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The Role of Tissue-Nonspecific Alkaline Phosphatase in Inflammation and Metabolic Syndrome

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 16818

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Prof. Dr. David Magne

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MEM2 Team, Metabolism, Enzymes and Molecular Mechanisms, Institute of Molecular and Supramolecular Chemistry and Biochemistry, ICBMS UMR CNRS 5246 University Lyon 1, CEDEX, 69622 Villeurbanne, France
Interests: vascular calcification; pathological bone formation; tissue-nonspecific alkaline phosphatase; inflammation; mineralization
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Dear Colleagues,

Tissue-nonspecific alkaline phosphatase (TNAP) is mainly known for its necessary function during bone mineralization, due to the dephosphorylation of the mineralization inhibitor inorganic pyrophosphate (PPi). TNAP is however a relatively ubiquitous enzyme expressed in liver, kidney or brain that is present in the blood, both as a soluble form and at the membrane of neutrophils. Serum TNAP activity is elevated in individuals with metabolic syndrome and is associated with their increased mortality risk. This association may result from the function of TNAP in inflammation, relying on the dephosphorylation of adenosine nucleotides and lipopolysaccharide. It may also rely on the stimulation of cardiovascular calcification resulting from PPi hydrolysis in the blood and/or cardiovascular tissues.

This Special Issue of IJMS aims to cover recent findings on the regulation of TNAP during metabolic syndrome, on its inflammatory functions, and the consequences of its activation on cardiovascular mortality. Original research articles, comprehensive reviews, and short communications are all welcome.

Prof. Dr. David Magne
Guest Editor

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Keywords

tissue-nonspecific alkaline phosphatase (TNAP)
inflammation
adenosine nucleotides
lipopolysaccharide
metabolic syndrome
vascular calcification

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The Role of Tissue-Nonspecific Alkaline Phosphatase in Inflammation and Metabolic Syndrome 2.0 in International Journal of Molecular Sciences (1 article)

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Research

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16 pages, 2617 KiB

Open AccessArticle

Hydrolysis of Extracellular ATP by Vascular Smooth Muscle Cells Transdifferentiated into Chondrocytes Generates P_i but Not PP_i

by Rene Buchet, Camille Tribes, Valentine Rouaix, Bastien Doumèche, Michele Fiore, Yuqing Wu, David Magne and Saida Mebarek

Int. J. Mol. Sci. 2021, 22(6), 2948; https://doi.org/10.3390/ijms22062948 - 14 Mar 2021

Cited by 9 | Viewed by 2693

Abstract

(1) Background: Tissue non-specific alkaline phosphatase (TNAP) is suspected to induce atherosclerosis plaque calcification. TNAP, during physiological mineralization, hydrolyzes the mineralization inhibitor inorganic pyrophosphate (PP_i). Since atherosclerosis plaques are characterized by the presence of necrotic cells that probably release supraphysiological concentrations of ATP, we explored whether this extracellular adenosine triphosphate (ATP) is hydrolyzed into the mineralization inhibitor PP_i or the mineralization stimulator inorganic phosphate (P_i), and whether TNAP is involved. (2) Methods: Murine aortic smooth muscle cell line (MOVAS cells) were transdifferentiated into chondrocyte-like cells in calcifying medium, containing ascorbic acid and β-glycerophosphate. ATP hydrolysis rates were determined in extracellular medium extracted from MOVAS cultures during their transdifferentiation, using ³¹P-NMR and IR spectroscopy. (3) Results: ATP and PP_i hydrolysis by MOVAS cells increased during transdifferentiation. ATP hydrolysis was sequential, yielding adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine without any detectable PP_i. The addition of levamisole partially inhibited ATP hydrolysis, indicating that TNAP and other types of ectonucleoside triphoshatediphosphohydrolases contributed to ATP hydrolysis. (4) Conclusions: Our findings suggest that high ATP levels released by cells in proximity to vascular smooth muscle cells (VSMCs) in atherosclerosis plaques generate P_i and not PP_i, which may exacerbate plaque calcification. Full article

(This article belongs to the Special Issue The Role of Tissue-Nonspecific Alkaline Phosphatase in Inflammation and Metabolic Syndrome)

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20 pages, 4362 KiB

Open AccessArticle

Tissue Nonspecific Alkaline Phosphatase Function in Bone and Muscle Progenitor Cells: Control of Mitochondrial Respiration and ATP Production

by Zhi Zhang, Hwa Kyung Nam, Spencer Crouch and Nan E. Hatch

Int. J. Mol. Sci. 2021, 22(3), 1140; https://doi.org/10.3390/ijms22031140 - 24 Jan 2021

Cited by 20 | Viewed by 3571

Abstract

Tissue nonspecific alkaline phosphatase (TNAP/Alpl) is associated with cell stemness; however, the function of TNAP in mesenchymal progenitor cells remains largely unknown. In this study, we aimed to establish an essential role for TNAP in bone and muscle progenitor cells. We investigated the impact of TNAP deficiency on bone formation, mineralization, and differentiation of bone marrow stromal cells. We also pursued studies of proliferation, mitochondrial function and ATP levels in TNAP deficient bone and muscle progenitor cells. We find that TNAP deficiency decreases trabecular bone volume fraction and trabeculation in addition to decreased mineralization. We also find that Alpl^−/− mice (global TNAP knockout mice) exhibit muscle and motor coordination deficiencies similar to those found in individuals with hypophosphatasia (TNAP deficiency). Subsequent studies demonstrate diminished proliferation, with mitochondrial hyperfunction and increased ATP levels in TNAP deficient bone and muscle progenitor cells, plus intracellular expression of TNAP in TNAP+ cranial osteoprogenitors, bone marrow stromal cells, and skeletal muscle progenitor cells. Together, our results indicate that TNAP functions inside bone and muscle progenitor cells to influence mitochondrial respiration and ATP production. Future studies are required to establish mechanisms by which TNAP influences mitochondrial function and determine if modulation of TNAP can alter mitochondrial respiration in vivo. Full article

