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1
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Razazian M, Bahiraii S, Jannat I, Tiffner A, Beilhack G, Levkau B, Voelkl J, Alesutan I. Sphingosine kinase 1 inhibition aggravates vascular smooth muscle cell calcification. Pflugers Arch 2025; 477:815-826. [PMID: 39899071 DOI: 10.1007/s00424-025-03068-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 01/19/2025] [Accepted: 01/20/2025] [Indexed: 02/04/2025]
Abstract
Medial vascular calcification is common in chronic kidney disease patients and linked to hyperphosphatemia. Upon phosphate exposure, intricate signaling events orchestrate pro-calcific effects in the vasculature mediated by vascular smooth muscle cells (VSMCs). Sphingosine kinase 1 (SPHK1) produces sphingosine-1-phosphate (S1P) and is associated with complex effects in the vascular system. The present study investigated a possible involvement of SPHK1 in VSMC calcification. Experiments were performed in primary human aortic VSMCs under pro-calcific conditions, with pharmacological inhibition or knockdown of SPHK1 or SPNS2 (a lysolipid transporter involved in cellular S1P export), as well as in Sphk1-deficient and wild-type mice treated with cholecalciferol. In VSMCs, SPHK1 expression was up-regulated by pro-calcific conditions. Calcification medium up-regulated osteogenic marker mRNA expression and activity as well as calcification of VSMCs, effects significantly augmented by co-treatment with the SPHK1 inhibitor SK1-IN-1. SK1-IN-1 alone was sufficient to up-regulate osteogenic signaling in VSMCs during control conditions. Similarly, the SPHK1 inhibitor PF-543 and SPHK1 knockdown up-regulated osteogenic signaling in VSMCs and aggravated VSMC calcification. In contrast, co-treatment with the SPNS2 inhibitor SLF1081851 suppressed osteogenic signaling and calcification of VSMCs, effects abolished by silencing of SPHK1. In addition, Sphk1 deficiency aggravated vascular calcification and aortic osteogenic marker expression in mice after cholecalciferol overload. In conclusion, SPHK1 inhibition, knockdown, or deficiency aggravates vascular pro-calcific signaling and calcification. The reduced calcification after inhibition of S1P export suggests a possible involvement of intracellular S1P, but further studies are required to elucidate the complex roles of SPHKs and S1P signaling in calcifying VSMCs.
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MESH Headings
- Animals
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/cytology
- Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors
- Phosphotransferases (Alcohol Group Acceptor)/metabolism
- Phosphotransferases (Alcohol Group Acceptor)/genetics
- Humans
- Vascular Calcification/metabolism
- Mice
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/drug effects
- Cells, Cultured
- Male
- Mice, Inbred C57BL
- Signal Transduction
- Anion Transport Proteins/metabolism
- Anion Transport Proteins/genetics
- Lysophospholipids/metabolism
- Sphingosine/metabolism
- Sphingosine/analogs & derivatives
- Osteogenesis/drug effects
- Methanol
- Pyrrolidines
- Sulfones
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Affiliation(s)
- Mehdi Razazian
- Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Krankenhausstrasse 5, 4020, Linz, Austria
| | - Sheyda Bahiraii
- Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Krankenhausstrasse 5, 4020, Linz, Austria
| | - Isratul Jannat
- Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Krankenhausstrasse 5, 4020, Linz, Austria
| | - Adéla Tiffner
- Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Krankenhausstrasse 5, 4020, Linz, Austria
- Institute of Biophysics, Johannes Kepler University Linz, Linz, Austria
| | - Georg Beilhack
- Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Bodo Levkau
- Institute of Molecular Medicine III, University Hospital and Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Jakob Voelkl
- Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Krankenhausstrasse 5, 4020, Linz, Austria.
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Berlin, Germany.
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
| | - Ioana Alesutan
- Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Krankenhausstrasse 5, 4020, Linz, Austria
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2
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Ramos-Brossier M, Romeo-Guitart D, Lanté F, Boitez V, Mailliet F, Saha S, Rivagorda M, Siopi E, Nemazanyy I, Leroy C, Moriceau S, Beck-Cormier S, Codogno P, Buisson A, Beck L, Friedlander G, Oury F. Slc20a1 and Slc20a2 regulate neuronal plasticity and cognition independently of their phosphate transport ability. Cell Death Dis 2024; 15:20. [PMID: 38195526 PMCID: PMC10776841 DOI: 10.1038/s41419-023-06292-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 11/01/2023] [Accepted: 11/13/2023] [Indexed: 01/11/2024]
Abstract
In recent years, primary familial brain calcification (PFBC), a rare neurological disease characterized by a wide spectrum of cognitive disorders, has been associated to mutations in the sodium (Na)-Phosphate (Pi) co-transporter SLC20A2. However, the functional roles of the Na-Pi co-transporters in the brain remain still largely elusive. Here we show that Slc20a1 (PiT-1) and Slc20a2 (PiT-2) are the most abundant Na-Pi co-transporters expressed in the brain and are involved in the control of hippocampal-dependent learning and memory. We reveal that Slc20a1 and Slc20a2 are differentially distributed in the hippocampus and associated with independent gene clusters, suggesting that they influence cognition by different mechanisms. Accordingly, using a combination of molecular, electrophysiological and behavioral analyses, we show that while PiT-2 favors hippocampal neuronal branching and survival, PiT-1 promotes synaptic plasticity. The latter relies on a likely Otoferlin-dependent regulation of synaptic vesicle trafficking, which impacts the GABAergic system. These results provide the first demonstration that Na-Pi co-transporters play key albeit distinct roles in the hippocampus pertaining to the control of neuronal plasticity and cognition. These findings could provide the foundation for the development of novel effective therapies for PFBC and cognitive disorders.
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Affiliation(s)
- Mariana Ramos-Brossier
- Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 8, F-75015, Paris, France.
| | - David Romeo-Guitart
- Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 8, F-75015, Paris, France
| | - Fabien Lanté
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
| | - Valérie Boitez
- Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 8, F-75015, Paris, France
| | - François Mailliet
- Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 8, F-75015, Paris, France
| | - Soham Saha
- Institut Pasteur, Perception & Memory Unit, F-75015, Paris, France
- MedInsights, 6 rue de l'église, F-02810, Veuilly la Poterie, France
| | - Manon Rivagorda
- Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 8, F-75015, Paris, France
| | - Eleni Siopi
- Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 8, F-75015, Paris, France
| | - Ivan Nemazanyy
- Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24/CNRS UAR, 3633, Paris, France
| | - Christine Leroy
- Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 6, F-75015, Paris, France
| | - Stéphanie Moriceau
- Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 8, F-75015, Paris, France
- Platform for Neurobehavioural and metabolism, Structure Fédérative de Recherche Necker, INSERM, US24/CNRS UAR, 3633, Paris, France
- Institute of Genetic Diseases, Imagine, 75015, Paris, France
| | - Sarah Beck-Cormier
- Nantes Université, CNRS, Inserm, l'Institut du Thorax, F-44000, Nantes, France
| | - Patrice Codogno
- Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 6, F-75015, Paris, France
| | - Alain Buisson
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
| | - Laurent Beck
- Nantes Université, CNRS, Inserm, l'Institut du Thorax, F-44000, Nantes, France.
| | - Gérard Friedlander
- Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 6, F-75015, Paris, France.
| | - Franck Oury
- Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 8, F-75015, Paris, France.
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3
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Wang J, Fang CL, Noller K, Wei Z, Liu G, Shen K, Song K, Cao X, Wan M. Bone-derived PDGF-BB drives brain vascular calcification in male mice. J Clin Invest 2023; 133:e168447. [PMID: 37815871 PMCID: PMC10688993 DOI: 10.1172/jci168447] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 10/05/2023] [Indexed: 10/12/2023] Open
Abstract
Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel calcifications in peripheral tissue is well studied, but microvascular calcification in the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contributed to cerebrovascular calcification in male mice. Aged male mice had higher serum PDGF-BB levels and a higher incidence of brain calcification compared with young mice, mainly in the thalamus. Transgenic mice with preosteoclast-specific Pdgfb overexpression exhibited elevated serum PDGF-BB levels and recapitulated age-associated thalamic calcification. Conversely, mice with preosteoclast-specific Pdgfb deletion displayed diminished age-associated thalamic calcification. In an ex vivo cerebral microvascular culture system, PDGF-BB dose-dependently promoted vascular calcification. Analysis of osteogenic gene array and single-cell RNA-Seq (scRNA-Seq) revealed that PDGF-BB upregulated multiple osteogenic differentiation genes and the phosphate transporter Slc20a1 in cerebral microvessels. Mechanistically, PDGF-BB stimulated the phosphorylation of its receptor PDGFRβ (p-PDGFRβ) and ERK (p-ERK), leading to the activation of RUNX2. This activation, in turn, induced the transcription of osteoblast differentiation genes in PCs and upregulated Slc20a1 in astrocytes. Thus, bone-derived PDGF-BB induced brain vascular calcification by activating the p-PDGFRβ/p-ERK/RUNX2 signaling cascade in cerebrovascular cells.
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Affiliation(s)
- Jiekang Wang
- Department of Orthopaedic Surgery
- Department of Biomedical Engineering, and
| | | | | | - Zhiliang Wei
- The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Ke Shen
- Department of Orthopaedic Surgery
| | - Kangping Song
- Department of Orthopaedic Surgery
- Department of Biomedical Engineering, and
| | - Xu Cao
- Department of Orthopaedic Surgery
- Department of Biomedical Engineering, and
| | - Mei Wan
- Department of Orthopaedic Surgery
- Department of Biomedical Engineering, and
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4
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Chen SY, Ho CJ, Lu YT, Lin CH, Lan MY, Tsai MH. The Genetics of Primary Familial Brain Calcification: A Literature Review. Int J Mol Sci 2023; 24:10886. [PMID: 37446066 DOI: 10.3390/ijms241310886] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 06/21/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Primary familial brain calcification (PFBC), also known as Fahr's disease, is a rare inherited disorder characterized by bilateral calcification in the basal ganglia according to neuroimaging. Other brain regions, such as the thalamus, cerebellum, and subcortical white matter, can also be affected. Among the diverse clinical phenotypes, the most common manifestations are movement disorders, cognitive deficits, and psychiatric disturbances. Although patients with PFBC always exhibit brain calcification, nearly one-third of cases remain clinically asymptomatic. Due to advances in the genetics of PFBC, the diagnostic criteria of PFBC may need to be modified. Hitherto, seven genes have been associated with PFBC, including four dominant inherited genes (SLC20A2, PDGFRB, PDGFB, and XPR1) and three recessive inherited genes (MYORG, JAM2, and CMPK2). Nevertheless, around 50% of patients with PFBC do not have pathogenic variants in these genes, and further PFBC-associated genes are waiting to be identified. The function of currently known genes suggests that PFBC could be caused by the dysfunction of the neurovascular unit, the dysregulation of phosphate homeostasis, or mitochondrial dysfunction. An improved understanding of the underlying pathogenic mechanisms for PFBC may facilitate the development of novel therapies.
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Affiliation(s)
- Shih-Ying Chen
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
| | - Chen-Jui Ho
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
| | - Yan-Ting Lu
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
| | - Chih-Hsiang Lin
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
| | - Min-Yu Lan
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
- Center for Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
- Center for Mitochondrial Research and Medicine, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
| | - Meng-Han Tsai
- Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 333323, Taiwan
- Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
- Genomics and Proteomics Core Laboratory, Kaohsiung Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kaohsiung 833401, Taiwan
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5
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The Pathology of Primary Familial Brain Calcification: Implications for Treatment. Neurosci Bull 2022; 39:659-674. [PMID: 36469195 PMCID: PMC10073384 DOI: 10.1007/s12264-022-00980-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Accepted: 07/10/2022] [Indexed: 12/08/2022] Open
Abstract
AbstractPrimary familial brain calcification (PFBC) is an inherited neurodegenerative disorder mainly characterized by progressive calcium deposition bilaterally in the brain, accompanied by various symptoms, such as dystonia, ataxia, parkinsonism, dementia, depression, headaches, and epilepsy. Currently, the etiology of PFBC is largely unknown, and no specific prevention or treatment is available. During the past 10 years, six causative genes (SLC20A2, PDGFRB, PDGFB, XPR1, MYORG, and JAM2) have been identified in PFBC. In this review, considering mechanistic studies of these genes at the cellular level and in animals, we summarize the pathogenesis and potential preventive and therapeutic strategies for PFBC patients. Our systematic analysis suggests a classification for PFBC genetic etiology based on several characteristics, provides a summary of the known composition of brain calcification, and identifies some potential therapeutic targets for PFBC.
