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Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals

Edited by

James F. Collins

AMSTERDAM • BOSTON • HEIDELBERG • LONDON • NEW ORK • OFORD • PARIS
SAN DIEGO • SAN FRANCISCO • SINGAPORE • SDNE • TOKO

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List of Contributors

Abedalrazaq Alkukhun Yale University School of Ralph Marsland Duckworth Teesside University,

  • Medicine, New Haven, CT, United States
  • Middlesbrough, United Kingdom; Newcastle University,

Newcastle-upon-Tyne, United Kingdom

Gregory Jon Anderson QIMR Berghofer Medical

Research Institute, Australia

Lynnette Robyn Ferguson University of Auckland,

Auckland, New Zealand

Tayze T. Antunes University of Ottawa, Ottawa, ON,

Canada

David Michael Frazer QIMR Berghofer Medical Research

Institute, Australia
Michael Aschner Albert Einstein College of Medicine,

New York, NY, United States

Toshiyuki Fukada Tokushima Bunri University, Tokushima,

Japan; Showa University, Tokyo, Japan; RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
Terry J. Aspray Newcastle University, Newcastle upon
Tyne, Tyne and Wear, United Kingdom; Freeman Hospital, Newcastle upon Tyne, Tyne and Wear, United Kazuhisa Fukue Kyoto University, Kyoto, Japan Kingdom

Priyanka V. Gangodkar GenePath Dx (Causeway
Thomas Bartnikas Brown University, Providence, Rhode

Healthcare Private Limited), Pune, India
Island, United States

Eduardo Garcia-Fuentes Institute of Biomedical

Research of Malaga (IBIMA), Regional University Hospital, Malaga, Spain; CIBEROBN, Institute of Health Carlos III, Malaga, Spain

Abdel A. Belaidi The University of Melbourne, Parkville,

VIC, Australia

Roberto Bravo-Sagua Universidad de Chile, Santiago,

Chile

Michael D. Garrick University at Buffalo, Buffalo, NY,

United States
Gregory A. Brent David Geffen School of Medicine at

UCLA, Los Angeles, CA, United States

John P. Geibel Yale University School of Medicine, New

Haven, CT, United States

George J. Brewer University of Michigan, Ann Arbor, MI,

  • United States
  • Fayez K. Ghishan University of Arizona, Tucson, AZ,

United States
Mona S. Calvo U.S. Food and Drug Administration,

Laurel, MD, United States

Vadim N. Gladyshev Harvard Medical School, Boston,

MA, United States

Bradley Allen Carlson National Institutes of Health,

Bethesda, MD, United States

A. Grubman The University of Melbourne, Parkville, VIC,

Australia

Wen-Hsing

Mississippi, MS, United States

Sylvia Christakos Rutgers, The State University of
Cheng Mississippi

  • State
  • University,

Thomas E. Gunter University of Rochester, Rochester,
NY, United States

New Jersey, New Jersey Medical School, Newark, NJ, Hajo Haase Berlin Institute of Technology, Berlin, United States Germany

Mariana Cifuentes Universidad de Chile, Santiago, Chile Dolph Lee Hatfield National Institutes of Health,

Bethesda, MD, United States
James F. Collins University of Florida, Gainesville, FL,

United States

Ka He Indiana University, Bloomington, IN, United

States
Puneet Dhawan Rutgers, The State University of New

Jersey, New Jersey Medical School, Newark, NJ, United Carolina Herrera Brown University, Providence, Rhode States Island, United States

xiii xiv List of Contributors

  • Kayo Ikuta Tokushima University, Tokushima, Japan
  • Thirayost Nimmanon Cardiff University, Cardiff, United

Kingdom; Phramongkutklao College of Medicine, Bangkok, Thailand

Francisco J. Rios University of Glasgow, Glasgow,

Scotland

Yukina Nishito Kyoto University, Kyoto, Japan
Sami Judeeba Yale University School of Medicine,

New Haven, CT, United States

Tanara Vieira Peres Albert Einstein College of Medicine,

New York, NY, United States

Lillian J. Juttukonda Vanderbilt University Medical

Center, Nashville, TN, United States

Anne-Laure Perraud National Jewish Health, Denver,

CO, United States; University of Colorado Denver, Denver, CO, United States

Taiho Kambe Kyoto University, Kyoto, Japan Ichiro Kaneko Tokushima University, Tokushima, Japan

Michael Pettiglio Brown University, Providence, Rhode

Yujian James Kang Sichuan University, Chengdu,

Sichuan, China; University of Louisville, School of Medicine, Louisville, KY, United States
Island, United States