(This article belongs to the Special Issue The Role of Tissue-Nonspecific Alkaline Phosphatase in Inflammation and Metabolic Syndrome)

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14 pages, 3500 KiB

Open AccessArticle

Deficiency in Tissue Non-Specific Alkaline Phosphatase Leads to Steatohepatitis in Mice Fed a High Fat Diet Similar to That Produced by a Methionine and Choline Deficient Diet

by Reyes Gámez-Belmonte, Mireia Tena-Garitaonaindia, Cristina Hernández-Chirlaque, Samir Córdova, Diego Ceacero-Heras, Fermín Sánchez de Medina and Olga Martínez-Augustin

Int. J. Mol. Sci. 2021, 22(1), 51; https://doi.org/10.3390/ijms22010051 - 23 Dec 2020

Cited by 4 | Viewed by 2526

Abstract

The liver expresses tissue-nonspecific alkaline phosphatase (TNAP), which may participate in the defense against bacterial components, in cell regulation as part of the purinome or in bile secretion, among other roles. We aimed to study the role of TNAP in the development of hepatosteatosis. TNAP^+/− haplodeficient and wild type (WT) mice were fed a control diet (containing 10% fat w/w) or the same diet deficient in methionine and choline (MCD diet). The MCD diet induced substantial weight loss together with hepatic steatosis and increased alanine aminotransferase (ALT) plasma levels, but no differences in IL-6, TNF, insulin or resistin. There were no substantial differences between TNAP^+/− and WT mice fed the MCD diet. In turn, TNAP^+/− mice receiving the control diet presented hepatic steatosis with alterations in metabolic parameters very similar to those induced by the MCD diet. Nevertheless, no weight loss, increased ALT plasma levels or hypoglycemia were observed. These mice also presented increased levels of liver TNF and systemic resistin and glucagon compared to WT mice. The phenotype of TNAP^+/− mice fed a standard diet was normal. In conclusion, TNAP haplodeficiency induces steatosis comparable to that produced by a MCD diet when fed a control diet. Full article

(This article belongs to the Special Issue The Role of Tissue-Nonspecific Alkaline Phosphatase in Inflammation and Metabolic Syndrome)

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Review

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15 pages, 28335 KiB

Open AccessReview

TNAP: A New Multitask Enzyme in Energy Metabolism

by Anne Briolay, Laurence Bessueille and David Magne

Int. J. Mol. Sci. 2021, 22(19), 10470; https://doi.org/10.3390/ijms221910470 - 28 Sep 2021

Cited by 10 | Viewed by 2829

Abstract

Tissue-nonspecific alkaline phosphatase (TNAP) is mainly known for its necessary role in skeletal and dental mineralization, which relies on the hydrolysis of the mineralization inhibitor inorganic pyrophosphate (PP_i). Mutations in the gene encoding TNAP leading to severe hypophosphatasia result in strongly reduced mineralization and perinatal death. Fortunately, the relatively recent development of a recombinant TNAP with a bone anchor has allowed to correct the bone defects and prolong the life of affected babies and children. Researches on TNAP must however not be slowed down, because accumulating evidence indicates that TNAP activation in individuals with metabolic syndrome (MetS) is associated with enhanced cardiovascular mortality, presumably in relation with cardiovascular calcification. On the other hand, TNAP appears to be necessary to prevent the development of steatohepatitis in mice, suggesting that TNAP plays protective roles. The aim of the present review is to highlight the known or suspected functions of TNAP in energy metabolism that may be associated with the development of MetS. The location of TNAP in liver and its function in bile excretion, lipopolysaccharide (LPS) detoxification and fatty acid transport will be presented. The expression and function of TNAP in adipocyte differentiation and thermogenesis will also be discussed. Given that TNAP is a tissue- and substrate-nonspecific phosphatase, we believe that it exerts several crucial pathophysiological functions that are just beginning to be discovered. Full article

(This article belongs to the Special Issue The Role of Tissue-Nonspecific Alkaline Phosphatase in Inflammation and Metabolic Syndrome)

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13 pages, 797 KiB

Open AccessReview

TNAP as a New Player in Chronic Inflammatory Conditions and Metabolism

by Stephanie Graser, Daniel Liedtke and Franz Jakob

Int. J. Mol. Sci. 2021, 22(2), 919; https://doi.org/10.3390/ijms22020919 - 18 Jan 2021

Cited by 17 | Viewed by 3772

Abstract

This review summarizes important information on the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP) and gives a brief insight into the symptoms, diagnostics, and treatment of the rare disease Hypophosphatasia (HPP), which is resulting from mutations in the TNAP encoding ALPL gene. We emphasize the role of TNAP beyond its well-known contribution to mineralization processes. Therefore, above all, the impact of the enzyme on central molecular processes in the nervous system and on inflammation is presented here. Full article

(This article belongs to the Special Issue The Role of Tissue-Nonspecific Alkaline Phosphatase in Inflammation and Metabolic Syndrome)

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