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Vitamin D

Vitamin D

Автором Academic Press

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Vitamin D

Автором Academic Press

Длина:
6,126 pages
71 hours
Издатель:
Издано:
Jan 25, 2005
ISBN:
9780080543642
Формат:
Книге

Описание

Vitamin D, a steroid hormone, has mainly been known for its effects on bone and osteoporosis. The current therapeutic practices expand into such markets as cancer research, pediatrics, nephrology, dermatology, immunology, and genetics. This second edition includes over 100 chapters covering everything from chemistry and metabolism to mechanisms of action, diagnosis and management, new analogs, and emerging therapies. This complete reference works is a must have resource for anyone working in endocrinology, osteology, bone biology, or cancer research.

*Most comprehensive, up-to-date two-volume set on Vitamin D
*New chapters on squamous cell cancer, brain cancer, thyroid cancer and many more
*Further sections on emerging uses for treatments of auto-immune diseases and diabetes
*Over 600 illustrations and figures available on CD
Издатель:
Издано:
Jan 25, 2005
ISBN:
9780080543642
Формат:
Книге

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Vitamin D - Academic Press

Vitamin D

Second Edition

DAVID FELDMAN

Division of Endocrinology, Gerontology, and Metabolism, Stanford University School of Medicine, Stanford, California 94305

