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Journal ArticleDOI

The role of phosphatases in the initiation of skeletal mineralization.

01 Oct 2013-Calcified Tissue International (Springer US)-Vol. 93, Iss: 4, pp 299-306
TL;DR: It is shown that PHOSPHO1, a soluble phosphatase with specificity for two molecules present in MVs, phosphoethanolamine and phosphocholine, is responsible for initiating HA crystal formation inside MVs and that PHosPHO 1 and TNAP have nonredundant functional roles during endochondral ossification.
Abstract: Endochondral ossification is a carefully orchestrated process mediated by promoters and inhibitors of mineralization. Phosphatases are implicated, but their identities and functions remain unclear. Mutations in the tissue-nonspecific alkaline phosphatase (TNAP) gene cause hypophosphatasia, a heritable form of rickets and osteomalacia, caused by an arrest in the propagation of hydroxyapatite (HA) crystals onto the collagenous extracellular matrix due to accumulation of extracellular inorganic pyrophosphate (PPi), a physiological TNAP substrate and a potent calcification inhibitor. However, TNAP knockout (Alpl(-/-)) mice are born with a mineralized skeleton and have HA crystals in their chondrocyte- and osteoblast-derived matrix vesicles (MVs). We have shown that PHOSPHO1, a soluble phosphatase with specificity for two molecules present in MVs, phosphoethanolamine and phosphocholine, is responsible for initiating HA crystal formation inside MVs and that PHOSPHO1 and TNAP have nonredundant functional roles during endochondral ossification. Double ablation of PHOSPHO1 and TNAP function leads to the complete absence of skeletal mineralization and perinatal lethality, despite normal systemic phosphate and calcium levels. This strongly suggests that the Pi needed for initiation of MV-mediated mineralization is produced locally in the perivesicular space. As both TNAP and nucleoside pyrophosphohydrolase-1 (NPP1) behave as potent ATPases and pyrophosphatases in the MV compartment, our current model of the mechanisms of skeletal mineralization implicate intravesicular PHOSPHO1 function and Pi influx into MVs in the initiation of mineralization and the functions of TNAP and NPP1 in the extravesicular progression of mineralization.

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Citations
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Journal ArticleDOI
TL;DR: Enzyme replacement using mineral-targeted TNAP from birth prevented severe HPP in TNAP-knockout mice and was then shown to rescue and substantially treat infants and young children with life-threatening HPP.
Abstract: Hypophosphatasia (HPP) results from ALPL mutations leading to deficient activity of the tissue-non-specific alkaline phosphatase isozyme (TNAP) and thereby extracellular accumulation of inorganic pyrophosphate (PPi), a natural substrate of TNAP and potent inhibitor of mineralization. Thus, HPP features rickets or osteomalacia and hypomineralization of teeth. Enzyme replacement using mineral-targeted TNAP from birth prevented severe HPP in TNAP-knockout mice and was then shown to rescue and substantially treat infants and young children with life-threatening HPP. Clinical trials are revealing aspects of HPP pathophysiology not yet fully understood, such as craniosynostosis and muscle weakness when HPP is severe. New treatment approaches are under development to improve patient care.

264 citations


Cites background from "The role of phosphatases in the ini..."

  • ...Thus, current understanding of TNAP function supports Robison’s hypothesis concerning skeletal mineralization [35, 70, 71]....

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Journal ArticleDOI
05 Sep 2020-Gene
TL;DR: The increased level of ALP expression and development in this environment would undoubtedly provide new and essential information about the fundamental molecular mechanisms of bone formation, offer therapeutic possibilities for the management of bone-related diseases.