Nikhil D. Phadke GenePath Dx (Causeway Healthcare

Private Limited), Pune, India

Nishi Karunasinghe University of Auckland, Auckland,
Ananda S. Prasad Wayne State University School of

New Zealand
Medicine, Detroit, MI, United States

Anuradha V. Khadilkar Jehangir Medical Research
Vijayababu M. Radhakrishnan University of Arizona,

Institute Jehangir Hospital, Pune, India
Tucson, AZ, United States

Pawel R. Kiela University of Arizona, Tucson, AZ, United
Marcela Reyes Universidad de Chile, Santiago, Chile

States

Loren Warren Runnels Rutgers-Robert Wood Johnson
Katerine S. Knust Universidade Federal do Estado do Rio

Medical School, Piscataway, NJ, United States de Janeiro (UNIRIO), Rio de Janeiro, Brazil

Carsten Schmitz University of Colorado Denver, Denver,

CO, United States; National Jewish Health, Denver, CO, United States

Mitchell D. Knutson University of Florida, Gainesville,

FL, United States

Yuko Komiya Rutgers-Robert Wood Johnson Medical
Guenter Schwarz University of Cologne, Cologne,

School, Piscataway, NJ, United States
Germany

Daniel Laubitz University of Arizona, Tucson, AZ, United
Hiroko Segawa Tokushima University, Tokushima, Japan

States

Yatrik Madhukar Shah University of Michigan, Ann
Sergio Lavandero Universidad de Chile, Santiago, Chile;

University of Texas Southwestern Medical Center, Dallas, TX, United States
Arbor, MI, United States

Eric P. Skaar Vanderbilt University Medical Center,

Nashville, TN, United States

Xin Gen Lei Cornell University, Ithaca, NY, United States

Laura Soldati Università degli Studi of Milan, Milan,

Angela M. Leung UCLA David Geffen School of

Medicine, Los Angeles, CA, United States; VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States
Italy

Michael Stowasser The University of Queensland, School

of Medicine, Brisbane, QLD, Australia

Sawako Tatsumi Tokushima University, Tokushima, Japan
Anna Milanesi David Geffen School of Medicine at

UCLA, Los Angeles, CA, United States
Kathryn M. Taylor Cardiff University, Cardiff, United

Kingdom

Ken-ichi Miyamoto Tokushima University, Tokushima,

Japan

Ryuta Tobe National Institutes of Health, Bethesda, MD,

United States

Augusto C. Montezano University of Glasgow, Glasgow,

Scotland

Rhian M. Touyz University of Glasgow, Glasgow,

Scotland
Stefano Mora IRCCS San Raffaele Scientific Institute,

Milan, Italy

Cari Lewis Tsinovoi Indiana University, Bloomington,

IN, United States

Armando Salim Munoz-Abraham Yale University

School of Medicine, New Haven, CT, United States

Petra Akiko Tsuji Towson University, Towson, MD,

United States

Forrest Harold Nielsen USDA, ARS, Grand Forks

Human Nutrition Research Center, Grand Forks, ND, Jaime Uribarri The Icahn School of Medicine at Mount United States Sinai, New York, NY, United States

List of Contributors xv

  • Inés Velasco Hospital Riotinto, Huelva, Spain
  • A.R. White The University of Melbourne, Parkville, VIC,

Australia

Vaishali Veldurthy Rutgers, The State University of New

Jersey, New Jersey Medical School, Newark, NJ, United Ying Xiao Sichuan University, Chengdu, Sichuan, China States

Xiang Xue University of Michigan, AnnArbor, MI, United
Giuseppe Vezzoli IRCCS San Raffaele Scientific Institute,

States
Milan, Italy

Hironori Yamamoto Jin-ai University, Fukui, Japan Wen Yin Sichuan University, Chengdu, Sichuan, China
John Bertram Vincent The University of Alabama,

Tuscaloosa, AL, United States
Wenjing Zhang Sichuan University, Chengdu, Sichuan,