J. Wesley Pike

Francis H. Glorieux

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Preface to the 2nd Edition

Preface to the 1st Edition

Abbreviations

VOLUME I: INTRODUCTION

Chapter 1: Historical Perspective

I. DISCOVERY OF THE VITAMINS

II. DISCOVERY THAT VITAMIN D IS NOT A VITAMIN

III. ISOLATION AND IDENTIFICATION OF NUTRITIONAL FORMS OF VITAMIN D

IV. DISCOVERY OF THE PHYSIOLOGICAL FUNCTIONS OF VITAMIN D

V. DISCOVERY OF THE HORMONAL FORM OF VITAMIN D

Acknowledgment

SECTION I: CHEMISTRY, METABOLISM, AND CIRCULATION

Chapter 2: Vitamin D Metabolism

I. INTRODUCTION

II. VITAMIN D METABOLISM

III. VITAMIN D TOXICITY

IV. SPECIES VARIATION IN VITAMIN D METABOLISM AND ACTION

V. CONCLUSION

Chapter 3: Photobiology of Vitamin D

I. INTRODUCTION

II. HISTORICAL PERSPECTIVE

III. PHOTOBIOLOGY OF VITAMIN D

IV. ROLE OF SUNLIGHT AND DIETARY VITAMIN D IN BONE HEALTH, OVERALL HEALTH, AND WELL-BEING

V. SUNLIGHT, VITAMIN D, AND SKIN CANCER

VI. CONCLUSION

Acknowledgment

Chapter 4: The Vitamin D 25-Hydroxylase

I. INTRODUCTION

II. HEPATIC UPTAKE OF VITAMIN D

III. THE MONOOXYGENASES ACTIVE IN THE HYDROXYLATION OF VITAMIN D AT C-25

IV. THE MICROSOMAL ENZYMES

V. THE MITOCHONDRIAL ENZYME

VI. CEREBROTENDINOUS XANTHOMATOSIS

VII. ONTOGENY OF THE VITAMIN D 25-HYDROXYLASES

VIII. SEX DIFFERENCES IN THE HYDROXYLATION OF VITAMIN D AT C-25

IX. CONCLUSIONS

X. ADDENDUM

Chapter 5: The 25-Hydroxyvitamin D 1α-Hydroxylase

I. OCCURRENCE AND CHARACTERISTICS OF 25OHD3 1α-HYDROXYLASE

II. CHARACTERISTICS OF THE PROTEINS INVOLVED IN THE 1α-HYDROXYLATION OF 25OHD3

III. CYTOCHROME P4501α: CLONING AND GENE STRUCTURE

IV. REGULATION OF KIDNEY 1α-HYDROXYLASE ACTIVITY AND GENE EXPRESSION

V. SUMMARY

Chapter 6: The 25-Hydroxyvitamin D 24-Hydroxylase

I. BACKGROUND

II. ENZYME STRUCTURE AND FUNCTION

III. CELLULAR EXPRESSION AND REGULATION

IV. MOLECULAR ASPECTS

Acknowledgments

Chapter 7: Mutant Mouse Models of Vitamin D Metabolic Enzymes

I. INTRODUCTION

II. HEPATIC 25-HYDROXYLATION AND cyp27A1 KNOCKOUT

III. 24-HYDROXYLATION AND cyp24A1 KNOCKOUT

IV. 1α-HYDROXYLATION AND cyp27B1 KNOCKOUT

V. SUMMARY AND PERSPECTIVES

Chapter 8: Vitamin D–Binding Protein

I. INTRODUCTION

II. VITAMIN D BINDING PROTEIN AND ITS GENE

III. FUNCTIONAL FEATURES OF VITAMIN D BINDING PROTEIN

IV. CONCLUDING REMARKS

Chapter 9: New Aspects of DBP

SUMMARY

I. INTRODUCTION

II. THREE-DIMENSIONAL STRUCTURE OF VITAMIN D–BINDING PROTEIN

III. THREE-DIMENSIONAL STRUCTURES OF VITAMIN D–BINDING PROTEIN IN COMPLEX WITH LIGANDS

IV. A STRUCTURAL EXPLANATION FOR THE UNIQUE FUNCTIONS OF VITAMIN D–BINDING PROTEIN WITHIN ITS GENE FAMILY

Chapter 10: Endocytic Pathways for 25-(OH) Vitamin D3

I. INTRODUCTION

II. RENAL ENDOCYTOSIS OF 25-(OH) VITAMIN D3

III. CONCLUSION

SECTION II: MECHANISM OF ACTION

Chapter 11: The Vitamin D Receptor

I. INTRODUCTION

II. DISCOVERY OF THE VITAMIN D RECEPTOR

III. CHARACTERIZATION OF THE VITAMIN D RECEPTOR

IV. STRUCTURAL GENE FOR THE VITAMIN D RECEPTOR

V. FUNCTIONAL ANALYSIS OF THE VITAMIN D RECEPTOR

VI. THE HUMAN VITAMIN D–RECEPTOR CHROMOSOMAL GENE

VII. CONCLUDING COMMENTS

Chapter 12: Vitamin D Receptor Promoter and Regulation of Receptor Expression

I. INTRODUCTION

II. TISSUE DISTRIBUTION

III. THE VITAMIN D RECEPTOR GENE LOCUS

IV. REGULATION OF VITAMIN D RECEPTOR EXPRESSION AND ABUNDANCE

V. CONCLUDING REMARKS

Chapter 13: Nuclear Vitamin D Receptor: Structure-Function, Molecular Control of Gene Transcription, and Novel Bioactions

I. INTRODUCTION

II. GENE TARGETS AND BIOLOGICAL ACTIONS OF THE VITAMIN D RECEPTOR

III. THE VITAMIN D RECEPTOR AS A MEMBER OF THE NUCLEAR RECEPTOR SUPERFAMILY

IV. STRUCTURE-FUNCTION OF THE VITAMIN D RECEPTOR

V. MECHANISMS OF VITAMIN D RECEPTOR-MEDIATED CONTROL OF GENE EXPRESSION

VI. IMPLICATIONS OF VITAMIN D RECEPTOR-MEDIATED SIGNALING FOR HUMAN HEALTH AND DISEASE

VII. SUMMARY AND PERSPECTIVES

Acknowledgments

Chapter 14: Vitamin D Receptor Cofactors: Function, Regulation, and Selectivity

I. INTRODUCTION

II. THE VITAMIN D RECEPTOR AND THE BASAL MACHINERY OF TRANSCRIPTION

III. COACTIVATORS

IV. INTEGRATION OF SIGNALING PATHWAYS

V. MOLECULAR BASIS FOR TISSUE-SELECTIVE VITAMIN D RECEPTOR LIGANDS

VI. CONCLUSIONS

Chapter 15: Vitamin D Nuclear Receptor Ligand-Binding Domain Crystal Structures

I. INTRODUCTION

II. BIOLOGICAL PROPERTIES OF hVDRΔ

III. SOLUTION STUDIES

IV. CRYSTAL STRUCTURE OF hVDRΔ BOUND TO 1α,25(OH)2D3

V. MUTANT ANALYSIS

VI. CRYSTAL STRUCTURE OF zVDR BOUND TO 1α,25(OH)2D3

VII. STRUCTURE OF hVDR COMPLEXED TO SUPERAGONIST LIGANDS

VIII. STRUCTURE OF zVDR IN COMPLEX WITH GEMINI

IX. CONCLUSION

Acknowledgment

Chapter 16: Comodulators of Vitamin D Receptor–Mediated Gene Expression

I. INTRODUCTION

II. COACTIVATORS

III. CO-REPRESSORS

IV. CONCLUSION—INTEGRATED MODEL OF COMODULATOR ACTIVITY

Chapter 17: Promoter Targeting of Vitamin D Receptor through a Chromatin Remodeling Complex