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6
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Kawtharany L, Bessueille L, Issa H, Hamade E, Zibara K, Magne D. Inflammation and Microcalcification: A Never-Ending Vicious Cycle in Atherosclerosis? J Vasc Res 2022; 59:137-150. [PMID: 35038712 DOI: 10.1159/000521161] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 11/17/2021] [Indexed: 11/19/2022] Open
Abstract
Inflammatory cells and cytokines are known for long to worsen the development of atherosclerotic plaques in mice, and intense efforts are today devoted to develop anti-inflammatory therapeutic strategies to slow down plaque development. Increasing data indicate that plaque inflammation is intimately associated with microcalcifications, which exert harmful effects eventually culminating with plaque rupture. In this review article, we will first introduce microcalcification location, detection, and effects in atherosclerotic plaques. Then, we will present the numerous data suggesting that inflammatory cells and molecules are responsible for the formation of microcalcifications and the articles showing that microcalcifications stimulate macrophages and smooth muscle cells to produce more pro-inflammatory cytokines. Finally, we will discuss the possibility that microcalcifications might stimulate smooth muscle cells to produce larger and more stable calcifications to stabilize plaques, to exit the vicious cycle associating inflammation and microcalcification in atherosclerotic plaques.
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Affiliation(s)
- Lynn Kawtharany
- ICBMS UMR CNRS 5246, Université Claude Bernard Lyon 1, Lyon, France
| | | | - Hawraa Issa
- College of Public Health, Phoenicia University, Zahrani, Lebanon
| | - Eva Hamade
- PRASE and Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - Kazem Zibara
- PRASE and Biology Department, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
| | - David Magne
- ICBMS UMR CNRS 5246, Université Claude Bernard Lyon 1, Lyon, France
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7
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Hu MC, Moe OW. Phosphate and Cellular Senescence. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1362:55-72. [PMID: 35288873 PMCID: PMC10513121 DOI: 10.1007/978-3-030-91623-7_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Cellular senescence is one type of permeant arrest of cell growth and one of increasingly recognized contributor to aging and age-associated disease. High phosphate and low Klotho individually and synergistically lead to age-related degeneration in multiple organs. Substantial evidence supports the causality of high phosphate in cellular senescence, and potential contribution to human aging, cancer, cardiovascular, kidney, neurodegenerative, and musculoskeletal diseases. Phosphate can induce cellular senescence both by direct phosphotoxicity, and indirectly through downregulation of Klotho and upregulation of plasminogen activator inhibitor-1. Restriction of dietary phosphate intake and blockage of intestinal absorption of phosphate help suppress cellular senescence. Supplementation of Klotho protein, cellular senescence inhibitor, and removal of senescent cells with senolytic agents are potential novel strategies to attenuate phosphate-induced cellular senescence, retard aging, and ameliorate age-associated, and phosphate-induced disorders.
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Affiliation(s)
- Ming Chang Hu
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Orson W Moe
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Departments of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Departments of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
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8
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Chronic Kidney Disease-Induced Arterial Media Calcification in Rats Prevented by Tissue Non-Specific Alkaline Phosphatase Substrate Supplementation Rather Than Inhibition of the Enzyme. Pharmaceutics 2021; 13:pharmaceutics13081138. [PMID: 34452102 PMCID: PMC8399849 DOI: 10.3390/pharmaceutics13081138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 07/02/2021] [Accepted: 07/19/2021] [Indexed: 11/30/2022] Open
Abstract
Patients with chronic kidney disease (CKD) suffer from arterial media calcification and a disturbed bone metabolism. Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes the calcification inhibitor pyrophosphate (PPi) into inorganic phosphate (Pi) and thereby stimulates arterial media calcification as well as physiological bone mineralization. This study investigates whether the TNAP inhibitor SBI-425, PPi or the combination of both inhibit arterial media calcification in an 0.75% adenine rat model of CKD. Treatments started with the induction of CKD, including (i) rats with normal renal function (control diet) treated with vehicle and CKD rats treated with either (ii) vehicle, (iii) 10 mg/kg/day SBI-425, (iv) 120 µmol/kg/day PPi and (v) 120 µmol/kg/day PPi and 10 mg/kg/day SBI-425. All CKD groups developed a stable chronic renal failure reflected by hyperphosphatemia, hypocalcemia and high serum creatinine levels. CKD induced arterial media calcification and bone metabolic defects. All treatments, except for SBI-425 alone, blocked CKD-related arterial media calcification. More important, SBI-425 alone and in combination with PPi increased osteoid area pointing to a less efficient bone mineralization. Clearly, potential side effects on bone mineralization will need to be assessed in any clinical trial aimed at modifying the Pi/PPi ratio in CKD patients who already suffer from a compromised bone status.
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Chavkin NW, Leaf EM, Brooks KE, Wallingford MC, Lund SM, Giachelli CM. Adapter Protein RapGEF1 Is Required for ERK1/2 Signaling in Response to Elevated Phosphate in Vascular Smooth Muscle Cells. J Vasc Res 2021; 58:277-285. [PMID: 33951626 PMCID: PMC8478708 DOI: 10.1159/000516044] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 03/17/2021] [Indexed: 11/19/2022] Open
Abstract
The sodium-dependent phosphate transporter, SLC20A1, is required for elevated inorganic phosphate (Pi) induced vascular smooth muscle cell (VSMC) matrix mineralization and phenotype transdifferentiation. Recently, elevated Pi was shown to induce ERK1/2 phosphorylation through SLC20A1 by Pi uptake-independent functions in VSMCs, suggesting a cell signaling response to elevated Pi. Previous studies identified Rap1 guanine nucleotide exchange factor (RapGEF1) as an SLC20A1-interacting protein and RapGEF1 promotes ERK1/2 phosphorylation through Rap1 activation. In this study, we tested the hypothesis that RapGEF1 is a critical component of the SLC20A1-mediated Pi-induced ERK1/2 phosphorylation pathway. Co-localization of SLC20A1 and RapGEF1, knockdown of RapGEF1 with siRNA, and small molecule inhibitors of Rap1, B-Raf, and Mek1/2 were investigated. SLC20A1 and RapGEF1 were co-localized in peri-membranous structures in VSMCs. Knockdown of RapGEF1 and small molecule inhibitors against Rap1, B-Raf, and Mek1/2 eliminated elevated Pi-induced ERK1/2 phosphorylation. Knockdown of RapGEF1 inhibited SM22α mRNA expression and blocked elevated Pi-induced downregulation of SM22α mRNA. Together, these data suggest that RapGEF1 is required for SLC20A1-mediated elevated Pi signaling through a Rap1/B-Raf/Mek1/2 cell signaling pathway, thereby promoting ERK1/2 phosphorylation and inhibiting SM22α gene expression in VSMCs.
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Affiliation(s)
| | - Elizabeth M. Leaf
- Department of Bioengineering, University of Washington, Seattle WA USA
| | - Kadin E. Brooks
- Department of Bioengineering, University of Washington, Seattle WA USA
| | | | - Susan M. Lund
- Department of Bioengineering, University of Washington, Seattle WA USA
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10
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Jeon YK, Shin MJ, Saini SK, Custodero C, Aggarwal M, Anton SD, Leeuwenburgh C, Mankowski RT. Vascular dysfunction as a potential culprit of sarcopenia. Exp Gerontol 2020; 145:111220. [PMID: 33373710 DOI: 10.1016/j.exger.2020.111220] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 12/17/2020] [Accepted: 12/18/2020] [Indexed: 02/08/2023]
Abstract
Aging-related changes to biological structures such as cardiovascular and musculoskeletal systems contribute to the development of comorbid conditions including cardiovascular disease and frailty, and ultimately lead to premature death. Although, frail older adults often demonstrate both cardiovascular and musculoskeletal comorbidities, the etiology of sarcopenia, and especially the contribution of cardiovascular aging is unclear. Aging-related vascular calcification is prevalent in older adults and is a known risk factor for cardiovascular disease and death. The effect vascular calcification has on function during aging is not well understood. Emerging findings suggest vascular calcification can impact skeletal muscle perfusion, negatively affecting nutrient and oxygen delivery to skeletal muscle, ultimately accelerating muscle loss and functional decline. The present review summarizes existing evidence on the biological mechanisms linking vascular calcification with sarcopenia during aging.
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Affiliation(s)
- Yun Kyung Jeon
- Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA; Division of Endocrinology and Metabolism, Department of Internal Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Myung Jun Shin
- Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA; Department of Rehabilitation Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, Republic of Korea
| | - Sunil Kumar Saini
- Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA
| | - Carlo Custodero
- Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA; Dipartimento Interdisciplinare di Medicina, Clinica Medica Cesare Frugoni, University of Bari Aldo Moro, Bari, Italy
| | - Monica Aggarwal
- Department of Medicine, Division of Cardiovascular Medicine, University of Florida, FL, USA
| | - Stephen D Anton
- Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA
| | | | - Robert T Mankowski
- Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA.
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11
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Rutsch F, Buers I, Nitschke Y. Hereditary Disorders of Cardiovascular Calcification. Arterioscler Thromb Vasc Biol 2020; 41:35-47. [PMID: 33176451 DOI: 10.1161/atvbaha.120.315577] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Arterial calcification is a common phenomenon in the elderly, in patients with atherosclerosis or renal failure and in diabetes. However, when present in very young individuals, it is likely to be associated with an underlying hereditary disorder of arterial calcification. Here, we present an overview of the few monogenic disorders presenting with early-onset cardiovascular calcification. These disorders can be classified according to the function of the respective disease gene into (1) disorders caused by an altered purine and phosphate/pyrophosphate metabolism, (2) interferonopathies, and (3) Gaucher disease. The finding of arterial calcification in early life should alert the clinician and prompt further genetic work-up to define the underlying genetic defect, to establish the correct diagnosis, and to enable appropriate therapy.
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Affiliation(s)
- Frank Rutsch
- Department of General Pediatrics, Muenster University Children's Hospital, Germany
| | - Insa Buers
- Department of General Pediatrics, Muenster University Children's Hospital, Germany
| | - Yvonne Nitschke
- Department of General Pediatrics, Muenster University Children's Hospital, Germany
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12
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Li H, Pan K, Meng Y, Deng J, Zhang P, Song W, Li S. Mutual promotions between periodontitis and vascular calcification by rat animal model. J Periodontal Res 2020; 55:810-820. [PMID: 32996601 DOI: 10.1111/jre.12757] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 03/09/2020] [Accepted: 04/06/2020] [Indexed: 01/07/2023]
Abstract
OBJECTIVE AND BACKGROUND To study the relationship between periodontitis and vascular calcification by establishing rat model of chronic periodontitis and vascular calcification. METHODS Forty male Wistar rats were divided into four groups randomly: control group, periodontitis group, vascular calcification group, and compound periodontitis and calcification group. Each group rats accepted the corresponding manages to establish the animal model. Clinical examinations and hematoxylin and eosin staining of periodontal tissue were taken to test the periodontal model; calcium assay, alkaline phosphatase activity, expression of mineral-related factors including osteopontin, alkaline phosphatase, core-binding factor-α1 and bone sialoprotein, hematoxylin and eosin staining and von Kossa staining of vascular tissue were taken to test the vascular calcification model; inflammatory factors including C-reactive protein, interleukin-1β, tumor necrosis factor-α, interleukin-6, prostaglandin E2, and serum lipid in serum were also detected at the same time. RESULTS The rat model was established. Inflammation of periodontal tissue and alveolar bone resorption in compound group and periodontitis group were more obvious than those in control group and vascular calcification group (P < .05). However, the calcium assay, alkaline phosphatase activity, and mineralized deposition in vascular calcification group and compound group were higher than those in control group and periodontitis group (P < .05), and compound group were the highest (P < .05); as for serum lipid, the level of total cholesterol and low-density lipoprotein-cholesterol in compound group and vascular calcification group were higher than that in control group and periodontitis group (P < .05), and compound group was the highest (P <.05); but the level of high-density lipoprotein cholesterol was higher in control group and periodontitis group. Inflammatory factors expression in serum were higher in compound group and periodontitis group, while mineral-related factors expression were higher in compoundgroup and vascular calcification group. CONCLUSION There are some mutual promotions between periodontitis and vascular calcification, which might be related to the increasing inflammatory factors, lipids level, and mineral-related factors.