Tao Wang Sichuan University, Chengdu, Sichuan, China

China
Ran Wei Rutgers, The State University of New Jersey,

FatemehVidaZohoori TeessideUniversity,Middlesbrough,

New Jersey Medical School, Newark, NJ, United States
United Kingdom

Marianne Wessling-Resnick Harvard T.H. Chan School

of Public Health, Boston, MA, United States

Series Preface

In this series on Molecular Nutrition, the editors of each book aim to disseminate important material pertaining to molecular nutrition in its broadest sense. The coverage ranges from molecular aspects to whole organs, and the impact of nutrition or malnutrition on individuals and whole communities. It includes concepts, policy, preclinical studies, and clinical investigations relating to molecular nutrition. The subject areas include molecular mechanisms, polymorphisms, SNPs, genomic wide analysis, genotypes, gene expression, genetic modifications, and many other aspects. Information given in the Molecular Nutrition series relates to national, international, and global issues.
A major feature of the series that sets it apart from other texts is the initiative to bridge the transintellectual divide so that it is suitable for novices and experts alike. It embraces traditional and nontraditional formats of nutritional sciences in different ways. Each book in the series has both overviews and detailed and focused chapters.
Molecular Nutrition is designed for nutritionists, dieticians, educationalists, health experts, epidemiologists, and healthrelated professionals such as chemists. It is also suitable for students, graduates, postgraduates, researchers, lecturers, teachers, and professors. Contributors are national or international experts, many of whom are from world-renowned institutions or universities. It is intended to be an authoritative text covering nutrition at the molecular level.

Victor R. Preedy

Series Editor

xvii

Chapter 1

Calcium-Sensing Receptor Polymorphisms and Human Disease

Giuseppe Vezzoli1, Laura Soldati2, Stefano Mora1

1IRCCS San Raffaele Scientific Institute, Milan, Italy; 2Università degli Studi of Milan, Milan, Italy

INTRODUCTION

Circulating calcium ions can directly modulate cell activity in humans by means of a plasma membrane receptor that is sensitive to extracellular calcium, the calcium-sensing receptor (CaSR). CaSR was firstly cloned from bovine parathyroid cells in 1993 (Brown et al., 1992) and then in human parathyroid cells and renal tubular cells (Aida et al., 1995; Garrett et al., 1995). CaSR is a 1078-amino–acid protein that belongs to the third class of G-protein-coupled receptor (GPCR) family. It is expressed as a disulfide-linked homodimer in caveolin-rich areas of the plasma membrane, although it may also form heterodimers with other members of the GPCR family (Kifor et al., 1998). As an environmental sensor, CaSR elicits the paracrine or autocrine adaptive responses of human cells to changes in local or serum calcium concentrations. This adaptive response is fundamental for the physiological effect of parathyroid and kidney cells in human calcium homeostasis. The parathyroid glands and renal distal tubules are the tissues with the highest expression of CaSR, and its presence enables them to regulate calcium excretion and parathyroid hormone (PTH) secretion in response to serum calcium changes (Fig. 1.1). CaSR stimulation by the increase of serum calcium is followed by the inhibition of calcium reabsorption in the renal tubules and PTH secretion to restore normal serum calcium levels (Riccardi and Brown, 2010; Riccardi and Kemp, 2012). CaSR was also shown to be essential for osteoblast-mediated bone remodeling (Dvorak et al., 2004). Therefore CaSR is a key factor in calcium homeostasis (Riccardi and Kemp, 2012).
The CaSR molecule includes a large bilobed Venus-flytrap–like extracellular domain of 612 amino acids, a sevenmembrane–spanning domain of 250 amino acids, and a C-terminal intracellular domain of 216 amino acids (Riccardi and Kemp, 2012). Calcium binding to the negatively charged residues in the pocket of the CaSR extracellular domain induces a conformational change of the CaSR molecule that causes the transmembrane and intracellular domains to activate intracellular signaling. Calcium ions are the main CaSR agonists, but CaSR also responds to other divalent (Ba, Cd, Co, Mg) and trivalent (Gd, La) cations and to polycationic compounds such as polyamines, aminoglycosides (neomycin, gentamycin), and polypeptides (poly-l-arginine, β-amyloid) (Riccardi and Kemp, 2012). The signaling cascade induced

by CaSR activation is tissue specific and mediated by G-proteins (Fig. 1.2) (Magno et al., 2011). However, CaSR has also been identified in many organs not directly involved in calcium homeostasis and is now considered as ubiquitously expressed in mammalian cells. It has been implicated in insulin secretion, adipocyte metabolism, smooth muscle cell activity, and gastric function (Table 1.1), although its effects in these tissues is not as crucial as that in calcium-regulating

organs (Riccardi and Kemp, 2012).