I. INTRODUCTION

II. CHROMATIN REMODELING IS A PREREQUISITE FOR TRANSCRIPTIONAL CONTROLS BY THE VITAMIN D RECEPTOR

III. PURIFICATION AND IDENTIFICATION OF WILLIAMS SYNDROME TRANSCRIPTION FACTOR AS A VITAMIN D RECEPTOR INTERACTANT

IV. PURIFICATION AND IDENTIFICATION OF A NOVEL WILLIAMS SYNDROME TRANSCRIPTION FACTOR COMPLEX ASSOCIATING WITH VITAMIN D RECEPTOR

V. WINAC IS A NOVEL MULTIFUNCTIONAL ATP-DEPENDENT CHROMATIN REMODELING COMPLEX THAT REARRANGES A NUCLEOSOME ARRAY AROUND A VITAMIN D RESPONSIVE ELEMENT IN VITRO

VI. WILLIAMS SYNDROME TRANSCRIPTION FACTOR COACTIVATED THE LIGAND-INDUCED TRANSACTIVATION FUNCTION OF VITAMIN D RECEPTOR

VII. MOLECULAR MECHANISM OF VDR PROMOTER TARGETING OF VITAMIN D RECEPTOR BY WINAC, AND COOPERATIVE WINAC FUNCTION WITH THE CO-REGULATOR COMPLEXES

Acknowledgment

Chapter 18: Molecular Basis of the Diversity of Vitamin D Target Genes

I. MOLECULAR BASIS OF THE GENOMIC ACTIONS OF 1,25(OH)2D3

II. CLASSICAL VITAMIN D–RECEPTOR BINDING SITES

III. COMPLEX VITAMIN D–RECEPTOR BINDING SITES

IV. CONCLUSION

Acknowledgment

Chapter 19: Intranuclear Organization of the Regulatory Machinery for Vitamin D–Mediated Control of Skeletal Gene Expression

I. INTRODUCTION

II. REQUIREMENTS FOR PHYSIOLOGICALLY RESPONSIVE CONTROL OF SKELETAL GENE EXPRESSION IN VIVO

III. GENE EXPRESSION WITHIN THE THREE-DIMENSIONAL CONTEXT OF NUCLEAR ARCHITECTURE

IV. CHROMATIN REMODELING FACILITATES VITAMIN D–MEDIATED PROMOTER ACCESSIBILITY AND INTEGRATION OF REGULATORY ACTIVITIES

V. NUCLEAR MICROENVIRONMENTS: ACCOMMODATING THE RULES THAT GOVERN IN VIVO TRANSCRIPTIONAL CONTROL

VI. SCAFFOLDING OF REGULATORY COMPONENTS FOR COMBINATORIAL CONTROL OF GENE EXPRESSION

VII. INTRANUCLEAR TRAFFICKING OF SKELETAL REGULATORY FACTORS TO SUBNUCLEAR SITES THAT SUPPORT TRANSCRIPTION: TO BE IN THE RIGHT PLACE AT THE RIGHT TIME