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Affiliation(s)
- Huixu Li
- The Affiliated Hospital of Qingdao University, Qingdao, China.,School of Stomatology of Qingdao University, Qingdao, China.,Department of Endodontics, Tianjin Stomatological Hospital, Hospital of Stomatology, Nankai University, TianJin, China
| | - Keqing Pan
- The Affiliated Hospital of Qingdao University, Qingdao, China.,School of Stomatology of Qingdao University, Qingdao, China
| | - Yun Meng
- The Affiliated Hospital of Qingdao University, Qingdao, China.,School of Stomatology of Qingdao University, Qingdao, China.,Department of Stomatology, The Traditional Chinese Medicine Hospital of Tianjin Dongli District, Tianjin, China
| | - Jing Deng
- The Affiliated Hospital of Qingdao University, Qingdao, China.,School of Stomatology of Qingdao University, Qingdao, China
| | - Pengmei Zhang
- The Affiliated Hospital of Qingdao University, Qingdao, China.,School of Stomatology of Qingdao University, Qingdao, China.,Department of Stomatology, The Huikang Hospital, Qingdao, China
| | - Wenbin Song
- The Affiliated Hospital of Qingdao University, Qingdao, China.,School of Stomatology of Qingdao University, Qingdao, China
| | - Shu Li
- Department of Periodontology, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
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13
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Maique J, Flores B, Shi M, Shepard S, Zhou Z, Yan S, Moe OW, Hu MC. High Phosphate Induces and Klotho Attenuates Kidney Epithelial Senescence and Fibrosis. Front Pharmacol 2020; 11:1273. [PMID: 32973510 PMCID: PMC7468469 DOI: 10.3389/fphar.2020.01273] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 07/31/2020] [Indexed: 12/18/2022] Open
Abstract
Cellular senescence is an irreversible cell growth arrest and is associated with aging and age-related diseases. High plasma phosphate (Pi) and deficiency of Klotho contribute to aging and kidney fibrosis, a pathological feature in the aging kidney and chronic kidney disease. This study examined the interactive role of Pi and Klotho in kidney senescence and fibrosis. Homozygous Klotho hypomorphic mice had high plasma Pi, undetectable Klotho in plasma and kidney, high senescence with massive collagen accumulation in kidney tubules, and fibrin deposits in peritubular capillaries. To examine the Pi effect on kidney senescence, a high (2%) Pi diet was given to wild-type mice. One week of high dietary Pi mildly increased plasma Pi, and upregulated kidney p16/p21 expression, but did not significantly decrease Klotho. Two weeks of high Pi intake led to increase in plasminogen activator inhibitor (PAI)-1, and decrease in kidney Klotho, but still without detectable increase in kidney fibrosis. More prolonged dietary Pi for 12 weeks exacerbated kidney senescence and fibrosis; more so in heterozygous Klotho hypomorphic mice compared to wild-type mice, and in mice with chronic kidney disease (CKD) on high Pi diet compared to CKD mice fed a normal Pi diet. In cultured kidney tubular cells, high Pi directly induced cellular senescence, injury and epithelial-mesenchymal transition, and enhanced H2O2-induced cellular senescence and injury, which were abrogated by Klotho. Fucoidan, a bioactive molecule with multiple biologic functions including senescence inhibition, blunted Pi-induced cellular senescence, oxidation, injury, epithelial-mesenchymal transition, and senescence-associated secretary phenotype. In conclusion, high Pi activates senescence through distinct but interconnected mechanisms: upregulating p16/p21 (early), and elevating plasminogen activator inhibitor-1 and downregulating Klotho (late). Klotho may be a promising agent to attenuate senescence and ameliorate age-associated, and Pi-induced kidney degeneration such as kidney fibrosis.
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Affiliation(s)
- Jenny Maique
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Brianna Flores
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Mingjun Shi
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Sierra Shepard
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Zhiyong Zhou
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Shirely Yan
- Departments of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Orson W Moe
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States.,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States.,Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Ming Chang Hu
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States.,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
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14
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López-Sánchez U, Tury S, Nicolas G, Wilson MS, Jurici S, Ayrignac X, Courgnaud V, Saiardi A, Sitbon M, Battini JL. Interplay between primary familial brain calcification-associated SLC20A2 and XPR1 phosphate transporters requires inositol polyphosphates for control of cellular phosphate homeostasis. J Biol Chem 2020; 295:9366-9378. [PMID: 32393577 PMCID: PMC7363132 DOI: 10.1074/jbc.ra119.011376] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 05/09/2020] [Indexed: 12/19/2022] Open
Abstract
Solute carrier family 20 member 2 (SLC20A2) and xenotropic and polytropic retrovirus receptor 1 (XPR1) are transporters with phosphate uptake and efflux functions, respectively. Both are associated with primary familial brain calcification (PFBC), a genetic disease characterized by cerebral calcium-phosphate deposition and associated with neuropsychiatric symptoms. The association of the two transporters with the same disease suggests that they jointly regulate phosphate fluxes and cellular homeostasis, but direct evidence is missing. Here, we found that cross-talk between SLC20A2 and XPR1 regulates phosphate homeostasis, and we identified XPR1 as a key inositol polyphosphate (IP)-dependent regulator of this process. We found that overexpression of WT SLC20A2 increased phosphate uptake, as expected, but also unexpectedly increased phosphate efflux, whereas PFBC-associated SLC20A2 variants did not. Conversely, SLC20A2 depletion decreased phosphate uptake only slightly, most likely compensated for by the related SLC20A1 transporter, but strongly decreased XPR1-mediated phosphate efflux. The SLC20A2-XPR1 axis maintained constant intracellular phosphate and ATP levels, which both increased in XPR1 KO cells. Elevated ATP levels are a hallmark of altered inositol pyrophosphate (PP-IP) synthesis, and basal ATP levels were restored after phosphate efflux rescue with WT XPR1 but not with XPR1 harboring a mutated PP-IP-binding pocket. Accordingly, inositol hexakisphosphate kinase 1-2 (IP6K1-2) gene inactivation or IP6K inhibitor treatment abolished XPR1-mediated phosphate efflux regulation and homeostasis. Our findings unveil an SLC20A2-XPR1 interplay that depends on IPs such as PP-IPs and controls cellular phosphate homeostasis via the efflux route, and alteration of this interplay likely contributes to PFBC.
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Affiliation(s)
- Uriel López-Sánchez
- Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS, Montpellier, France.,Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier, CNRS, Montpellier, France
| | - Sandrine Tury
- Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS, Montpellier, France
| | - Gaël Nicolas
- Normandie Univ, UNIROUEN, Inserm U1245, and Rouen University Hospital, Department of Genetics and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France
| | - Miranda S Wilson
- MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
| | - Snejana Jurici
- Department of Neurology, Perpignan Hospital, Perpignan, France
| | - Xavier Ayrignac
- Department of Neurology, Montpellier University Hospital, Montpellier, France
| | - Valérie Courgnaud
- Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier, CNRS, Montpellier, France
| | - Adolfo Saiardi
- MRC Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
| | - Marc Sitbon
- Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier, CNRS, Montpellier, France
| | - Jean-Luc Battini
- Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS, Montpellier, France .,Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier, CNRS, Montpellier, France
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15
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Abstract
Phosphate is an essential nutrient for life and is a critical component of bone formation, a major signaling molecule, and structural component of cell walls. Phosphate is also a component of high-energy compounds (i.e., AMP, ADP, and ATP) and essential for nucleic acid helical structure (i.e., RNA and DNA). Phosphate plays a central role in the process of mineralization, normal serum levels being associated with appropriate bone mineralization, while high and low serum levels are associated with soft tissue calcification. The serum concentration of phosphate and the total body content of phosphate are highly regulated, a process that is accomplished by the coordinated effort of two families of sodium-dependent transporter proteins. The three isoforms of the SLC34 family (SLC34A1-A3) show very restricted tissue expression and regulate intestinal absorption and renal excretion of phosphate. SLC34A2 also regulates the phosphate concentration in multiple lumen fluids including milk, saliva, pancreatic fluid, and surfactant. Both isoforms of the SLC20 family exhibit ubiquitous expression (with some variation as to which one or both are expressed), are regulated by ambient phosphate, and likely serve the phosphate needs of the individual cell. These proteins exhibit similarities to phosphate transporters in nonmammalian organisms. The proteins are nonredundant as mutations in each yield unique clinical presentations. Further research is essential to understand the function, regulation, and coordination of the various phosphate transporters, both the ones described in this review and the phosphate transporters involved in intracellular transport.
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Affiliation(s)
- Nati Hernando
- University of Zurich-Irchel, Institute of Physiology, Zurich, Switzerland; Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; and Robley Rex VA Medical Center, Louisville, Kentucky
| | - Kenneth Gagnon
- University of Zurich-Irchel, Institute of Physiology, Zurich, Switzerland; Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; and Robley Rex VA Medical Center, Louisville, Kentucky
| | - Eleanor Lederer
- University of Zurich-Irchel, Institute of Physiology, Zurich, Switzerland; Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky; and Robley Rex VA Medical Center, Louisville, Kentucky
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16
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Hortells L, Guillén N, Sosa C, Sorribas V. Several phosphate transport processes are present in vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 2019; 318:H448-H460. [PMID: 31886722 DOI: 10.1152/ajpheart.00433.2019] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
We have studied inorganic phosphate (Pi) handling in rat aortic vascular smooth muscle cells (VSMC) using 32P-radiotracer assays. Our results have revealed a complex set of mechanisms consisting of 1) well-known PiT1/PiT2-mediated sodium-dependent Pi transport; 2) Slc20-unrelated sodium-dependent Pi transport that is sensitive to the stilbene derivatives 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and 4-acetamido-4-isothiocyanostilbene-2,2-disulfonate (SITS); 3) a sodium-independent Pi uptake system that is competitively inhibited by sulfate, bicarbonate, and arsenate and is weakly inhibited by DIDS, SITS, and phosphonoformate; and 4) an exit pathway from the cell that is partially chloride dependent and unrelated to the known anion-exchangers expressed in VSMC. The inhibitions of sodium-independent Pi transport by sulfate and of sodium-dependent transport by SITS were studied in greater detail. The maximal inhibition by sulfate was similar to that of Pi itself, with a very high inhibition constant (212 mM). SITS only partially inhibited sodium-dependent Pi transport, but the Ki was very low (14 µM). Nevertheless, SITS and DIDS did not inhibit Pi transport in Xenopus laevis oocytes expressing PiT1 or PiT2. Both the sodium-dependent and sodium-independent transport systems were highly dependent on VSMC confluence and on the differentiation state, but they were not modified by incubating VSMC for 7 days with 2 mM Pi under nonprecipitating conditions. This work not only shows that the Pi handling by cells is highly complex but also that the transport systems are shared with other ions such as bicarbonate or sulfate.NEW & NOTEWORTHY In addition to the inorganic phosphate (Pi) transporters PiT1 and PiT2, rat vascular smooth muscle cells show a sodium-dependent Pi transport system that is inhibited by DIDS and SITS. A sodium-independent Pi uptake system of high affinity is also expressed, which is inhibited by sulfate, bicarbonate, and arsenate. The exit of excess Pi is through an exchange with extracellular chloride. Whereas the metabolic effects of the inhibitors, if any, cannot be discarded, kinetic analysis during initial velocity suggests competitive inhibition.