The human CaSR gene (3q13.3–21) spans 103kb and comprises eight exons with two promoters, P1 and P2, having unknown functional differences (Fig. 1.3) (Canaff and Hendy, 2002). Loss-of-function mutations cause familial hypocalciuric hypercalcemia (FHH; OMIM #145980) in heterozygous patients and severe neonatal hyperparathyroidism (SNH; OMIM #239200) in homozygous patients (Hofer and Brown, 2003; Pearce et al., 1995). In these patients, CaSR cannot inhibit PTH production and renal tubular calcium reabsorption appropriately and patient phenotype is characterized by hypercalcemia and low calcium excretion. Serum PTH and calcium are slightly or moderately high in FHH, but severely high in SNH. SNH patients also develop bone demineralization and failure to thrive in the first 6months of life. Mutations of two other genes, GNA11 (19p13) and AP2S1 (19q13), may also cause FHH. Gain-of-function mutations of CaSR cause autosomal dominant hypercalcemia (ADH; OMIM #601198), a disorder characterized by high urinary calcium excretion and inappropriately low serum PTH and hypocalcemia. ADH in patients with highly activating mutations is associated with Bartter syndrome type 5 because of a urinary sodium and potassium leak resulting in renal hypokalemia

(Vezzoli et al., 2006).

Molecular, Genetic, and Nutritional Aspects of Major and Trace Minerals. http://dx.doi.org/10.1016/B978-0-12-802168-2.00001-4

Copyright © 2017 Elsevier Inc. All rights reserved.

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PART I Calcium

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    Supplementary Table I Genes regulated by myc/ras transformation signal Probe set Gene symbol gene + dox/ - E2 - dox/ - E2 - dox/ +E2 100011_at Klf3 Kruppel-like factor 3 (basic) 308 120 270 100013_at 2010008K16Rik RIKEN cDNA 2010008K16 gene 127 215 859 100016_at Mmp11 matrix metalloproteinase 11 187 71 150 100019_at Cspg2 chondroitin sulfate proteoglycan 2 1148 342 669 100023_at Mybl2 myeloblastosis oncogene-like 2 13 105 12 100030_at Upp uridine phosphorylase 18 39 110 100033_at Msh2 mutS homolog 2 (E. coli) 120 246 92 100037_at 2310005B10Rik RIKEN cDNA 2310005B10 gene 178 351 188 100039_at Tmem4 transmembrane protein 4 316 135 274 100040_at Mrpl17 mitochondrial ribosomal protein L17 88 142 89 100041_at 3010027G13Rik RIKEN cDNA 3010027G13 gene 818 1430 1033 methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate 100046_at Mthfd2 cyclohydrolase 213 720 376 100064_f_at Gja1 gap junction membrane channel protein alpha 1 143 574 92 100066_at Gart phosphoribosylglycinamide formyltransferase 133 385 180 100071_at Mup2 major urinary protein 2 26 74 30 100081_at Stip1 stress-induced phosphoprotein 1 148 341 163 100089_at Ppic peptidylprolyl isomerase C 358 214 181 100091_at Ugalt2 UDP-galactose translocator 2 1456 896 1530 100095_at Scarb1 scavenger receptor class B, member 1 638 1044 570 100113_s_at Kifap3 kinesin-associated protein 3 482 168 311 100116_at 2810417H13Rik RIKEN cDNA 2810417H13 gene 134 261 53 100120_at Nid1 nidogen 1 81 47 54 100125_at Pa2g4 proliferation-associated 2G4, 38kD 62 286 44 100128_at Cdc2a cell division cycle 2 homolog A (S. pombe) 459 1382 247 100133_at Fyn Fyn proto-oncogene 168 44 82 100144_at Ncl nucleolin 1283 3452 1215 100151_at Tde1 tumor differentially expressed 1 620 351 620 100153_at Ncam1 neural cell adhesion molecule 1 302 144 234 100155_at Ddr1 discoidin domain receptor family, member 1 304 117 310 100156_at Mcmd5 mini chromosome maintenance deficient 5 (S.
  • NF-Κb Signaling in Gastric Cancer

