricular hypertrophy and increased prevalence of vascular calcification (VC). Previously VC was thought to be a passive process which involved the deposition of calcium and phosphate into the vessel wall. However, recent studies have shown that VC is a highly regulated, cell-mediated process similar to bone formation, in that it is associated with expression of bone-related proteins, such as type I collagen and alkaline phosphatase. Animal and in vitro models of VC have shown that a multitude of factors including phosphate, matrix gla protein (MGP) and fetuin are involved in regulating VC. Certain factors induce calcification whereas others inhibit the process. Despite these insights, it is still not fully known how VC is regulated and a treatment for VC remains elusive. Ongoing research will hopefully elucidate these mechanisms and thereby produce targets for future therapeutic intervention. This review will highlight some of the scientific models of VC and how they have increased the understanding of this complex process.

Topics: Alkaline Phosphatase; alpha-Fetoproteins; Animals; Apoptosis; Atherosclerosis; Calcinosis; Calcium-Binding Proteins; Cardiovascular Diseases; Collagen Type I; Diphosphates; Disease Models, Animal; Extracellular Matrix Proteins; Humans; Hypertrophy, Left Ventricular; Inflammation; Kidney Failure, Chronic; Matrix Gla Protein; Mice; Osteopontin; Phosphorus; Prevalence; Risk Factors; Vascular Diseases; Vitamin D; Vitamins

In the last decade, the nephrology community has focused its attention on the main cause of morbidity and mortality in chronic renal failure patients: cardiovascular disease. In addition, recent studies pointed out that vascular calcification (VC) is a major cause of cardiovascular disease in the dialysis population. Interestingly, the pathogenesis of VC and soft tissue calcification in chronic kidney disease (CKD) has been extensively investigated. Nowadays we know that VC is associated not only with passive calcium phosphate deposition, but also with an active, cell-mediated process. To better understand the pathogenesis of VC in CKD, numerous regulatory proteins have been studied, because of their ability to inhibit mineral deposition in the vessels. We here examine the state of the art of those substances recognized as regulatory key factors in preventing VC in uremic conditions, such as fetuin A (alpha2-Heremans-Schmid glycoprotein), matrix gamma-carboxyglutamic acid protein, pyrophosphate, osteoprotegerin and bone morphogenetic protein. We conclude that at present it is too early to introduce these novel markers into clinical practice.

Topics: 1-Carboxyglutamic Acid; alpha-Fetoproteins; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Calcinosis; Diphosphates; Humans; Kidney Failure, Chronic; Models, Biological; Osteoprotegerin; Risk Factors; Transforming Growth Factor beta; Uremia; Vascular Diseases

The cardiovascular risk of patients undergoing dialysis is 20-30 times higher than that of individuals of the same age, without abnormal renal function, from the general population. Observational studies of patients with normal and abnormal renal function have shown that there is an association between bone disease, vascular calcification and cardiovascular outcome and that worsening of these conditions happens in parallel. Basic science studies are elucidating several mechanisms that could explain the interaction between bone disease, vascular calcification and cardiovascular outcome. For example, the expression of osteoprotegerin-a protein that regulates bone resorption by binding receptor activator of nuclear factor kappaB (RANK) ligand (RANKL), thus preventing interaction with the receptor RANK and the stimulation of osteoclast maturation-is regulated by several cytokines. Additionally, osteoprotegerin seems involved in the genesis of atherosclerosis. Imbalances of bone mineral metabolism, bone matrix secretion and vascular smooth-muscle-cell apoptosis seem involved in the ossification of the arterial wall in chronic kidney disease, and could explain some of the complex interactions between bone and vascular disease in renal failure. In this article we present a brief review of some of the basic mechanisms involved in vascular calcification and the clinical evidence of an association of vascular and bone disease.