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Affiliation(s)
- Luis Hortells
- Veterinary Faculty, Department of Toxicology, University of Zaragoza, Zaragoza, Spain
| | - Natalia Guillén
- Veterinary Faculty, Department of Toxicology, University of Zaragoza, Zaragoza, Spain
| | - Cecilia Sosa
- Veterinary Faculty, Department of Toxicology, University of Zaragoza, Zaragoza, Spain
| | - Víctor Sorribas
- Veterinary Faculty, Department of Toxicology, University of Zaragoza, Zaragoza, Spain
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17
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Voelkl J, Lang F, Eckardt KU, Amann K, Kuro-O M, Pasch A, Pieske B, Alesutan I. Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia. Cell Mol Life Sci 2019; 76:2077-2091. [PMID: 30887097 PMCID: PMC6502780 DOI: 10.1007/s00018-019-03054-z] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 02/13/2019] [Accepted: 02/21/2019] [Indexed: 02/06/2023]
Abstract
Medial vascular calcification has emerged as a putative key factor contributing to the excessive cardiovascular mortality of patients with chronic kidney disease (CKD). Hyperphosphatemia is considered a decisive determinant of vascular calcification in CKD. A critical role in initiation and progression of vascular calcification during elevated phosphate conditions is attributed to vascular smooth muscle cells (VSMCs), which are able to change their phenotype into osteo-/chondroblasts-like cells. These transdifferentiated VSMCs actively promote calcification in the medial layer of the arteries by producing a local pro-calcifying environment as well as nidus sites for precipitation of calcium and phosphate and growth of calcium phosphate crystals. Elevated extracellular phosphate induces osteo-/chondrogenic transdifferentiation of VSMCs through complex intracellular signaling pathways, which are still incompletely understood. The present review addresses critical intracellular pathways controlling osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification during hyperphosphatemia. Elucidating these pathways holds a significant promise to open novel therapeutic opportunities counteracting the progression of vascular calcification in CKD.
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MESH Headings
- Animals
- Calcium Phosphates/chemistry
- Calcium Phosphates/metabolism
- Cell Transdifferentiation
- Chondrocytes/metabolism
- Chondrocytes/pathology
- Gene Expression Regulation
- Humans
- Hyperphosphatemia/complications
- Hyperphosphatemia/genetics
- Hyperphosphatemia/metabolism
- Hyperphosphatemia/pathology
- Muscle, Smooth, Vascular/metabolism
- Muscle, Smooth, Vascular/pathology
- Myocytes, Smooth Muscle/metabolism
- Myocytes, Smooth Muscle/pathology
- NF-kappa B/genetics
- NF-kappa B/metabolism
- Osteoblasts/metabolism
- Osteoblasts/pathology
- RANK Ligand/genetics
- RANK Ligand/metabolism
- Receptor Activator of Nuclear Factor-kappa B/genetics
- Receptor Activator of Nuclear Factor-kappa B/metabolism
- Renal Insufficiency, Chronic/complications
- Renal Insufficiency, Chronic/genetics
- Renal Insufficiency, Chronic/metabolism
- Renal Insufficiency, Chronic/pathology
- Signal Transduction
- Vascular Calcification/complications
- Vascular Calcification/genetics
- Vascular Calcification/metabolism
- Vascular Calcification/pathology
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Affiliation(s)
- Jakob Voelkl
- Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Altenberger Strasse 69, 4040, Linz, Austria.
- Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburgerplatz 1, 13353, Berlin, Germany.
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347, Berlin, Germany.
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Augustenburgerplatz 1, 13353, Berlin, Germany.
| | - Florian Lang
- Department of Physiology I, Eberhard-Karls University, Wilhelmstr. 56, 72076, Tübingen, Germany
| | - Kai-Uwe Eckardt
- Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, Augustenburgerplatz 1, 13353, Berlin, Germany
| | - Kerstin Amann
- Department of Nephropathology, Universität Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054, Erlangen, Germany
| | - Makoto Kuro-O
- Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan
| | - Andreas Pasch
- Calciscon AG, Aarbergstrasse 5, 2560, Nidau-Biel, Switzerland
| | - Burkert Pieske
- Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburgerplatz 1, 13353, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347, Berlin, Germany
- Berlin Institute of Health (BIH), Anna-Louisa-Karsch Str. 2, 10178, Berlin, Germany
- Department of Internal Medicine and Cardiology, German Heart Center Berlin (DHZB), Augustenburger Platz 1, 13353, Berlin, Germany
| | - Ioana Alesutan
- Institute for Physiology and Pathophysiology, Johannes Kepler University Linz, Altenberger Strasse 69, 4040, Linz, Austria
- Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburgerplatz 1, 13353, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347, Berlin, Germany
- Berlin Institute of Health (BIH), Anna-Louisa-Karsch Str. 2, 10178, Berlin, Germany
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18
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SLC20A2 variants cause dysfunctional phosphate transport activity in endothelial cells induced from Idiopathic Basal Ganglia Calcification patients-derived iPSCs. Biochem Biophys Res Commun 2019; 510:303-308. [DOI: 10.1016/j.bbrc.2019.01.096] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 01/22/2019] [Indexed: 12/16/2022]
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19
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Wang P, Zhou P, Chen W, Peng D. Combined effects of hyperphosphatemia and hyperglycemia on the calcification of cultured human aortic smooth muscle cells. Exp Ther Med 2018; 17:863-868. [PMID: 30651873 DOI: 10.3892/etm.2018.7024] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 11/11/2018] [Indexed: 02/07/2023] Open
Abstract
Vascular calcification (VC) is common in patients with diabetes and/or chronic kidney disease (CKD). It is strongly associated with cardiovascular morbidity and mortality. Hyperphosphatemia caused by CKD induces the transformation of vascular smooth muscle cells (VSMCs) into chondrocytes or osteoblast-like cells. Hyperglycemia may also accelerate VC. However, the exact mechanisms of this remain unclear. The effects of simultaneous hyperphosphatemia and hyperglycemia require investigation. CKD rat models are typically used to study VC, which are far removed from the clinical situations of patients with CKD. The present study cultured human aortic smooth muscle cells (HASMCs) in normal, hyperphosphatemic and/or hyperglycemic conditions for 14 days. Alizarin red staining, calcification content, VSMC differentiation marker gene expression, phenotypic osteoblast gene expression and type III sodium-dependent phosphate cotransporter-1 (Pit-1) protein expression was examined. Hyperphosphatemia and hyperglycemia had combined effects in promoting calcification, phenotypic transition and Pit-1 expression in cultured HASMCs. In the present study, the combined effects of hyperphosphatemia and hyperglycemia on the calcification and phenotypic transition of HASMCs were demonstrated. Hyperphosphatemia combined with hyperglycemia medium should be considered an appropriate experimental model to study VC in diabetic kidney disease (DKD). Pit-1 should be considered as a promising index of VC.
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Affiliation(s)
- Ping Wang
- Nephrology Department, The First People's Hospital of Jingmen, Jingmen, Hubei 448000, P.R. China
| | - Ping Zhou
- Gastrointestinal Surgery Department, The Central Hospital of Hengyang, Hengyang, Hunan 421001, P.R. China
| | - Wangshan Chen
- Nephrology Department, The First People's Hospital of Jingmen, Jingmen, Hubei 448000, P.R. China
| | - Dan Peng
- Neonatology Department, The First People's Hospital of Jingmen, Jingmen, Hubei 448000, P.R. China
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20
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Guillén N, Caldas YA, Levi M, Sorribas V. Identification and expression analysis of type II and type III P i transporters in the opossum kidney cell line. Exp Physiol 2018; 104:149-161. [PMID: 30379374 DOI: 10.1113/ep087217] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 10/30/2018] [Indexed: 12/25/2022]
Abstract
NEW FINDINGS What is the central question of this study? The opossum kidney (OK) cell line is the main in vitro model of proximal tubular Pi transport, but it is incomplete because only the NaPiIIa Pi transporter has been identified. What is the main finding and its importance? We have cloned and characterized the Pi transporters NaPiIIc, PiT1 and PiT2 from OK cells and have analysed the relevance of the four transporters to Pi transport. All four transporters are involved in the upregulated Pi transport of cells incubated using a low-Pi medium, and only PiT1 is not involved in basal transport. ABSTRACT The apical membrane of renal proximal tubular epithelial cells is the main controller of phosphate homeostasis, because it determines the rate of urinary Pi excretion. The opossum kidney (OK) cell line is a good model for studying this function, but only NaPiIIa (NaPi4) has been identified to date as a Pi transporter in this cell line. In this work, we have identified three additional Pi transporters that are present in OK cells: NaPiIIc, PiT1 and PiT2. All three sequences are similar to the corresponding orthologues, but PiT1 is missing the first transmembrane domain. Confluent cells exhibit characteristics of type II Pi transport, which increases with alkalinity and is inhibited by phosphonoformic acid (PFA), and they mainly express NaPiIIa and NaPiIIc, with a low abundance of PiT1 and PiT2. Proliferating cells show a higher expression of PiT1 and PiT2 and a low expression of NaPiIIa and NaPiIIc. Adaptation to a low Pi concentration for 24 h induces the expression of RNA from NaPiIIa and NaPiIIc, which is not prevented by actinomycin D. Small interfering RNA transfections revealed that PiT1 is not necessary for Pi transport, but it is necessary for adaptation to a low Pi , similar to NaPiIIa and PiT2. Our study reveals the complexity of the coordination between the four Pi transporters, the variability of RNA expression according to confluence and the heterogeneous correlation between Pi transport and RNA levels.
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Affiliation(s)
- Natalia Guillén
- Department of Toxicology, University of Zaragoza, Zaragoza, Spain
| | - Yupanqui A Caldas
- Department of Toxicology, University of Zaragoza, Zaragoza, Spain.,Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, CO, USA
| | - Moshe Levi
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, CO, USA.,Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC, USA
| | - Víctor Sorribas
- Department of Toxicology, University of Zaragoza, Zaragoza, Spain
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21
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Potapenko E, Cordeiro CD, Huang G, Storey M, Wittwer C, Dutta AK, Jessen HJ, Starai VJ, Docampo R. 5-Diphosphoinositol pentakisphosphate (5-IP 7) regulates phosphate release from acidocalcisomes and yeast vacuoles. J Biol Chem 2018; 293:19101-19112. [PMID: 30315104 DOI: 10.1074/jbc.ra118.005884] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 10/10/2018] [Indexed: 12/21/2022] Open
Abstract
Acidocalcisomes of Trypanosoma brucei and the acidocalcisome-like vacuoles of Saccharomyces cerevisiae are acidic calcium compartments that store polyphosphate (polyP). Both organelles possess a phosphate-sodium symporter (TbPho91 and Pho91p in T. brucei and yeast, respectively), but the roles of these transporters in growth and orthophosphate (Pi) transport are unclear. We found here that Tbpho91 -/- trypanosomes have a lower growth rate under phosphate starvation and contain larger acidocalcisomes that have increased Pi content. Heterologous expression of TbPHO91 in Xenopus oocytes followed by two-electrode voltage clamp recordings disclosed that myo-inositol polyphosphates stimulate both sodium-dependent depolarization of the oocyte membrane potential and Pi conductance. Deletion of the SPX domain in TbPho91 abolished this stimulation. Inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate generated outward currents in Na+/Pi-loaded giant vacuoles prepared from WT or from TbPHO91-expressing pho91Δ strains but not from the pho91Δ yeast strains or from the pho91Δ strains expressing PHO91 or TbPHO91 with mutated SPX domains. Our results indicate that TbPho91 and Pho91p are responsible for vacuolar Pi and Na+ efflux and that myo-inositol polyphosphates stimulate the Na+/Pi symporter activities through their SPX domains.