VIII. THE REGULATED AND REGULATORY PARAMETERS OF SUBNUCLEAR ORGANIZATION

Acknowledgments

Chapter 20: Mouse Models of Vitamin D Receptor Ablation

I. INTRODUCTION

II. EFFECT ON GROWTH AND MINERAL ION HOMEOSTASIS

III. EFFECT ON VASCULAR SYSTEM

IV. EFFECT ON REPRODUCTION

V. EFFECT ON THE IMMUNE SYSTEM

VI. INTEGUMENT

VII. CONCLUSIONS

Chapter 21: Intracellular Vitamin D Response Element Binding Proteins

I. INTRODUCTION

II. NEW WORLD PRIMATES

III. THE BIOCHEMICAL NATURE OF VITAMIN D RESISTANCE IN NEW WORLD PRIMATES

IV. NEW WORLD PRIMATE–LIKE VITAMIN D RESISTANCE IN MAN

V. CHARACTERIZATION OF THE HUMAN RESPONSE ELEMENT BINDING PROTEIN (REBiP)

VI. HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEINS (hnRNPs)

VII. COMPENSATION FOR THE DOMINANT-NEGATIVE ACTING, RESPONSE ELEMENT BINDING PROTEINS

VIII. CONCLUSION

Chapter 22: Vitamin D Receptor and Retinoid X Receptor Subcellular Trafficking

I. EVOLVING CONCEPTS OF RECEPTOR LOCALIZATION

II. NUCLEOCYTOPLASMIC TRAFFICKING OF VITAMIN D RECEPTOR AND RETINOID X RECEPTOR

III. INTRANUCLEAR TRAFFICKING OF VITAMIN D RECEPTOR AND RETINOID X RECEPTOR

IV. SUMMARY AND FUTURE DIRECTIONS

Chapter 23: 1α,25(OH)2-Vitamin D3–Mediated Rapid and Genomic Responses Are Dependent upon Critical Structure–Function Relationships for Both the Ligand and Receptor(s)

I. INTRODUCTION TO VITAMIN D3 AND 1α,25(OH)2D3

II. VITAMIN D ENDOCRINE SYSTEM

III. PROTEINS WITH LIGAND BINDING DOMAINS FOR 1α,25(OH)2D3

IV. STRUCTURE–FUNCTION EVALUATION OF SELECTED RAPID RESPONSES MEDIATED BY 1α,25(OH)2D3

V. SUMMARY

VI. ADDENDUM

SECTION III: MINERAL HOMEOSTASIS

Chapter 24: Vitamin D and the Intestinal Absorption of Calcium: A View and Overview