Topics: Aged; alpha-2-HS-Glycoprotein; Blood Proteins; Bone and Bones; Bone Diseases; Calcinosis; Calcium; Calcium-Binding Proteins; Diphosphates; Extracellular Matrix Proteins; Female; Humans; Male; Matrix Gla Protein; Middle Aged; Osteoporosis; Phosphates; Practice Guidelines as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors; Vascular Diseases

Idiopathic infantile arterial calcification (IIAC) is a rare, but important, cause of rapidly progressive ischemic heart disease in children. In this paper, we report two recent cases of IIAC seen at tertiary referral hospitals. Both cases presented in infancy with signs of heart failure and, ultimately, died with the diagnosis of IIAC confirmed at postmortem examination. A thorough review of the literature reveals approximately 160 reported cases of IIAC. The clinical outcomes, radiographic findings and pathologic details are summarized. Proposed etiologic mechanisms are reviewed, including promising research into the role of inorganic pyrophosphate as a regulatory factor in the development of IIAC. Because of the typically fatal outcome of IIAC and the lack of proven therapies, the potential role for cardiac transplantation is discussed.

Topics: Arteries; Basement Membrane; Calcinosis; Cardiomyopathies; Coronary Vessels; Diphosphates; Disease Progression; Fatal Outcome; Female; Heart Transplantation; Humans; Infant; Myocardial Ischemia; Myocardium; Tunica Intima; Vascular Diseases

Cardiovascular disease is the leading cause of death in patients with chronic kidney disease. A growing body of data points to nontraditional risk factors, including disturbances in mineral metabolism, as important determinants of the extremely high cardiovascular morbidity and mortality rates in these patients. Disturbances in mineral metabolism, especially elevated calcium and phosphate levels, have been linked to vascular and valvular calcification, both of which are associated with poor prognosis in chronic kidney disease patients. This review highlights important recent findings regarding the etiology of vascular calcification, with special emphasis on pathways that may be particularly relevant in chronic kidney disease patients.. New studies indicate that not only vascular intimal calcification (associated with atherosclerosis) but also vascular medial calcification are correlated with decreased survival in chronic kidney disease patients. With the relatively recent recognition of vascular calcification as an actively regulated process, a growing list of inducers (calcium, phosphate, inflammatory cytokines) and inhibitors (matrix Gla protein, fetuin, pyrophosphate, osteopontin) have been discovered. Interesting recent evidence suggests that they may contribute to the prevalence of this pathology in chronic kidney disease patients.. Vascular calcification is associated with decreased survival in chronic kidney disease patients. Understanding the causes and regulatory factors controlling vascular calcification will help refine therapeutic modalities currently in use, as well as develop novel therapeutics to abate and potentially reverse this deleterious process.

Topics: alpha-2-HS-Glycoprotein; Animals; Arteriosclerosis; Blood Proteins; Calcinosis; Calcium Phosphates; Diphosphates; Humans; Osteopontin; Sialoglycoproteins; Uremia; Vascular Diseases

Pyrophosphate, which may be deficient in advanced renal failure, is a potent inhibitor of vascular calcification. To explore its use as a potential therapeutic, we injected exogenous pyrophosphate subcutaneously or intraperitoneally in normal rats and found that their plasma pyrophosphate concentrations peaked within 15 min. There was a single exponential decay with a half-life of 33 min. The kinetics were indistinguishable between the two routes of administration or in anephric rats. The effect of daily intraperitoneal pyrophosphate injections on uremic vascular calcification was then tested in rats fed a high-phosphate diet containing adenine for 28 days to induce uremia. Although the incidence of aortic calcification varied and was not altered by pyrophosphate, the calcium content of calcified aortas was significantly reduced by 70%. Studies were repeated in uremic rats given calcitriol to produce more consistent aortic calcification and treated with sodium pyrophosphate delivered intraperitoneally in a larger volume of glucose-containing solution to prolong plasma pyrophosphate levels. This maneuver significantly reduced both the incidence and amount of calcification. Quantitative histomorphometry of bone samples after double-labeling with calcein indicated that there was no effect of pyrophosphate on the rates of bone formation or mineralization. Thus, exogenous pyrophosphate can inhibit uremic vascular calcification without producing adverse effects on bone.