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Affiliation(s)
- Evgeniy Potapenko
- From the Center for Tropical and Emerging Global Diseases and.,the Departments of Cellular Biology and
| | - Ciro D Cordeiro
- From the Center for Tropical and Emerging Global Diseases and.,the Departments of Cellular Biology and
| | - Guozhong Huang
- From the Center for Tropical and Emerging Global Diseases and
| | - Melissa Storey
- From the Center for Tropical and Emerging Global Diseases and
| | - Christopher Wittwer
- the Department of Chemistry and Pharmacy, University of Freiburg, 79098 Freiburg, Germany
| | - Amit K Dutta
- the Department of Chemistry and Pharmacy, University of Freiburg, 79098 Freiburg, Germany
| | - Henning J Jessen
- the Department of Chemistry and Pharmacy, University of Freiburg, 79098 Freiburg, Germany
| | - Vincent J Starai
- Microbiology and Infectious Diseases, University of Georgia, Athens, Georgia 30602 and
| | - Roberto Docampo
- From the Center for Tropical and Emerging Global Diseases and .,the Departments of Cellular Biology and
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22
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Gu J, Wang C, Zhang H, Yue H, Hu W, He J, Fu W, Zhang Z. Targeted resequencing of phosphorus metabolism‑related genes in 86 patients with hypophosphatemic rickets/osteomalacia. Int J Mol Med 2018; 42:1603-1614. [PMID: 29901142 DOI: 10.3892/ijmm.2018.3730] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 06/08/2018] [Indexed: 11/05/2022] Open
Abstract
Hypophosphatemic rickets/osteomalacia is characterized by defective renal phosphate reabsorption and abnormal bone mineralization. Hypophosphatemic rickets/osteomalacia consists of inherited and acquired forms, many of which have unknown aetiology. In the present study, next‑generation sequencing‑based resequencing was used on samples from Chinese subjects with hypophosphatemic rickets/osteomalacia, aiming to detect the spectrum of pathogenic genes in these patients. A total of 86 hypophosphatemic rickets/osteomalacia patients (ranging from 3 to 70 years old) were recruited. Patients with tumour‑induced osteomalacia (TIO), renal tubular acidosis, renal osteodystrophy, and adefovir‑induced Fanconi syndrome were excluded. Targeted massively parallel resequencing of 196 candidate genes for hypophosphatemic rickets/osteomalacia was performed in the 86 affected unrelated individuals (cases) and in 100 unrelated healthy controls to identify new genes and mutations in known genes that cause hypophosphatemic rickets/osteomalacia. The results identified seven phosphate‑regulating gene with homologies to endopeptidases on the X chromosome (PHEX) mutations (of which two were novel) and one novel dentin matrix protein 1 (DMP1) mutation in eight patients. Following targeted exome sequencing data analysis, 14 candidate disease‑related gene loci were selected, two of which were of most concern regarding disease severity. Further validation of the present results is warranted, with additional sequencing projects and functional tests. To our knowledge, the present study is the largest cohort of cases with hypophosphatemic rickets/osteomalacia to undergo targeted resequencing. The diagnosis and understanding of the molecular aetiologies of these disorders will be improved by this fast and efficient approach.
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Affiliation(s)
- Jiemei Gu
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Chun Wang
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Hao Zhang
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Hua Yue
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Weiwei Hu
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Jinwei He
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Wenzhen Fu
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
| | - Zhenlin Zhang
- Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, P.R. China
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23
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Quintáns B, Oliveira J, Sobrido MJ. Primary familial brain calcifications. HANDBOOK OF CLINICAL NEUROLOGY 2018; 147:307-317. [PMID: 29325620 DOI: 10.1016/b978-0-444-63233-3.00020-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Primary familial brain calcification (PFBC) is a neurodegenerative disease with characteristic calcium deposits in the basal ganglia and other brain regions. The disease usually presents as a combination of abnormal movements, cognitive and psychiatric manifestations, clinically indistinguishable from other adult-onset neurodegenerative disorders. The differential diagnosis must be established with genetic and nongenetic disorders that can also lead to calcium deposits in encephalic structures. In the past years PFBC causal mutations have been discovered in genes related to calcium phosphate homeostasis (SLC20A2, XPR1) and in genes involved with endothelial function and integrity (PDGFB, PDGFRB). The most frequently mutated gene is SLC20A2, where mutations can affect any domain of the protein. There is no clearcut relationship between the specific mutation/gene, onset age, neuroimaging pattern, and severity of clinical manifestations. The discovery of the genetic basis of PFBC provides not only a diagnostic tool, but also an insight into the pathomechanisms and potential therapeutic trials for this rare disease.
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Affiliation(s)
- Beatriz Quintáns
- Instituto de Investigación Sanitaria (IDIS), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain
| | | | - María-Jesús Sobrido
- Instituto de Investigación Sanitaria (IDIS), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain.
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Abstract
During the process of endochondral bone formation, chondrocytes and osteoblasts mineralize their extracellular matrix (ECM) by promoting the synthesis of hydroxyapatite (HA) seed crystals in the sheltered interior of membrane-limited matrix vesicles (MVs). Several lipid and proteins present in the membrane of the MVs mediate the interactions of MVs with the ECM and regulate the initial mineral deposition and posterior propagation. Among the proteins of MV membranes, ion transporters control the availability of phosphate and calcium needed for initial HA deposition. Phosphatases (orphan phosphatase 1, ectonucleotide pyrophosphatase/phosphodiesterase 1 and tissue-nonspecific alkaline phosphatase) play a crucial role in controlling the inorganic pyrophosphate/inorganic phosphate ratio that allows MV-mediated initiation of mineralization. The lipidic microenvironment can help in the nucleation process of first crystals and also plays a crucial physiological role in the function of MV-associated enzymes and transporters (type III sodium-dependent phosphate transporters, annexins and Na+/K+ ATPase). The whole process is mediated and regulated by the action of several molecules and steps, which make the process complex and highly regulated. Liposomes and proteoliposomes, as models of biological membranes, facilitate the understanding of lipid-protein interactions with emphasis on the properties of physicochemical and biochemical processes. In this review, we discuss the use of proteoliposomes as multiple protein carrier systems intended to mimic the various functions of MVs during the initiation and propagation of mineral growth in the course of biomineralization. We focus on studies applying biophysical tools to characterize the biomimetic models in order to gain an understanding of the importance of lipid-protein and lipid-lipid interfaces throughout the process.
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25
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Abstract
PURPOSE OF REVIEW We give an update on the etiology and potential treatment options of rare inherited monogenic disorders associated with arterial calcification and calcific cardiac valve disease. RECENT FINDINGS Genetic studies of rare inherited syndromes have identified key regulators of ectopic calcification. Based on the pathogenic principles causing the diseases, these can be classified into three groups: (1) disorders of an increased extracellular inorganic phosphate/inorganic pyrophosphate ratio (generalized arterial calcification of infancy, pseudoxanthoma elasticum, arterial calcification and distal joint calcification, progeria, idiopathic basal ganglia calcification, and hyperphosphatemic familial tumoral calcinosis; (2) interferonopathies (Singleton-Merten syndrome); and (3) others, including Keutel syndrome and Gaucher disease type IIIC. Although some of the identified causative mechanisms are not easy to target for treatment, it has become clear that a disturbed serum phosphate/pyrophosphate ratio is a major force triggering arterial and cardiac valve calcification. Further studies will focus on targeting the phosphate/pyrophosphate ratio to effectively prevent and treat these calcific disease phenotypes.
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MESH Headings
- Abnormalities, Multiple/drug therapy
- Abnormalities, Multiple/genetics
- Abnormalities, Multiple/metabolism
- Aortic Diseases/drug therapy
- Aortic Diseases/genetics
- Aortic Diseases/metabolism
- Basal Ganglia Diseases/drug therapy
- Basal Ganglia Diseases/genetics
- Basal Ganglia Diseases/metabolism
- Calcinosis/drug therapy
- Calcinosis/genetics
- Calcinosis/metabolism
- Cartilage Diseases/drug therapy
- Cartilage Diseases/genetics
- Cartilage Diseases/metabolism
- Dental Enamel Hypoplasia/drug therapy
- Dental Enamel Hypoplasia/genetics
- Dental Enamel Hypoplasia/metabolism
- Diphosphates/metabolism
- Enzyme Replacement Therapy
- Gaucher Disease/drug therapy
- Gaucher Disease/genetics
- Gaucher Disease/metabolism
- Hand Deformities, Congenital/drug therapy
- Hand Deformities, Congenital/genetics
- Hand Deformities, Congenital/metabolism
- Humans
- Hyperostosis, Cortical, Congenital/drug therapy
- Hyperostosis, Cortical, Congenital/genetics
- Hyperostosis, Cortical, Congenital/metabolism
- Hyperphosphatemia/drug therapy
- Hyperphosphatemia/genetics
- Hyperphosphatemia/metabolism
- Interferons/metabolism
- Metacarpus/abnormalities
- Metacarpus/metabolism
- Muscular Diseases/drug therapy
- Muscular Diseases/genetics
- Muscular Diseases/metabolism
- Odontodysplasia/drug therapy
- Odontodysplasia/genetics
- Odontodysplasia/metabolism
- Osteoporosis/drug therapy
- Osteoporosis/genetics
- Osteoporosis/metabolism
- Phosphates/metabolism
- Progeria/drug therapy
- Progeria/genetics
- Progeria/metabolism
- Pseudoxanthoma Elasticum/drug therapy
- Pseudoxanthoma Elasticum/genetics
- Pseudoxanthoma Elasticum/metabolism
- Pulmonary Valve Stenosis/drug therapy
- Pulmonary Valve Stenosis/genetics
- Pulmonary Valve Stenosis/metabolism
- Vascular Calcification/drug therapy
- Vascular Calcification/genetics
- Vascular Calcification/metabolism
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Affiliation(s)
- Yvonne Nitschke
- Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany
| | - Frank Rutsch
- Department of General Pediatrics, Münster University Children's Hospital, Albert-Schweitzer-Campus 1, D-48149, Münster, Germany.
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26
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Ouyang L, Zhang K, Chen J, Wang J, Huang H. Roles of platelet-derived growth factor in vascular calcification. J Cell Physiol 2017; 233:2804-2814. [PMID: 28467642 DOI: 10.1002/jcp.25985] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 05/02/2017] [Indexed: 02/06/2023]
Abstract
Vascular calcification (VC) is prevalent in aging, and patients with hypertension, chronic kidney disease (CKD), or diabetes. VC is regarded as an active and complex process that involves multiple mechanisms responsible for calcium deposition in vessel wall. In light of the complicated pathogenesis of VC, effective therapy for ameliorating VC is limited. Thus, it is urgent to explore the potential mechanisms and find new targets for the therapy of VC. Platelet-derived growth factor (PDGF), a potent mitogen, and chemoattractant have been found to disturb the vascular homeostasis by inducing inflammation, oxidative stress, and phenotype transition, all of which accelerate the process of VC. The aim of current review is to present a review about the roles of PDGF in affecting VC and to establish a potential target for treating VC.
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Affiliation(s)
- Liu Ouyang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, Guangdong Province, China
| | - Kun Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, Guangdong Province, China
| | - Jie Chen
- Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, Guangdong Province, China.,Department of Radiation Oncology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jingfeng Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, Guangdong Province, China
| | - Hui Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Province Key Laboratory of Arrhythmia and Electrophysiology, Guangzhou, Guangdong Province, China
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27
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Batla A, Tai XY, Schottlaender L, Erro R, Balint B, Bhatia KP. Deconstructing Fahr's disease/syndrome of brain calcification in the era of new genes. Parkinsonism Relat Disord 2016; 37:1-10. [PMID: 28162874 DOI: 10.1016/j.parkreldis.2016.12.024] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 12/08/2016] [Accepted: 12/26/2016] [Indexed: 12/23/2022]
Abstract
INTRODUCTION There are now a number genes, known to be associated with familial primary brain calcification (PFBC), causing the so called 'Fahr's' disease or syndrome. These are SCL20A2, PDGFB, PDGFRB and XPR1. In this systematic review, we analyse the clinical and radiological features reported in genetically confirmed cases with PFBC. We have additionally reviewed pseudohypoparathyroidism which is a close differential diagnosis of PFBC in clinical presentation and is also genetically determined. METHODS We performed a Medline search, from 1st Jan 2012 through to 7th November 2016, for publications with confirmed mutations of SCL20A2, PDGFB, PDGFRB, and XPR1 and found twenty papers with 137 eligible cases. A second search was done for publications of cases with Pseudohypoparathyroidism or pseudopseudohypoparathyroidism, and found 18 publications with 20 eligible cases. RESULTS SLC20A2 was the most common gene involved with 75 out of 137 cases included with PFBC (55%) followed by PDGFB (31%) and PDGFRB (11%). Statistically significant correlation was found between the presence of parkinsonism with SLC20A2 mutations, headache in PDGFB and generalised tonic-clonic seizures in patients with pseudohypoparathyroidism. CONCLUSION We combine statistical analysis and clinical inference to suggest a diagnostic algorithm based on the observations in this study to help with investigation of a patient with neurological features and brain calcification.