    NF-Κb Signaling in Gastric Cancer

    Review NF‐κB Signaling in Gastric Cancer Olga Sokolova and Michael Naumann * Institute of Experimental Internal Medicine, Otto von Guericke University Magdeburg, Magdeburg 39120, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49‐391‐671‐3227 Abstract: Gastric cancer is a leading cause of cancer death worldwide. Diet, obesity, smoking and chronic infections, especially with Helicobacter pylori, contribute to stomach cancer development. H. pylori possesses a variety of virulence factors including encoded factors from the cytotoxin‐associated gene pathogenicity island (cagPAI) or vacuolating cytotoxin A (VacA). Most of the cagPAI‐encoded products form a type 4 secretion system (T4SS), a pilus‐like macromolecular transporter, which translocates CagA into the cytoplasm of the host cell. Only H. pylori strains carrying the cagPAI induce the transcription factor NF‐κB, but CagA and VacA are dispensable for direct NF‐κB activation. NF‐κB‐driven gene products include cytokines/chemokines, growth factors, anti‐apoptotic factors, angiogenesis regulators and metalloproteinases. Many of the genes transcribed by NF‐κB promote gastric carcinogenesis. Since it has been shown that chemotherapy‐caused cellular stress could elicit activation of the survival factor NF‐κB, which leads to acquisition of chemoresistance, the NF‐κB system is recommended for therapeutic targeting. Research is motivated for further search of predisposing conditions, diagnostic markers and efficient drugs to improve significantly the overall survival of patients. In this review, we provide an overview about mechanisms and consequences of NF‐κB activation in gastric mucosa in order to understand the role of NF‐κB in gastric carcinogenesis. Keywords: NF‐κB; inflammation; gastric cancer; Helicobacter pylori; VacA toxin; Type 4 secretion system; tumor microenvironment; chemoresistance 1.
  • NR4A2 Is Regulated by Gastrin and Influences Cellular Responses of Gastric Adenocarcinoma Cells

    NR4A2 Is Regulated by Gastrin and Influences Cellular Responses of Gastric Adenocarcinoma Cells

    NR4A2 Is Regulated by Gastrin and Influences Cellular Responses of Gastric Adenocarcinoma Cells Kristine Misund1, Linn-Karina Myrland Selvik1,2, Shalini Rao1,2, Kristin Nørsett1, Ingunn Bakke1, Arne K. Sandvik1,3, Astrid Lægreid1, Torunn Bruland1, Wenche S. Prestvik2, Liv Thommesen1,2* 1 Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway, 2 Faculty of Technology, Sør-Trøndelag University College, Trondheim, Norway, 3 Department of Gastroenterology and Hepatology, Medical Clinic, St. Olav’s University Hospital, Trondheim, Norway Abstract The peptide hormone gastrin is known to play a role in differentiation, growth and apoptosis of cells in the gastric mucosa. In this study we demonstrate that gastrin induces Nuclear Receptor 4A2 (NR4A2) expression in the adenocarcinoma cell lines AR42J and AGS-GR, which both possess the gastrin/CCK2 receptor. In vivo, NR4A2 is strongly expressed in the gastrin responsive neuroendocrine ECL cells in normal mucosa, whereas gastric adenocarcinoma tissue reveals a more diffuse and variable expression in tumor cells. We show that NR4A2 is a primary early transient gastrin induced gene in adenocarcinoma cell lines, and that NR4A2 expression is negatively regulated by inducible cAMP early repressor (ICER) and zinc finger protein 36, C3H1 type-like 1 (Zfp36l1), suggesting that these gastrin regulated proteins exert a negative feedback control of NR4A2 activated responses. FRAP analyses indicate that gastrin also modifies the nucleus-cytosol shuttling of NR4A2, with more NR4A2 localized to cytoplasm upon gastrin treatment. Knock-down experiments with siRNA targeting NR4A2 increase migration of gastrin treated adenocarcinoma AGS-GR cells, while ectopically expressed NR4A2 increases apoptosis and hampers gastrin induced invasion, indicating a tumor suppressor function of NR4A2.
  • 2004 Eastern Society for Pediatric Research 16Th Annual Meeting