Topics: Animals; Calcification, Physiologic; Calcinosis; Diphosphates; Male; Osteogenesis; Rats; Rats, Sprague-Dawley; Uremia; Vascular Diseases

Pyrophosphate, a ubiquitous small-molecule inhibitor of mineralization abundantly present in the extracellular environment, binds to calcium and mineral surfaces to inhibit crystal growth. O'Neill and colleagues show in uremic rats that systemic administration of pyrophosphate prevents or reduces uremia-related vascular calcification, without overt negative consequences for bone and without calcium pyrophosphate deposition disease. These findings prompt further research into the potential of pyrophosphate as treatment for vascular calcification in chronic kidney disease patients.

Topics: Alkaline Phosphatase; Animals; Calcinosis; Diphosphates; Humans; Osteopontin; Rats; Uremia; Vascular Diseases

Pyrophosphate is a potent inhibitor of medial vascular calcification where its level is controlled by hydrolysis via a tissue-nonspecific alkaline phosphatase (TNAP). We sought to determine if increased TNAP activity could explain the pyrophosphate deficiency and vascular calcification seen in renal failure. TNAP activity increased twofold in intact aortas and in aortic homogenates from rats made uremic by feeding adenine or by 5/6 nephrectomy. Immunoblotting showed an increase in protein abundance but there was no increase in TNAP mRNA assessed by quantitative polymerase chain reaction. Hydrolysis of pyrophosphate by rat aortic rings was inhibited about half by the nonspecific alkaline phosphatase inhibitor levamisole and was reduced about half in aortas from mice lacking TNAP. Hydrolysis was increased in aortic rings from uremic rats and all of this increase was inhibited by levamisole. An increase in TNAP activity and pyrophosphate hydrolysis also occurred when aortic rings from normal rats were incubated with uremic rat plasma. These results suggest that a circulating factor causes pyrophosphate deficiency by regulating TNAP activity and that vascular calcification in renal failure may result from the action of this factor. If proven by future studies, this mechanism will identify alkaline phosphatase as a potential therapeutic target.

Topics: Alkaline Phosphatase; Animals; Calcinosis; Diphosphates; Hydrolysis; Rats; Up-Regulation; Uremia; Vascular Diseases

Topics: Arteries; Calcinosis; Diphosphates; Humans; Infant; Vascular Diseases

Recently the authors introduced a new technique of intravenous (IV) radionuclide total-body arteriography. The major arterial system, multiple organs of the whole body, and cardiac function can be evaluated with one small IV injection in the arm. After analyzing more than 1000 cases, they have found that many pathologies can be detected and/or confirmed in this procedure. This new technique may be used as a general whole-body screening test for those patients at high risk for disease.

Topics: Aged; Aged, 80 and over; Aorta, Abdominal; Diphosphates; Humans; Iliac Artery; Injections, Intravenous; Male; Meningeal Neoplasms; Meningioma; Radioisotopes; Radionuclide Angiography; Technetium; Technetium Tc 99m Pyrophosphate; Vascular Diseases

Topics: Diagnosis, Differential; Diphosphates; Hand; Humans; Nervous System Diseases; Occupational Diseases; Radionuclide Angiography; Technetium; Technetium Tc 99m Pyrophosphate; Vascular Diseases; Vibration

Topics: Animals; Aorta; Arteries; Calcinosis; Coronary Vessels; Dihydrotachysterol; Diphosphates; Female; Glycerophosphates; Histological Techniques; Injections, Intraperitoneal; Injections, Subcutaneous; Kidney; Myocardium; Nephrocalcinosis; Phosphates; Phosphoric Monoester Hydrolases; Pulmonary Artery; Rats; Vascular Diseases