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Affiliation(s)
- Amit Batla
- UCL Institute of Neurology, Queen Square, London, UK
| | - Xin You Tai
- UCL Institute of Neurology, Queen Square, London, UK
| | - Lucia Schottlaender
- Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, WC1N 3BG, UK
| | - Robert Erro
- Dipartimento di Scienze Neurologiche e del Movimento, Università di Verona, Verona, Italy
| | - Bettina Balint
- Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany; Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, UK
| | - Kailash P Bhatia
- Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, UK.
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28
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Han C, Alkhater R, Froukh T, Minassian AG, Galati M, Liu RH, Fotouhi M, Sommerfeld J, Alfrook AJ, Marshall C, Walker S, Bauer P, Scherer SW, Riess O, Buchert R, Minassian BA, McPherson PS. Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A. Am J Hum Genet 2016; 99:1359-1367. [PMID: 27866705 DOI: 10.1016/j.ajhg.2016.10.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 10/10/2016] [Indexed: 12/21/2022] Open
Abstract
Epileptic encephalopathies are a catastrophic group of epilepsies characterized by refractory seizures and cognitive arrest, often resulting from abnormal brain development. Here, we have identified an epileptic encephalopathy additionally featuring cerebral calcifications and coarse facial features caused by recessive loss-of-function mutations in DENND5A. DENND5A contains a DENN domain, an evolutionarily ancient enzymatic module conferring guanine nucleotide exchange factor (GEF) activity to multiple proteins serving as GEFs for Rabs, which are key regulators of membrane trafficking. DENND5A is detected predominantly in neuronal tissues, and its highest levels occur during development. Knockdown of DENND5A leads to striking alterations in neuronal development. Mechanistically, these changes appear to result from upregulation of neurotrophin receptors, leading to enhanced downstream signaling. Thus, we have identified a link between a DENN domain protein and neuronal development, dysfunction of which is responsible for a form of epileptic encephalopathy.
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Affiliation(s)
- Chanshuai Han
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada
| | - Reem Alkhater
- Johns Hopkins Aramco Healthcare, Dhahran 34465, Saudi Arabia
| | - Tawfiq Froukh
- Department of Biotechnology and Genetic Engineering, Faculty of Science, Philadelphia University, Amman 11118, Jordan
| | - Arakel G Minassian
- Centre for Applied Genomics, Genetics, and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Melissa Galati
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada
| | - Rui Han Liu
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada
| | - Maryam Fotouhi
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada
| | - Julia Sommerfeld
- Institute of Medical Genetics and Applied Genomics, Rare Disease Center, University of Tübingen, Tübingen 72076, Germany
| | | | - Christian Marshall
- Centre for Applied Genomics, Genetics, and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Susan Walker
- Centre for Applied Genomics, Genetics, and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Peter Bauer
- Institute of Medical Genetics and Applied Genomics, Rare Disease Center, University of Tübingen, Tübingen 72076, Germany
| | - Stephen W Scherer
- Centre for Applied Genomics, Genetics, and Genome Biology, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, ON M5G 0A4, Canada
| | - Olaf Riess
- Institute of Medical Genetics and Applied Genomics, Rare Disease Center, University of Tübingen, Tübingen 72076, Germany
| | - Rebecca Buchert
- Institute of Medical Genetics and Applied Genomics, Rare Disease Center, University of Tübingen, Tübingen 72076, Germany
| | - Berge A Minassian
- Program in Genetics and Genome Biology, Department of Pediatrics (Neurology), Hospital for Sick Children and University of Toronto, Toronto, ON M5G 0A4, Canada
| | - Peter S McPherson
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada.
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TWEAK favors phosphate-induced calcification of vascular smooth muscle cells through canonical and non-canonical activation of NFκB. Cell Death Dis 2016; 7:e2305. [PMID: 27441657 PMCID: PMC4973358 DOI: 10.1038/cddis.2016.220] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 06/10/2016] [Accepted: 06/14/2016] [Indexed: 12/24/2022]
Abstract
Vascular calcification (VC) is associated with increased cardiovascular mortality in aging, chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM) and atherosclerosis. TNF-like weak inducer of apoptosis (TWEAK) recently emerged as a new biomarker for the diagnosis and prognosis of cardiovascular diseases. TWEAK binding to its functional receptor Fn14 was reported to promote several steps of atherosclerotic plaque progression. However, no information is currently available on the role of TWEAK/Fn14 on the development of medial calcification, which is highly prevalent in aging, CKD and T2DM. This study explored the involvement of TWEAK in human vascular smooth muscle cells (h-VSMCs) calcification in vitro. We report that TWEAK binding to Fn14 promotes inorganic phosphate-induced h-VSMCs calcification, favors h-VSMCs osteogenic transition, decreasing acta2 and myh11 and increasing bmp2 mRNA and tissue non-specific alkaline phosphatase (TNAP), and increases MMP9 activity. Blockade of the canonical NFκB pathway reduced by 80% TWEAK pro-calcific properties and decreased osteogenic transition, TNAP and MMP9 activity. Blockade of non-canonical NFκB signaling by a siRNA targeting RelB reduced by 20% TWEAK pro-calcific effects and decreased TWEAK-induced loss of h-VSMCs contractile phenotype and MMP9 activity, without modulating bmp2 mRNA or TNAP activity. Inhibition of ERK1/2 activation by a MAPK kinase inhibitor did not influence TWEAK pro-calcific properties. Our results suggest that TWEAK/Fn14 directly favors inorganic phosphate-induced h-VSMCs calcification by activation of both canonical and non-canonical NFκB pathways. Given the availability of neutralizing anti-TWEAK strategies, our study sheds light on the TWEAK/Fn14 axis as a novel therapeutic target in the prevention of VC.
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30
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New perspectives on rare connective tissue calcifying diseases. Curr Opin Pharmacol 2016; 28:14-23. [DOI: 10.1016/j.coph.2016.02.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Revised: 01/27/2016] [Accepted: 02/08/2016] [Indexed: 12/27/2022]
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31
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Cell compatibility of a maghemite/polymer biomedical nanoplatform. Toxicol In Vitro 2015; 29:962-75. [DOI: 10.1016/j.tiv.2015.04.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Revised: 04/06/2015] [Accepted: 04/08/2015] [Indexed: 11/19/2022]
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32
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Betsholtz C, Keller A. PDGF, pericytes and the pathogenesis of idiopathic basal ganglia calcification (IBGC). Brain Pathol 2015; 24:387-95. [PMID: 24946076 DOI: 10.1111/bpa.12158] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 05/13/2014] [Indexed: 01/09/2023] Open
Abstract
Platelet-derived growth factors (PDGFs) are important mitogens for various types of mesenchymal cells, and as such, they exert critical functions during organogenesis in mammalian embryonic and early postnatal development. Increased or ectopic PDGF activity may also cause or contribute to diseases such as cancer and tissue fibrosis. Until recently, no loss-of-function (LOF) mutations in PDGF or PDGF receptor genes were reported as causally linked to a human disease. This changed in 2013 when reports appeared on presumed LOF mutations in the genes encoding PDGF-B and its receptor PDGF receptor-beta (PDGF-Rβ) in familial idiopathic basal ganglia calcification (IBGC), a brain disease characterized by anatomically localized calcifications in or near the blood microvessels. Here, we review PDGF-B and PDGF-Rβ biology with special reference to their functions in brain-blood vessel development, pericyte recruitment and the regulation of the blood-brain barrier. We also discuss various scenarios for IBGC pathogenesis suggested by observations in patients and genetically engineered animal models of the disease.
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Affiliation(s)
- Christer Betsholtz
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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33
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Vilder EYGD, Vanakker OM. From variome to phenome: Pathogenesis, diagnosis and management of ectopic mineralization disorders. World J Clin Cases 2015; 3:556-574. [PMID: 26244149 PMCID: PMC4517332 DOI: 10.12998/wjcc.v3.i7.556] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2014] [Revised: 02/27/2015] [Accepted: 05/18/2015] [Indexed: 02/05/2023] Open
Abstract
Ectopic mineralization - inappropriate biomineralization in soft tissues - is a frequent finding in physiological aging processes and several common disorders, which can be associated with significant morbidity and mortality. Further, pathologic mineralization is seen in several rare genetic disorders, which often present life-threatening phenotypes. These disorders are classified based on the mechanisms through which the mineralization occurs: metastatic or dystrophic calcification or ectopic ossification. Underlying mechanisms have been extensively studied, which resulted in several hypotheses regarding the etiology of mineralization in the extracellular matrix of soft tissue. These hypotheses include intracellular and extracellular mechanisms, such as the formation of matrix vesicles, aberrant osteogenic and chondrogenic signaling, apoptosis and oxidative stress. Though coherence between the different findings is not always clear, current insights have led to improvement of the diagnosis and management of ectopic mineralization patients, thus translating pathogenetic knowledge (variome) to the phenotype (phenome). In this review, we will focus on the clinical presentation, pathogenesis and management of primary genetic soft tissue mineralization disorders. As examples of dystrophic calcification disorders Pseudoxanthoma elasticum, Generalized arterial calcification of infancy, Keutel syndrome, Idiopathic basal ganglia calcification and Arterial calcification due to CD73 (NT5E) deficiency will be discussed. Hyperphosphatemic familial tumoral calcinosis will be reviewed as an example of mineralization disorders caused by metastatic calcification.
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Bessueille L, Magne D. Inflammation: a culprit for vascular calcification in atherosclerosis and diabetes. Cell Mol Life Sci 2015; 72:2475-89. [PMID: 25746430 PMCID: PMC11113748 DOI: 10.1007/s00018-015-1876-4] [Citation(s) in RCA: 122] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 02/06/2015] [Accepted: 02/26/2015] [Indexed: 12/16/2022]
Abstract
It is today acknowledged that aging is associated with a low-grade chronic inflammatory status, and that inflammation exacerbates age-related diseases such as osteoporosis, Alzheimer's disease, atherosclerosis and type 2 diabetes mellitus (T2DM). Vascular calcification is a complication that also occurs during aging, in particular in association with atherosclerosis and T2DM. Recent studies provided compelling evidence that vascular calcification is associated with inflammatory status and is enhanced by inflammatory cytokines. In the present review, we propose on one hand to highlight the most important and recent findings on the cellular and molecular mechanisms of vascular inflammation in atherosclerosis and T2DM. On the other hand, we will present the effects of inflammatory mediators on the trans-differentiation of vascular smooth muscle cell and on the deposition of crystals. Since vascular calcification significantly impacts morbidity and mortality in affected individuals, a better understanding of its induction and development will pave the way to develop new therapeutic strategies.
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Affiliation(s)
- L. Bessueille
- University of Lyon, ICBMS UMR CNRS 5246, Bâtiment Raulin, 43 Bd du 11 novembre 1918, 69622 Villeurbanne Cedex, France
| | - D. Magne
- University of Lyon, ICBMS UMR CNRS 5246, Bâtiment Raulin, 43 Bd du 11 novembre 1918, 69622 Villeurbanne Cedex, France
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Taglia I, Bonifati V, Mignarri A, Dotti MT, Federico A. Primary familial brain calcification: update on molecular genetics. Neurol Sci 2015; 36:787-94. [PMID: 25686613 DOI: 10.1007/s10072-015-2110-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 02/10/2015] [Indexed: 12/17/2022]
Abstract
Primary familial brain calcification is a neuropsychiatric disorder with calcium deposits in the brain, especially in basal ganglia, cerebellum and subcortical white matter. The disease is characterized by a clinical heterogeneity, with a various combination of symptoms that include movement disorders and psychiatric disturbances; asymptomatic patients have been also reported. To date, three causative genes have been found: SLC20A2, PDGFRB and PDGFB. SLC20A2 gene codes for the 'sodium-dependent phosphate transporter 2' (PiT-2), a cell membrane transporters of inorganic phosphate, involved in Pi uptake by cells and maintenance of Pi body levels. Over 40 pathogenic variants of SLC20A2 have been reported, affecting the regulation of Pi homeostasis. It was hypothesized that SLC20A2 mutations cause brain calcification most likely through haploinsufficiency. PDGFRB encodes for the platelet-derived growth factor receptor-β (PDGFRβ), a cell-surface tyrosine-kinase (RTK) receptor that regulates cell proliferation, migration, survival and differentiation. PDGFB encodes for the 'platelet-derived growth factor beta' (PDGFβ), the ligand of PDGFRβ. The loss of function of PDGFRβ and PDGFβ could lead to the impairment of the pericytes function and blood brain barrier integrity, causing vascular and perivascular calcium accumulation. SLC20A2 accounts for about 40 % of familial form and 14 % of sporadic cases, while PDGFRB and PDGFB mutations are likely rare. However, approximately 50 % of patients are not genetically defined and there should be at least another causative gene.