I. INTRODUCTION

II. THE VITAMIN D HORMONE

III. OVERVIEW

IV. TRANSCELLULAR CALCIUM ABSORPTION

V. VITAMIN D AND THE PARACELLULAR PATH

VI. VESICULAR TRANSPORT OF CALCIUM

VII. COMMENTARY ON SEGMENT-SPECIFIC INTESTINAL ABSORPTION OF CALCIUM

VIII. SUMMARY

Acknowledgments

Chapter 25: Intestinal Calcium Absorption: Lessons from Knockout Mice and Men

I. INTRODUCTION

II. THE EPITHELIAL CALCIUM CHANNELS: GATEKEEPERS FOR CALCIUM INFLUX

III. ACTIVE INTESTINAL CALCIUM ABSORPTION: VITAMIN D–DEPENDENT MECHANISMS

IV. ACTIVE CALCIUM ABSORPTION DURING REPRODUCTION

V. ACTIVE CALCIUM ABSORPTION AND CORTICOSTEROIDS

VI. SUMMARY

Chapter 26: Phosphate Homeostasis

I. INTRODUCTION

II. PHOSPHATE HOMEOSTASIS

III. INTESTINAL PHOSPHATE ABSORPTION

IV. RENAL PHOSPHATE TRANSPORT

V. ROLE OF PHOSPHATE IN THE REGULATION OF RENAL VITAMIN D METABOLISM

VI. PHOSPHATE TRANSPORT IN BONE

VII. DISORDERS CAUSING PHOSPHATE DEFICIENCY

VIII. SUMMARY AND CONCLUSIONS

Chapter 27: Mineralization

I. INTRODUCTION

II. MINERALIZATION AND MINERAL PROPERTIES IN MODEL SYSTEMS WITH VITAMIN D ALTERATIONS

III. CONCLUSIONS

Chapter 28: Modeling and Remodeling: How Bone Cells Work Together

I. INTRODUCTION

II. THE STRUCTURAL AND CELLULAR BASIS OF BONE GROWTH

III. THE PURPOSES OF BONE REMODELING

IV. THE BASIC MULTICELLULAR UNIT AS THE INSTRUMENT OF BONE REMODELING

V. DISORDERED REMODELING AND AGE-RELATED BONE LOSS

VI. POSSIBLE TARGETS FOR VITAMIN D ACTION

VII. CONCLUSIONS

Chapter 29: Vitamin D and the Kidney

I. INTRODUCTION

II. ROLE OF THE KIDNEY IN THE METABOLISM OF 25OH D

III. EFFECTS OF VITAMIN D, 25(OH)D3 AND 1,25(OH)2D3 ON THE RENAL HANDLING OF CALCIUM AND PHOSPHORUS

IV. DISTRIBUTION AND REGULATION OF VITAMIN D–DEPENDENT PROTEINS IN THE KIDNEY

V. CONCLUSION

Chapter 30: Vitamin D and the Parathyroids

I. INTRODUCTION

II. PARATHYROID HORMONE BIOSYNTHESIS

III. PARATHYROID HORMONE SECRETION AND THE CALCIUM SENSOR

IV. REGULATION OF THE PARATHYROID HORMONE GENE

V. THE PARATHYROID HORMONE GENE

VI. REGULATION OF PARATHYROID HORMONE GENE EXPRESSION BY CALCITRIOL

VII. REGULATION OF THE CALCIUM RECEPTOR BY CALCITRIOL

VIII. CALRETICULIN AND THE ACTION OF 1,25(OH)2D3 ON THE PARATHYROID HORMONE GENE

IX. PARATHYROID HORMONE DEGRADATION

X. SECONDARY HYPERPARA-THYROIDISM AND PARATHYROID CELL PROLIFERATION

XI. CONCLUSIONS

Chapter 31: Calcium-Sensing Receptor

I. INTRODUCTION

II. THE CaR: ISOLATION, STRUCTURE, AND INTRACELLULAR SIGNALING

III. ROLE OF THE CaR IN THE PARATHYROID

IV. ROLE OF THE CaR IN THE C-CELL

V. ROLE OF THE CaR IN THE KIDNEY

VI. THE CaR IN BONE AND INTESTINE

VII. SUMMARY

SECTION IV: TARGET ORGANS AND TISSUES

Chapter 32: Bone

I. INTRODUCTION

II. VITAMIN D ACTIONS ON BONE MINERALIZATION

III. VITAMIN D AND BONE TARGET GENES

IV. VITAMIN D ACTIONS ON BONE RESORPTION

V. SUMMARY AND CONCLUSIONS

Chapter 33: Cartilage and Vitamin D: Genomic and Nongenomic Regulation by 1,25(OH)2D3 and 24,25(OH)2D3