    2004 Eastern Society for Pediatric Research 16Th Annual Meeting

    2004 Eastern Society for Pediatric Research 16th Annual Meeting Program Guide March 26–28, 2004 Hyatt Regency Old Greenwich, CT In cooperation with the New York Academy of Medicine New for 2004 We are pleased to announce that we have engaged the services of the New York Academy of Medicine (NYAM) to run our 2004 meeting. They will also sponsor the CME program. While our recent meetings have been terrific, the administrative burden has exceeded what could reasonably be expected of our volunteers. We expect the engagement of the professional meeting planners at the NYAM will further enhance our meeting. This will include improved informatics enabling presenters to load their PowerPoint presentations at a central station in advance, avoiding some of the glitches we encountered last year. ESPR Officers and Council Sponsorship Honor Roll 2003–2004 President The ESPR expresses its appreciation to all of our Luc P. Brion, M.D. sponsors of the 2004 ESPR Annual Meeting Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Established Sponsors Bronx, New York Curative Pharmacy Services Mead-Johnson Nutritionals Secretary-Treasurer Rashmin C. Savani, M.B.Ch.B. MedImmune, Inc. The University of Pennsylvania School of Medicine, Philips Medical Systems Philadelphia, Pennsylvania Ross Products Division of Abbott Laboratories, Inc. Chairperson, Planning Committee Additional Sponsors Bruce D. Gelb, M.D. Mount Sinai School of Medicine Dey L. P. New York, New York INO Therapeutics, Inc. Council Members Immediate Past President Mercury Medical Anthony Alario, MD Viasys Healthcare Mitchell J. Kresch, MD Clifford Bogue, MD Bruce D. Gelb, MD Academic Sponsors Ian Holzman, MD Past Presidents Alan R.
  • Role of Nurr1 in Carcinogenesis and Tumor Immunology: a State of the Art Review

    Role of Nurr1 in Carcinogenesis and Tumor Immunology: a State of the Art Review

    cancers Review Role of Nurr1 in Carcinogenesis and Tumor Immunology: A State of the Art Review Peter Kok-Ting Wan , Michelle Kwan-Yee Siu, Thomas Ho-Yin Leung, Xue-Tang Mo, Karen Kar-Loen Chan and Hextan Yuen-Sheung Ngan * Department of Obstetrics and Gynaecology, LKS Faculty of Medicine, the University of Hong Kong, Pok Fu Lam, Hong Kong, China; [email protected] (P.K.-T.W.); [email protected] (M.K.-Y.S.); [email protected] (T.H.-Y.L.); [email protected] (X.-T.M.); [email protected] (K.K.-L.C.) * Correspondence: [email protected]; Tel.: +852-2255-4260; Fax: +852-2855-0947 Received: 26 August 2020; Accepted: 14 October 2020; Published: 19 October 2020 Simple Summary: Nuclear receptor related-1 protein (Nurr1) emerges as a therapeutic target in multiple malignancies and immunotherapies. Previous studies have highlighted its association with clinicopathological parameters, tumorigenesis and therapeutic resistance in cancers. In addition, recent studies unraveled its contribution to the suppression of antitumor immunity, suggesting that inhibition of Nurr1 is a potential method to repress cancer aggressiveness and disrupt tumor immune tolerance. In line with this evidence, the present review provides the roles of Nurr1 in tumor progression and the associated underlying molecular mechanisms. Moreover, the significance of Nurr1 in promoting immune tolerance and potential strategies for Nurr1 inhibition are highlighted. Abstract: Nuclear receptor related-1 protein (Nurr1), coded by an early response gene, is involved in multiple cellular and physiological functions, including proliferation, survival, and self-renewal. Dysregulation of Nurr1 has been frequently observed in many cancers and is attributed to multiple transcriptional and post-transcriptional mechanisms.
  • PTH and Vitamin D

    PTH and Vitamin D

    PTH and Vitamin D Syed Jalal Khundmiri,1,2 Rebecca D. Murray,1,2 and Eleanor Lederer*1,2,3 ABSTRACT PTH and Vitamin D are two major regulators of mineral metabolism. They play critical roles in the maintenance of calcium and phosphate homeostasis as well as the development and mainte- nance of bone health. PTH and Vitamin D form a tightly controlled feedback cycle, PTH being a major stimulator of vitamin D synthesis in the kidney while vitamin D exerts negative feedback on PTH secretion. The major function of PTH and major physiologic regulator is circulating ionized calcium. The effects of PTH on gut, kidney, and bone serve to maintain serum calcium within a tight range. PTH has a reciprocal effect on phosphate metabolism. In contrast, vitamin D has a stimulatory effect on both calcium and phosphate homeostasis, playing a key role in providing adequate mineral for normal bone formation. Both hormones act in concert with the more recently discovered FGF23 and klotho, hormones involved predominantly in phosphate metabolism, which also participate in this closely knit feedback circuit. Of great interest are recent studies demon- strating effects of both PTH and vitamin D on the cardiovascular system. Hyperparathyroidism and vitamin D deficiency have been implicated in a variety of cardiovascular disorders including hypertension, atherosclerosis, vascular calcification, and kidney failure. Both hormones have di- rect effects on the endothelium, heart, and other vascular structures. How these effects of PTH and vitamin D interface with the regulation of bone formation are the subject of intense investigation. Published 2016. Compr Physiol 6:561-601, 2016.