263 citations

Journal ArticleDOI
TL;DR: Novel mechanisms that link ALP to vascular calcification, inflammation, and endothelial dysfunction in kidney and cardiovascular diseases are reviewed and new drugs that target ALP are discussed, which have the potential to improve cardiovascular outcomes without inhibiting skeletal mineralization.
Abstract: Cardiovascular disease is the main cause of early death in the settings of chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and ageing Cardiovascular events can be caused by an imbalance between promoters and inhibitors of mineralization, which leads to vascular calcification This process is akin to skeletal mineralization, which is carefully regulated and in which isozymes of alkaline phosphatase (ALP) have a crucial role Four genes encode ALP isozymes in humans Intestinal, placental and germ cell ALPs are tissue-specific, whereas the tissue-nonspecific isozyme of ALP (TNALP) is present in several tissues, including bone, liver and kidney TNALP has a pivotal role in bone calcification Experimental overexpression of TNALP in the vasculature is sufficient to induce vascular calcification, cardiac hypertrophy and premature death, mimicking the cardiovascular phenotype often found in CKD and T2DM Intestinal ALP contributes to the gut mucosal defence and intestinal and liver ALPs might contribute to the acute inflammatory response to endogenous or pathogenic stimuli Here we review novel mechanisms that link ALP to vascular calcification, inflammation, and endothelial dysfunction in kidney and cardiovascular diseases We also discuss new drugs that target ALP, which have the potential to improve cardiovascular outcomes without inhibiting skeletal mineralization

192 citations

Book ChapterDOI
TL;DR: The brush border enzyme intestinal alkaline phosphatase (IAP) plays an important role in fatty acid (FA) absorption, in protecting gut barrier function, and in determining the composition of the gut microbiota via its ability to dephosphorylate lipopolysaccharide (LPS).
Abstract: Human and mouse alkaline phosphatases (AP) are encoded by a multigene family expressed ubiquitously in multiple tissues. Gene knockout (KO) findings have helped define some of the precise exocytic functions of individual isozymes in bone, teeth, the central nervous system, and in the gut. For instance, deficiency in tissue-nonspecific alkaline phosphatase (TNAP) in mice (Alpl (-/-) mice) and humans leads to hypophosphatasia (HPP), an inborn error of metabolism characterized by epileptic seizures in the most severe cases, caused by abnormal metabolism of pyridoxal-5'-phosphate (the predominant form of vitamin B6) and by hypomineralization of the skeleton and teeth featuring rickets and early loss of teeth in children or osteomalacia and dental problems in adults caused by accumulation of inorganic pyrophosphate (PPi). Enzyme replacement therapy with mineral-targeting TNAP prevented all the manifestations of HPP in mice, and clinical trials with this protein therapeutic are showing promising results in rescuing life-threatening HPP in infants. Conversely, TNAP induction in the vasculature during generalized arterial calcification of infancy (GACI), type II diabetes, obesity, and aging can cause medial vascular calcification. TNAP inhibitors, discussed extensively in this book, are in development to prevent pathological arterial calcification. The brush border enzyme intestinal alkaline phosphatase (IAP) plays an important role in fatty acid (FA) absorption, in protecting gut barrier function, and in determining the composition of the gut microbiota via its ability to dephosphorylate lipopolysaccharide (LPS). Knockout mice (Akp3 (-/-)) deficient in duodenal-specific IAP (dIAP) become obese, and develop hyperlipidemia and hepatic steatosis when fed a high-fat diet (HFD). These changes are accompanied by upregulation in the jejunal-ileal expression of the Akp6 IAP isozyme (global IAP, or gIAP) and concomitant upregulation of FAT/CD36, a phosphorylated fatty acid translocase thought to play a role in facilitating the transport of long-chain fatty acids into cells. gIAP, but not dIAP, is able to modulate the phosphorylation status of FAT/CD36. dIAP, even though it is expressed in the duodenum, is shed into the gut lumen and is active in LPS dephosphorylation throughout the gut lumen and in the feces. Akp3 (-/-) mice display gut dysbiosis and are more prone to dextran sodium sulfate-induced colitis than wild-type mice. Of relevance, oral administration of recombinant calf IAP prevents the dysbiosis and protects the gut from chronic colitis. Analogous to the role of IAP in the gut, TNAP expression in the liver may have a proactive role from bacterial endotoxin insult. Finally, more recent studies suggest that neuronal death in Alzheimer's disease may also be associated with TNAP function on certain brain-specific phosphoproteins. This review recounts the established roles of TNAP and IAP and briefly discusses new areas of investigation related to multisystemic functions of these isozymes.