I. CHONDROGENESIS AND ENDOCHONDRAL OSSIFICATION IN VIVO

II. SEPARATE ROLES FOR 24,25(OH)2D3 AND 1,25(OH)2D3 IN CARTILAGE

III. RAPID ACTIONS OF VITAMIN D AND NONGENOMIC MECHANISMS

IV. PHYSIOLOGIC RELEVANCE OF NONGENOMIC REGULATION OF MATRIX VESICLES

V. SUMMARY

Chapter 34: Dento-alveolar Bone Complex and Vitamin D

I. INTRODUCTION

II. DENTAL AND PERIODONTAL FORMATION AND FUNCTIONS

III. VITAMIN D, DENTAL AND PERIODONTAL DEVELOPMENT, AND BIOMINERALIZATION

IV. CONCLUSION

Acknowledgments

Chapter 35: Vitamin D: Role in Skin and Hair

I. INTRODUCTION

II. CUTANEOUS PRODUCTION OF 1,25–DIHYDROXYVITAMIN D

III. REGULATION OF KERATINOCYTE DIFFERENTIATION

IV. REGULATION OF HAIR FOLLICLE CYCLING

Chapter 36: Regulation of Immune Responses by Vitamin D Receptor Ligands

I. INTRODUCTION

II. MAJOR TARGET CELLS IN IMMUNOREGULATION BY VDR LIGANDS: DENDRITIC CELLS AND T CELLS

III. POSSIBLE MECHANISMS FOR THE IMMUNOMODULATORY EFFECTS OF VITAMIN D RECEPTOR LIGANDS IN AUTOIMMUNE DISEASE MODELS

IV. BENEFICIAL EFFECTS OF VDR LIGANDS IN ALLOGRAFT REJECTION

V. CONCLUSIONS

Chapter 37: Vitamin D and Osteoblasts

I. INTRODUCTION

II. EFFECTS OF 1,25(OH)2D3 ON OSTEOBLASTS IN VITRO

III. EFFECTS OF 1,25(OH)2D3 ON BONE APPOSITION RATES IN VIVO

IV. CONCLUSIONS

Acknowledgments

Chapter 38: Vitamin D and Osteoclastogenesis

I. INTRODUCTION

II. DISCOVERY OF BONE MINERAL MOBILIZATION ACTIVITY OF VITAMIN D

III. ESTABLISHMENT OF A MOUSE COCULTURE SYSTEM TO RECRUIT OSTEOCLASTS

IV. DISCOVERY OF KEY FACTORS TO UNDERSTAND THE MOLECULAR MECHANISM OF OSTEOCLASTOGENESIS

V. SIGNAL TRANSDUCTION PATHWAYS OF THE RANKL–RANK SYSTEM IN OSTEOCLAST DEVELOPMENT

VI. THE BIOLOGICAL RELEVANCE OF VITAMIN D TO OSTEOCLASTIC BONE RESORPTION

VII. CONCLUSION

Chapter 39: Vitamin D Control of the Calcitonin Gene in Thyroid C Cells

I. INTRODUCTION

II. ORIGIN OF THYROID C CELLS AND THEIR FUNCTION IN HEALTH AND DISEASE

III. CALCITONIN AND CGRP PRODUCTION BY NORMAL AND TRANSFORMED C CELLS

IV. REGULATION OF CALCITONIN LEVELS BY VITAMIN D

V. REGULATION OF CALCITONIN CGRP GENE TRANSCRIPTION

VI. MECHANISM FOR DOWN-REGULATION OF CALCITONIN GENE TRANSCRIPTION BY VITAMIN D

VII. EFFECTS OF VITAMIN D ON CELL GROWTH

VIII. SUMMARY AND FUTURE DIRECTIONS

Chapter 40: Vitamin D Regulation of Type I Collagen Expression in Bone

I. INTRODUCTION

II. REGULATION OF BONE COLLAGEN SYNTHESIS

III. MOLECULAR MECHANISMS OF REGULATION

IV. CONCLUSIONS AND PERSPECTIVES

Chapter 41: Target Genes: Bone Proteins

I. VITAMIN D AND SKELETAL HOMEOSTASIS

II. OSTEOBLAST DIFFERENTIATION AND VITAMIN D

III. EFFECTS OF VITAMIN D ON GENE EXPRESSION DURING PROLIFERATION

IV. EFFECTS OF VITAMIN D ON GENE EXPRESSION DURING MATRIX SYNTHESIS

V. EFFECTS OF VITAMIN D ON GENE EXPRESSION DURING MINERALIZATION

VI. OSTEOBLASTS AS A SOURCE OF 1,25D?

VII. CONCLUDING REMARKS

Chapter 42: The Calbindins: Calbindin-D9K and Calbindin-D28K

I. INTRODUCTION AND GENERAL CONSIDERATIONS

II. LOCALIZATION AND PROPOSED FUNCTIONAL SIGNIFICANCE

I. Calbindin-D28K Enzyme Activation and Other Potential Targets

III. REGULATION OF CALBINDIN GENE EXPRESSION

IV. CONCLUSION

Chapter 43: Target Genes: PTHrP

I. INTRODUCTION

II. PTHrP GENE AND ITS PRODUCTS

III. MECHANISM OF ACTION OF PTHrP

IV. REGULATION OF PTHRP PRODUCTION

V. THERAPEUTIC STRATEGIES TO INHIBIT PTHrP PRODUCTION

VI. SUMMARY

Chapter 44: Effects of 1,25-Dihydroxyvitamin D3 on Voltage-Sensitive Calcium Channels in the Vitamin D Endocrine System

I. SYSTEMIC AND INTRACELLULAR Ca2+ HOMEOSTASIS

II. VOLTAGE-SENSITIVE CALCIUM CHANNELS

III. 1,25-DIHYDROXYVITAMIN D3 AND VOLTAGE-SENSITIVE Ca2+ CHANNELS

IV. MEMBRANE-INITIATED Ca2+ RESPONSES TO 1,25(OH)2D3

V. Ca2+-INDUCED INACTIVATION OF VSCCS

VI. CALCIUM AND TRANSCRIPTIONAL RESPONSES TO 1,25(OH)2D3

VII. CROSS-TALK BETWEEN MEMBRANE AND NUCLEAR ACTIONS

VIII. SUMMARY AND CONCLUSIONS

Acknowledgments

Chapter 45: Vitamin D and the Cellular Response to Oxidative Stress

I. REACTIVE OXYGEN SPECIES AND REDOX HOMEOSTASIS

II. VITAMIN D AS A PROOXIDANT

III. VITAMIN D AS AN ANTIOXIDANT

IV. DISCUSSION

Acknowledgments

SECTION V: HUMAN PHYSIOLOGY

Chapter 46: Vitamin D: Role in the Calcium Economy

I. INTRODUCTION

II. OVERVIEW OF THE CALCIUM ECONOMY

III. CALCIUM ABSORPTIVE INPUT

IV. PHYSIOLOGICAL SOURCES OF VITAMIN D ACTIVITY

V. OPTIMAL VITAMIN D STATUS

VI. SUMMARY AND CONCLUSIONS

Chapter 47: Effects of Race, Geography, Body Habitus, Diet, and Exercise on Vitamin D Metabolism