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Affiliation(s)
- Ilaria Taglia
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100, Siena, Italy,
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36
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Lang F, Ritz E, Alesutan I, Voelkl J. Impact of aldosterone on osteoinductive signaling and vascular calcification. Nephron Clin Pract 2014; 128:40-5. [PMID: 25377380 DOI: 10.1159/000368268] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Vascular calcification is frequently found already in early stages of chronic kidney disease (CKD) patients and is associated with high cardiovascular risk. The process of vascular calcification is not considered a passive phenomenon but involves, at least in part, phenotypical transformation of vascular smooth muscle cells (VSMCs). Following exposure to excessive extracellular phosphate concentrations, VSMCs undergo a reprogramming into osteo-/chondroblast-like cells. Such 'vascular osteoinduction' is characterized by expression of osteogenic transcription factors and triggered by increased phosphate concentrations. A key role in this process is assigned to cellular phosphate transporters, most notably the type III sodium-dependent phosphate transporter Pit1. Pit1 expression is stimulated by mineralocorticoid receptor activation. Therefore, aldosterone participates in the phenotypical transformation of VSMCs. In preclinical models, aldosterone antagonism reduces vascular osteoinduction. Patients with CKD suffer from hyperphosphatemia predisposing to vascular osteogenic transformation, potentially further fostered by concomitant hyperaldosteronism. Clearly, additional research is required to define the role of aldosterone in the regulation of osteogenic signaling and the consecutive vascular calcification in CKD, but more generally also other diseases associated with excessive vascular calcification and even in individuals without overt disease.
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Affiliation(s)
- Florian Lang
- Department of Physiology, University of Tübingen, Tübingen, Germany
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Myakala K, Motta S, Murer H, Wagner CA, Koesters R, Biber J, Hernando N. Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice. Am J Physiol Renal Physiol 2014; 306:F833-43. [PMID: 24553430 DOI: 10.1152/ajprenal.00133.2013] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The proximal renal epithelia express three different Na-dependent inorganic phosphate (Pi) cotransporters: NaPi-IIa/SLC34A1, NaPi-IIc/SLC34A3, and PiT2/SLC20A2. Constitutive mouse knockout models of NaPi-IIa and NaPi-IIc suggested that NaPi-IIa mediates the bulk of renal reabsorption of Pi whereas the contribution of NaPi-IIc to this process is minor and probably restricted to young mice. However, many reports indicate that mutations of NaPi-IIc in humans lead to hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report the generation of a kidney-specific and inducible NaPi-IIc-deficient mouse model based on the loxP-Cre system. We found that the specific removal of the cotransporter from the kidneys of young mice does not impair the capacity of the renal epithelia to transport Pi. Moreover, the levels of Pi in plasma and urine as well as the circulating levels of parathyroid hormone, FGF-23, and vitamin D3 remained unchanged. These findings are in agreement with the data obtained with the constitutive knockout model and suggest that, under steady-state conditions of normal dietary Pi, NaPi-IIc is not an essential Na-Pi cotransporter in murine kidneys. However, and unlike the constitutive mutants, the kidney-specific depletion of NaPi-IIc does not result in alteration of the homeostasis of calcium. This suggests that the calcium-related phenotype observed in constitutive knockout mice may not be related to inactivation of the cotransporter in kidney.
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Affiliation(s)
- Komuraiah Myakala
- Institute of Physiology and Zurich Center for Integrative Human Physiology. Univ. of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
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38
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Martín-Pardillos A, Sosa C, Millán Á, Sorribas V. Effect of water fluoridation on the development of medial vascular calcification in uremic rats. Toxicology 2014; 318:40-50. [PMID: 24561004 DOI: 10.1016/j.tox.2014.01.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/08/2014] [Accepted: 01/26/2014] [Indexed: 10/25/2022]
Abstract
Public water fluoridation is a common policy for improving dental health. Fluoride replaces the hydroxyls of hydroxyapatite, thereby improving the strength of tooth enamel, but this process can also occur in other active calcifications. This paper studies the effects of water fluoridation during the course of vascular calcification in renal disease. The effect of fluoride was studied in vitro and in vivo. Rat aortic smooth muscle cells were calcified with 2mM Pi for 5 days. Fluoride concentrations of 5-10 μM--similar to those found in people who drink fluoridated water--partially prevented calcification, death, and osteogene expression in vitro. The anticalcifying mechanism was independent of cell activity, matrix Gla protein, and fetuin A expressions, and it exhibited an IC50 of 8.7 μM fluoride. In vivo, however, fluoridation of drinking water at 1.5mg/L (concentration recommended by the WHO) and 15 mg/L dramatically increased the incipient aortic calcification observed in rats with experimental chronic kidney disease (CKD, 5/6-nephrectomy), fed a Pi-rich fodder (1.2% Pi). Fluoride further declined the remaining renal function of the CKD animals, an effect that most likely overwhelmed the positive effect of fluoride on calcification in vitro. Ultrastructural analysis revealed that fluoride did not modify the Ca/P atomic ratio, but it was incorporated into the lattice of in vivo deposits. Fluoride also converted the crystallization pattern from plate to rode-like structures. In conclusion, while fluoride prevents calcification in vitro, the WHO's recommended concentrations in drinking water become nephrotoxic to CKD rats, thereby aggravating renal disease and making media vascular calcification significant.
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Affiliation(s)
- Ana Martín-Pardillos
- Department of Toxicology, University of Zaragoza, Veterinary Faculty, Calle Miguel Servet 177, E50013 Zaragoza, Spain.
| | - Cecilia Sosa
- Department of Toxicology, University of Zaragoza, Veterinary Faculty, Calle Miguel Servet 177, E50013 Zaragoza, Spain.
| | - Ángel Millán
- Instituto de Ciencia de Materiales de Aragón, Consejo Superior de Investigaciones Científicas-University of Zaragoza, Calle Pedro Cerbuna, s/n. E50009 Zaragoza, Spain.
| | - Víctor Sorribas
- Department of Toxicology, University of Zaragoza, Veterinary Faculty, Calle Miguel Servet 177, E50013 Zaragoza, Spain.
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Shobeiri N, Adams MA, Holden RM. Phosphate: an old bone molecule but new cardiovascular risk factor. Br J Clin Pharmacol 2014; 77:39-54. [PMID: 23506202 PMCID: PMC3895346 DOI: 10.1111/bcp.12117] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Accepted: 02/21/2013] [Indexed: 12/24/2022] Open
Abstract
Phosphate handling in the body is complex and involves hormones produced by the bone, the parathyroid gland and the kidneys. Phosphate is mostly found in hydroxyapatite. however recent evidence suggests that phosphate is also a signalling molecule associated with bone formation. Phosphate balance requires careful regulation of gut and kidney phosphate transporters, SLC34 transporter family, but phosphate signalling in osteoblasts and vascular smooth muscle cells is likely mediated by the SLC20 transporter family (PiT1 and PiT2). If not properly regulated, phosphate imblanace could lead to mineral disorders as well as vascular calcification. In chronic kidney disease-mineral bone disorder, hyperphosphataemia has been consistently associated with extra-osseous calcification and cardiovascular disease. This review focuses on the physiological mechanisms involved in phosphate balance and cell signalling (i.e. osteoblasts and vascular smooth muscle cells) as well as pathological consequences of hyperphosphataemia. Finally, conventional as well as new and experimental therapeutics in the treatment of hyperphosphataemia are explored.
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Affiliation(s)
- Navid Shobeiri
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
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40
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Crouthamel MH, Lau WL, Leaf EM, Chavkin NW, Wallingford MC, Peterson DF, Li X, Liu Y, Chin MT, Levi M, Giachelli CM. Sodium-dependent phosphate cotransporters and phosphate-induced calcification of vascular smooth muscle cells: redundant roles for PiT-1 and PiT-2. Arterioscler Thromb Vasc Biol 2013; 33:2625-32. [PMID: 23968976 DOI: 10.1161/atvbaha.113.302249] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Elevated serum phosphate has emerged as a major risk factor for vascular calcification. The sodium-dependent phosphate cotransporter, PiT-1, was previously shown to be required for phosphate-induced osteogenic differentiation and calcification of cultured human vascular smooth muscle cells (VSMCs), but its importance in vascular calcification in vivo and the potential role of its homologue, PiT-2, have not been determined. We investigated the in vivo requirement for PiT-1 in vascular calcification using a mouse model of chronic kidney disease and the potential compensatory role of PiT-2 using in vitro knockdown and overexpression strategies. APPROACH AND RESULTS Mice with targeted deletion of PiT-1 in VSMCs were generated (PiT-1(Δsm)). PiT-1 mRNA levels were undetectable, whereas PiT-2 mRNA levels were increased 2-fold in the vascular aortic media of PiT-1(Δsm) compared with PiT-1(flox/flox) control. When arterial medial calcification was induced in PiT-1(Δsm) and PiT-1(flox/flox) by chronic kidney disease followed by dietary phosphate loading, the degree of aortic calcification was not different between genotypes, suggesting compensation by PiT-2. Consistent with this possibility, VSMCs isolated from PiT-1(Δsm) mice had no PiT-1 mRNA expression, increased PiT-2 mRNA levels, and no difference in sodium-dependent phosphate uptake or phosphate-induced matrix calcification compared with PiT-1(flox/flox) VSMCs. Knockdown of PiT-2 decreased phosphate uptake and phosphate-induced calcification of PiT-1(Δsm) VSMCs. Furthermore, overexpression of PiT-2 restored these parameters in human PiT-1-deficient VSMCs. CONCLUSIONS PiT-2 can mediate phosphate uptake and calcification of VSMCs in the absence of PiT-1. Mechanistically, PiT-1 and PiT-2 seem to serve redundant roles in phosphate-induced calcification of VSMCs.
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Affiliation(s)
- Matthew H Crouthamel
- From the Departments of Bioengineering (M.H.C., E.M.L., N.W.C., M.C.W., D.F.P., X.L., C.M.G.), Nephrology (W.L.L.), and Cardiology (Y.L., M.T.C.), University of Washington, Seattle; and Department of Medicine, University of Colorado, Denver (M.L.)
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41
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Lang F, Ritz E, Voelkl J, Alesutan I. Vascular calcification--is aldosterone a culprit? Nephrol Dial Transplant 2013; 28:1080-4. [PMID: 23476041 DOI: 10.1093/ndt/gft041] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
In chronic kidney disease (CKD), increased plasma phosphate concentrations cause vascular calcification which substantially contribute to cardiovascular events and increased mortality of CKD patients. Similar to CKD patients, klotho-hypomorphic mice (kl/kl) also suffer from excessive vascular calcification leading to growth deficit, rapid ageing and early death. The hyperphosphataemia of kl/kl mice results from excessive formation of 1,25(OH)2D3 causing excessive intestinal phosphate absorption. Further, kl/kl mice further suffer from hyperaldosteronism and compelling evidence points to an active role of mineralocorticoids in triggering osteoinductive programmes in the vasculature, thus further contributing to the development of vascular calcification. Conversely, in kl/kl mice, the mineralocorticoid receptor antagonist spironolactone decreased the vascular osteoinductive processes and reversed the excessive expression of osteogenic programmes, i.e. type III sodium-dependent phosphate transporter Pit1, tumour necrosis factor α (Tnfα), transcription factors Msx2, Cbfa1/Runx2 and osterix as well as alkaline phosphatase (Alp). In human aortic vascular smooth muscle cells (HAoSMCs), aldosterone alone similarly triggered an 'osteogenic' programme, thus increasing PIT1, TNFα, MSX2, CBFA1/RUNX2 and ALP expression as well as ALP activity and potentiated the effects of phosphate treatment. These effects were again reversed by spironolactone and in addition by PIT1 silencing. The above observations reveal that the severe vascular calcification is not only the result of high plasma phosphate concentrations, but also promoted by aldosterone-driven osteoinductive signalling. Future studies in CKD patients will be required to define the role of aldosterone and the potential impact of its inhibition by spironolactone in the pathophysiology of vascular calcification.