155 citations

Journal ArticleDOI
TL;DR: The level of DNA methylation at the ABCG1 locus cg06500161 in blood DNA correlated positively with BMI, HbA1c, fasting insulin, and triglyceride levels, and was increased in adipose tissue and blood from the diabetic twin among monozygotic twin pairs discordant for T2D.
Abstract: Identification of subjects with a high risk of developing type 2 diabetes (T2D) is fundamental for prevention of the disease. Consequently, it is essential to search for new biomarkers that can improve the prediction of T2D. The aim of this study was to examine whether 5 DNA methylation loci in blood DNA (ABCG1, PHOSPHO1, SOCS3, SREBF1, and TXNIP), recently reported to be associated with T2D, might predict future T2D in subjects from the Botnia prospective study. We also tested if these CpG sites exhibit altered DNA methylation in human pancreatic islets, liver, adipose tissue, and skeletal muscle from diabetic vs. non-diabetic subjects. DNA methylation at the ABCG1 locus cg06500161 in blood DNA was associated with an increased risk for future T2D (OR = 1.09, 95% CI = 1.02–1.16, P-value = 0.007, Q-value = 0.018), while DNA methylation at the PHOSPHO1 locus cg02650017 in blood DNA was associated with a decreased risk for future T2D (OR = 0.85, 95% CI = 0.75–0.95, P-value = 0.006, Q-value = 0.018) after adjustment for age, gender, fasting glucose, and family relation. Furthermore, the level of DNA methylation at the ABCG1 locus cg06500161 in blood DNA correlated positively with BMI, HbA1c, fasting insulin, and triglyceride levels, and was increased in adipose tissue and blood from the diabetic twin among monozygotic twin pairs discordant for T2D. DNA methylation at the PHOSPHO1 locus cg02650017 in blood correlated positively with HDL levels, and was decreased in skeletal muscle from diabetic vs. non-diabetic monozygotic twins. DNA methylation of cg18181703 (SOCS3), cg11024682 (SREBF1), and cg19693031 (TXNIP) was not associated with future T2D risk in subjects from the Botnia prospective study.

144 citations

References
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Book
01 Jan 1995
TL;DR: In this paper, the authors present a list of disorders of MITOCHONDRIAL FUNCTION, including the following: DISORDERS OF MIOCHONDRIC FERTILITY XIX, XVI, XIX.
Abstract: I. INTRODUCTION II. PERSPECTIVES III. GENERAL THEMES IV. CANCER V. CHROMOSOMES VI. DIAGNOSTIC APPROACHES VII. CARBOHYDRATES VIII. AMINO ACIDS IX. ORGANIC ACIDS X. DISORDERS OF MITOCHONDRIAL FUNCTION XI. PURINES AND PYRIMIDINES XII. LIPIDS XIII. PORPHYRINS XIV. METALS XV. PEROXISOMES XVI. LYSOSOMAL DISORDERS XVII. VITAMINS XVIII. HORMONES XIX. BLOOD XX. IMMUNE AND DEFENSE SYSTEMS XXI. MEMBRANE TRANSPORT DISORDERS XXII. CONNECTIVE TISSUE XXIII. CARDIOVASCULAR SYSTEM XXIV. KIDNEY XXV. MUSCLE XXVI. LUNG XXVII. SKIN XXVIII. NEUROGENETICS XXIX. EYE XXX. MULTISYSTEM INBORN ERRORS OF DEVELOPMENT