I. INTRODUCTION

II. EFFECTS OF RACE AND GEOGRAPHY

III. EFFECTS OF DIET

IV. EFFECTS OF BODY HABITUS

V. EFFECTS OF EXERCISE

VI. SUMMARY

Chapter 48: Perinatal Vitamin D Actions

I. INTRODUCTION

II. THE LAST TRIMESTER OF PREGNANCY

III. THE NORMAL TERM INFANT

IV. THE TERM GROWTH-RETARDED INFANT

V. THE PREMATURE INFANT

VI. INFANTS OF DIABETIC MOTHERS

VII. LATE NEONATAL HYPOCALCEMIA

VIII. RECOMMENDATIONS FOR VITAMIN D INTAKE IN THE PERINATAL PERIOD

IX. SUMMARY

Chapter 49: Vitamin D Deficiency and Calcium Absorption during Infancy and Childhood

I. INTRODUCTION

II. PREMATURE INFANTS

III. FULL-TERM INFANTS

IV. TODDLERS AND PREPUBERTAL CHILDREN

V. CALCIUM ABSORPTION IN ADOLESCENTS

VI. FORTIFICATION OF FOODS WITH CALCIUM AND VITAMIN D FOR CHILDREN

VII. SUMMARY AND CONCLUSIONS

Acknowledgment

Chapter 50: Vitamin D Metabolism and Aging

I. INTRODUCTION

II. CUTANEOUS PRODUCTION OF VITAMIN D

III. DIETARY VITAMIN D AND INTESTINAL ABSORPTION

IV. SYNTHESIS OF 25-HYDROXYVITAMIN D

V. SYNTHESIS AND METABOLISM OF 1,25-DIHYDROXYVITAMIN D

VI. TISSUE RESPONSIVENESS AND THE ROLE OF VITAMIN D IN THE AGING PROCESS

VII. CONCLUSIONS

Chapter 51: Vitamin D Metabolism in Pregnancy and Lactation

I. INTRODUCTION

II. ADAPTATIONS IN VITAMIN D AND CALCIUM METABOLISM DURING PREGNANCY

III. EFFECTS OF LOW MATERNAL VITAMIN D AND CALCIUM INTAKE DURING PREGNANCY ON THE FETUS AND NEONATE

IV. ADAPTATIONS IN VITAMIN D AND CALCIUM METABOLISM DURING LACTATION AND AFTER WEANING

V. EFFECTS OF LOW MATERNAL VITAMIN D AND CALCIUM INTAKES ON BREAST MILK VITAMIN D AND CALCIUM CONCENTRATIONS

VI. CONCLUSIONS

Chapter 52: Vitamin D and Reproductive Organs

I. HISTORICAL VIEW

II. CHICK EMBRYONIC DEVELOPMENT AND EGG HATCHABILITY

III. MOUSE MODELS FOR A LACK OF VITAMIN D FUNCTION

IV. FETAL DEVELOPMENT AND VITAMIN D SYNTHESIS

V. CALCIUM HOMEOSTASIS IN THE FETUS AND ITS MOTHER

VI. FERTILITY

VII. TESTIS

VIII. OVARY

IX. UTERUS

X. MAMMARY GLAND

XI. AROMATASE

XII. PLACENTA

XIII. CONCLUDING REMARKS

Chapter 53: Vitamin D Receptor as a Sensor for Toxic Bile Acids

I. INTRODUCTION

II. BILE ACIDS: PHYSIOLOGIC ROLES IN LIPID DIGESTION AND ABSORPTION

III. THE FATE OF BILE ACIDS

IV. NUCLEAR RECEPTORS: KEY REGULATORS OF BILE ACID METABOLISM

V. BILE ACIDS, VITAMIN D RECEPTOR, AND COLON CANCER

VI. A MODEL OF LITHOCHOLIC ACID DETOXIFICATION IN THE INTESTINE

VII. PERSPECTIVES

Chapter 54: Vitamin D and the Renin—Angiotensin System

I. INTRODUCTION

II. THE RENIN–ANGIOTENSIN SYSTEM

III. SUNLIGHT, VITAMIN D, AND BLOOD PRESSURE: EPIDEMIOLOGICAL AND CLINICAL OBSERVATIONS

IV. VITAMIN D AND CARDIOVASCULAR FUNCTIONS

V. 1,25-DIHYDROXYVITAMIN D3 AS A NEGATIVE ENDOCRINE REGULATOR OF THE RENIN–ANGIOTENSIN SYSTEM