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Affiliation(s)
- Florian Lang
- Department of Physiology, University of Tübingen, Tübingen, Germany.
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42
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Inorganic phosphate modulates the expression of the NaPi-2a transporter in the trans-Golgi network and the interaction with PIST in the proximal tubule. BIOMED RESEARCH INTERNATIONAL 2013; 2013:513932. [PMID: 23509734 PMCID: PMC3586470 DOI: 10.1155/2013/513932] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 01/08/2013] [Indexed: 11/23/2022]
Abstract
Inorganic phosphate (Pi) homeostasis is maintained by the tight regulation of renal Pi excretion versus reabsorption rates that are in turn modulated by adjusting the number of Pi transporters (mainly NaPi-2a) in the proximal tubules. In response to some hormones and a high dietary Pi content, NaPi-2a is endocytosed and degraded in the lysosomes; however, we show here that some NaPi-2a molecules are targeted to the trans-Golgi network (TGN) during the endocytosis. In the TGN, NaPi-2a interacts with PIST (PDZ-domain protein interacting specifically with TC10), a TGN-resident PDZ-domain-containing protein. The extension of the interaction is proportional to the expression of NaPi-2a in the TGN, and, consistent with that, it is increased with a high Pi diet. When overexpressed in opossum kidney (OK) cells, PIST retains NaPi-2a in the TGN and inhibits Na-dependent Pi transport. Overexpression of PIST also prevents the adaptation of OK cells to a low Pi culture medium. Our data supports the view that NaPi-2a is subjected to retrograde trafficking from the plasma membrane to the TGN using one of the machineries involved in endosomal transport and explains the reported expression of NaPi-2a in the TGN.
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43
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Voelkl J, Alesutan I, Leibrock CB, Quintanilla-Martinez L, Kuhn V, Feger M, Mia S, Ahmed MSE, Rosenblatt KP, Kuro-O M, Lang F. Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice. J Clin Invest 2013; 123:812-22. [PMID: 23298834 DOI: 10.1172/jci64093] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Accepted: 11/01/2012] [Indexed: 12/21/2022] Open
Abstract
Klotho is a potent regulator of 1,25-hydroxyvitamin D3 [1,25(OH)2D3] formation and calcium-phosphate metabolism. Klotho-hypomorphic mice (kl/kl mice) suffer from severe growth deficits, rapid aging, hyperphosphatemia, hyperaldosteronism, and extensive vascular and soft tissue calcification. Sequelae of klotho deficiency are similar to those of end-stage renal disease. We show here that the mineralocorticoid receptor antagonist spironolactone reduced vascular and soft tissue calcification and increased the life span of kl/kl mice, without significant effects on 1,25(OH)2D3, FGF23, calcium, and phosphate plasma concentrations. Spironolactone also reduced the expression of osteoinductive Pit1 and Tnfa mRNA, osteogenic transcription factors, and alkaline phosphatase (Alpl) in calcified tissues of kl/kl mice. In human aortic smooth muscle cells (HAoSMCs), aldosterone dose-dependently increased PIT1 mRNA expression, an effect paralleled by increased expression of osteogenic transcription factors and enhanced ALP activity. The effects of aldosterone were reversed by both spironolactone treatment and PIT1 silencing and were mitigated by FGF23 cotreatment in HAoSMCs. In conclusion, aldosterone contributes to vascular and soft tissue calcification, an effect due, at least in part, to stimulation of spironolactone-sensitive, PIT1-dependent osteoinductive signaling.
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Affiliation(s)
- Jakob Voelkl
- Department of Physiology, University of Tübingen, Tübingen, Germany
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44
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Martín-Pardillos A, Sosa C, Sorribas V. Arsenic Increases Pi-Mediated Vascular Calcification and Induces Premature Senescence in Vascular Smooth Muscle Cells. Toxicol Sci 2012; 131:641-53. [DOI: 10.1093/toxsci/kfs313] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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Abstract
Bone never forms without vascular interactions. This simple statement of fact does not adequately reflect the physiological and pharmacological implications of the relationship. The vasculature is the conduit for nutrient exchange between bone and the rest of the body. The vasculature provides the sustentacular niche for development of osteoblast progenitors and is the conduit for egress of bone marrow cell products arising, in turn, from the osteoblast-dependent haematopoietic niche. Importantly, the second most calcified structure in humans after the skeleton is the vasculature. Once considered a passive process of dead and dying cells, vascular calcification has emerged as an actively regulated form of tissue biomineralization. Skeletal morphogens and osteochondrogenic transcription factors are expressed by cells within the vessel wall, which regulates the deposition of vascular calcium. Osteotropic hormones, including parathyroid hormone, regulate both vascular and skeletal mineralization. Cellular, endocrine and metabolic signals that flow bidirectionally between the vasculature and bone are necessary for both bone health and vascular health. Dysmetabolic states including diabetes mellitus, uraemia and hyperlipidaemia perturb the bone-vascular axis, giving rise to devastating vascular and skeletal disease. A detailed understanding of bone-vascular interactions is necessary to address the unmet clinical needs of an increasingly aged and dysmetabolic population.
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Affiliation(s)
- Bithika Thompson
- Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St Louis, MO 63110, USA
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Lai CF, Shao JS, Behrmann A, Krchma K, Cheng SL, Towler DA. TNFR1-activated reactive oxidative species signals up-regulate osteogenic Msx2 programs in aortic myofibroblasts. Endocrinology 2012; 153:3897-910. [PMID: 22685265 PMCID: PMC3404358 DOI: 10.1210/en.2012-1216] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Accepted: 05/11/2012] [Indexed: 12/25/2022]
Abstract
In LDLR(-/-) mice fed high-fat diabetogenic diets, osteogenic gene-regulatory programs are ectopically activated in vascular myofibroblasts and smooth muscle cells that promote arteriosclerotic calcium deposition. Msx2-Wnt signaling pathways previously identified as important for craniofacial skeletal development are induced in the vasculature by TNF, a prototypic cytokine mediator of the low-grade systemic inflammation of diabesity. To better understand this biology, we studied TNF actions on Msx2 in aortic myofibroblasts. TNF up-regulated Msx2 mRNA 4-fold within 3 h but did not regulate Msx1. Although IL-1β could also induce Msx2 expression, TNF-related apoptosis inducing ligand, receptor activator of nuclear factor-κB ligand, and IL-6 were inactive. Inhibition of nicotinamide adenine dinucleotide phosphate oxidase (Nox) activity and genetically induced Nox deficiency (p47phox(-/-)) reduced Msx2 induction, indicating contributions of reactive oxygen species (ROS) and redox signaling. Consistent with this, rotenone, an antagonist of mitochondrial complex I, inhibited TNF induction of Msx2 and Nox2, whereas pyruvate, an anapleurotic mitochondrial metabolic substrate, enhanced induction. Moreover, the glutathione peroxidase-mimetic ebselen abrogated this TNF response. Treatment of aortic myofibroblasts with hydrogen peroxide up-regulated Msx2 mRNA, promoter activity, and DNA-protein interactions. In vivo, SM22-TNF transgenic mice exhibit increased aortic Msx2 with no change in Msx1. Dosing SM22-TNF mice with either 20 ng/g Nox1 + 20 ng/g Nox2 antisense oligonucleotides or low-dose rotenone reduced arterial Msx2 expression. Aortic myofibroblasts from TNFR1(-/-) mice expressed levels of Msx2 that were 5% that of wild-type and were not inducible by TNF. Wnt7b and active β-catenin levels were also reduced. By contrast, TNF-inducible Msx2 expression was not reduced in TNFR2(-/-) cells. Finally, when cultured under mineralizing conditions, TNFR1(-/-) aortic myofibroblasts exhibited reduced calcification compared with wild-type and TNFR2(-/-) cells. Thus, ROS metabolism contributes to TNF induction of Msx2 and procalcific responses in myofibroblasts via TNFR1. Strategies that reduce vascular Nox- or mitochondrially activated ROS signals may prove useful in mitigating arteriosclerotic calcification.
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Affiliation(s)
- Chung-Fang Lai
- Department of Internal Medicine, Washington University in St. Louis, Missouri 63110, USA
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47
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Guerrero F, Montes de Oca A, Aguilera-Tejero E, Zafra R, Rodriguez M, Lopez I. The effect of vitamin D derivatives on vascular calcification associated with inflammation. Nephrol Dial Transplant 2011; 27:2206-12. [DOI: 10.1093/ndt/gfr555] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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48
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49
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Miyamoto KI, Haito-Sugino S, Kuwahara S, Ohi A, Nomura K, Ito M, Kuwahata M, Kido S, Tatsumi S, Kaneko I, Segawa H. Sodium-dependent phosphate cotransporters: lessons from gene knockout and mutation studies. J Pharm Sci 2011; 100:3719-30. [PMID: 21567407 DOI: 10.1002/jps.22614] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2011] [Revised: 04/13/2011] [Accepted: 04/20/2011] [Indexed: 12/22/2022]
Abstract
Inorganic phosphate (Pi) is an essential physiological compound, highlighted by the syndromes caused by hypo or hyperphosphatemic states. Hyperphosphatemia is associated with ectopic calcification, cardiovascular disease, and increased mortality in patients with chronic kidney disease (CKD). As phosphate control is not efficient with diet or dialysis, oral Pi binders are used in over 90% of patients with renal failure. However, achieving tight control of serum Pi is difficult, and lower levels of serum Pi (severe hypophosphatemia) do not lead to better outcomes. The inhibition of sodium-dependent Pi (NaPi) transporter would be a preferable method to control serum Pi levels in patients with CKD or patients undergoing dialysis. Three types of NaPi transporters (types I-III) have been identified: solute carrier series SLC17A1 (NPT1/NaPi-I/OATv1), SLC34 (NaPi-IIa, NaPi-IIb, NaPi-IIc), and SLC20 (PiT1, PiT2), respectively. Knockout mice have been created for types I-III NaPi transporters. In this review, we discuss the roles of the NaPi transporters in Pi homeostasis.
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Affiliation(s)
- Ken-ichi Miyamoto
- Department of Molecular Nutrition, Institute of Health Biosciences, University of Tokushima Graduate School Tokushima 770-8503, Japan.
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50
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Forster I, Hernando N, Sorribas V, Werner A. Phosphate transporters in renal, gastrointestinal, and other tissues. Adv Chronic Kidney Dis 2011; 18:63-76. [PMID: 21406290 DOI: 10.1053/j.ackd.2011.01.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Revised: 01/17/2011] [Accepted: 01/18/2011] [Indexed: 11/11/2022]
Abstract
Inorganic phosphate (Pi) is essential for all living organisms. Bound to organic molecules, Pi fulfills structural, metabolic, and signaling tasks. Therefore, cell growth and maintenance depends on efficient transport of Pi across cellular membranes into the intracellular space. Uptake of Pi requires energy because the substrate is transported against its electrochemical gradient. Till recently, 2 major families of physiologically relevant Pi-specific transporters have been identified: the solute carrier families Slc34 and Slc20. Interestingly, phylogenetic links can be detected between prokaryotic and eukaryotic transporters in both families. Because less complex model organisms are often instrumental in establishing paradigms for protein function in human beings, a brief assessment of Slc34 and Slc20 phylogeny is of interest.
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