10,525 citations

Journal ArticleDOI
TL;DR: It is suggested that matrix vesicles are derived from cells and that they may play a role in initiating calcification at the epiphysis.
Abstract: Vesicles have been identified within the cartilage matrix of the upper tibial epiphyseal plate of normal mice. They were seen at all levels within the plate and usually did not appear to be in contact with cartilage cells. Vesicles were concentrated within the matrix of the longitudinal septa from the proliferative zone downward. They varied considerably in size (∼300 A to ∼1 µ) and in shape. They were bounded by unit membranes, and contained materials of varying density including, rarely, ribosomes. A close association was demonstrated between matrix vesicles and calcification: in the lower hypertrophic and calcifying zones of the epiphysis, vesicles were found in juxtaposition to needle-like structures removed by demineralization with ethylenediaminetetraacetate and identified by electron diffraction as hydroxyapatite and/or fluorapatite crystal structure—the former being indistinguishable from the latter for most cases in which electron diffraction methods are employed. Decalcification also revealed electron-opaque, partially membrane-bounded structures within previously calcified cartilage of the epiphyseal plate and underlying metaphysis which corresponded in size and distribution to matrix vesicles. It is suggested that matrix vesicles are derived from cells and that they may play a role in initiating calcification at the epiphysis.

951 citations

Journal ArticleDOI
TL;DR: The results suggest that inhibiting PC-1 function may be a viable therapeutic strategy for hypophosphatasia, and interfere with TNAP activity may correct pathological hyperossification because of PPi insufficiency.
Abstract: Osteoblasts mineralize bone matrix by promoting hydroxyapatite crystal formation and growth in the interior of membrane-limited matrix vesicles (MVs) and by propagating the crystals onto the collagenous extracellular matrix. Two osteoblast proteins, tissue-nonspecific alkaline phosphatase (TNAP) and plasma cell membrane glycoprotein-1 (PC-1) are involved in this process. Mutations in the TNAP gene result in the inborn error of metabolism known as hypophosphatasia, characterized by poorly mineralized bones, spontaneous fractures, and elevated extracellular concentrations of inorganic pyrophosphate (PP(i)). PP(i) suppresses the formation and growth of hydroxyapatite crystals. PP(i) is produced by the nucleoside triphosphate pyrophosphohydrolase activity of a family of isozymes, with PC-1 being the only member present in MVs. Mice with spontaneous mutations in the PC-1 gene have hypermineralization abnormalities that include osteoarthritis and ossification of the posterior longitudinal ligament of the spine. Here, we show the respective correction of bone mineralization abnormalities in knockout mice null for both the TNAP (Akp2) and PC-1 (Enpp1) genes. Each allele of Akp2 and Enpp1 has a measurable influence on mineralization status in vivo. Ex vivo experiments using cultured double-knockout osteoblasts and their MVs demonstrate normalization of PP(i) content and mineral deposition. Our data provide evidence that TNAP and PC-1 are key regulators of the extracellular PP(i) concentrations required for controlled bone mineralization. Our results suggest that inhibiting PC-1 function may be a viable therapeutic strategy for hypophosphatasia. Conversely, interfering with TNAP activity may correct pathological hyperossification because of PP(i) insufficiency.

812 citations

Journal ArticleDOI
TL;DR: Robison was able to study for two years in Leipzig in the kdbordtories of Professor Hantz as mentioned in this paper, where he obtained a scholarship to attend the University of Nottingham.
Abstract: Robert Robison (Fig. 1) was born in 1883 in Newark-on-Trent. He attended the University College. Nottingham. He began his career in research before he obtained his initial degree. Having obtained a scholarship, Robison was able to study for two years in Leipzig in the kdbordtories of Professor Hantz

706 citations

Journal ArticleDOI
14 Jul 2000-Science
TL;DR: It is shown that the mouse progressive ankylosis locus encodes a multipass transmembrane protein (ANK) that is expressed in joints and other tissues and controls pyrophosphate levels in cultured cells.
Abstract: Mutation at the mouse progressive ankylosis (ank) locus causes a generalized, progressive form of arthritis accompanied by mineral deposition, formation of bony outgrowths, and joint destruction. Here, we show that the ank locus encodes a multipass transmembrane protein (ANK) that is expressed in joints and other tissues and controls pyrophosphate levels in cultured cells. A highly conserved gene is present in humans and other vertebrates. These results identify ANK-mediated control of pyrophosphate levels as a possible mechanism regulating tissue calcification and susceptibility to arthritis in higher animals.

636 citations

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