VI. VITAMIN D ANALOGS AS POTENTIAL ANTIHYPERTENSIVE AGENTS

VII. CONCLUSION

Chapter 55: Vitamin D and Muscle

I. INTRODUCTION

II. VITAMIN D–DEPENDENT MYOPATHIES

III. MUSCLE VITAMIN D RECEPTOR

IV. 1α,25(OH)2D3 REGULATION OF CALCIUM HOMEOSTASIS IN MUSCLE CELLS

V. MODULATION OF MUSCLE CELL PHOSPHATE UPTAKE BY VITAMIN D3 METABOLITES

VI. EFFECT OF 1α,25(OH)2D3 ON MUSCLE CELL PROLIFERATION AND DIFFERENTIATION

VII. MECHANISMS OF ACTION OF 1α,25(OH)2D3 IN MUSCLE

VIII. SUMMARY

Acknowledgments

Chapter 56: Vitamin D and Cardiovascular Medicine

I. INTRODUCTION

II. CLINICAL EVIDENCE FOR VITAMIN D SIGNALING IN CARDIOVASCULAR HEALTH

III. INDIRECT CARDIOVASCULAR ACTIONS OF VITAMIN D

IV. DIRECT ACTIONS OF VITAMIN D IN THE VASCULATURE

V. VASCULAR CALCIFICATION AND CALCITROPIC HORMONES: CARDIOVASCULAR TOXICOLOGY OF VITAMIN D

VI. SUMMARY AND CONCLUSIONS

VOLUME II

SECTION VI: DIAGNOSIS AND MANAGEMENT

Chapter 57: Approach to the Patient with Metabolic Bone Disease

I. INTRODUCTION

II. DIAGNOSTIC EVALUATION

III. TREATMENT

IV. SUMMARY

Acknowledgments

Chapter 58: Detection of Vitamin D and Its Major Metabolites

I. INTRODUCTION

II. DETECTION OF VITAMIN D

III. DETECTION OF 25OHD

IV. ADDENDUM

V. DETECTION OF 24,25(OH2)D

VI. DETECTION OF 1,25(OH)2D

VII. CLINICAL INTERPRETATION AND RELEVANCE OF ANTIRACHITIC STEROL MEASUREMENTS

Chapter 59: Bone Histomorphometry

I. INTRODUCTION

II. BONE BIOPSY

III. HISTOMORPHOMETRY

IV. ASSESSMENT OF MINERALIZATION

V. HISTOLOGICAL DIAGNOSIS OF OSTEOMALACIA

VI. ASSESSMENT OF BONE TURNOVER

VII. ASSESSMENT OF REMODELING BALANCE

VIII. ASSESSMENT OF BONE STRUCTURE

IX. CONCLUSIONS AND FUTURE DEVELOPMENTS

Chapter 60: Radiology of Rickets and Osteomalacia

I. INTRODUCTION AND HISTORICAL ASPECTS

II. VITAMIN D DEFICIENCY

III. RENAL OSTEODYSTROPHY

IV. RENAL TUBULAR DEFECTS AND HYPOPHOSPHATEMIA

V. ACIDEMIA

VI. DIFFERENTIAL DIAGNOSES

VII. VITAMIN D INTOXICATION

VIII. TECHNICAL ASPECTS OF IMAGING

IX. CONCLUSIONS

Chapter 61: The Pharmacology of Vitamin D, Including Fortification Strategies

I. INTRODUCTION

II. INDICATIONS AND CLINICAL USE: POTENTIAL HEALTH EFFECTS OF VITAMIN D

III. OVERVIEW OF THE SYSTEM OF VITAMIN D METABOLISM, AND ITS REGULATION

IV. DOSAGE CONSIDERATIONS

V. PHARMACOKINETIC PRINCIPLES, VOLUME OF DISTRIBUTION, TURNOVER AND HALF-LIFE AS IT PERTAINS TO VITAMIN D

VI. VITAMIN D TOXICITY AND SAFETY ISSUES

VII. SUMMARY

SECTION VII: DISORDERS OF THE VITAMIN D ENDOCRINE SYSTEM

Chapter 62: How to Define Normal Values for Serum Concentrations of 25-Hydroxyvitamin D? An Overview

I. INTRODUCTION

II. HOW TO DEFINE NORMAL VALUES

III. VARIABLES INFLUENCING NORMAL VALUES OF SERUM 25(OH)D

IV. CLASSIFICATION OF VITAMIN D REPLETE AND DEFICIENT STATES

V. DIETARY VITAMIN D INTAKE AND RECOMMENDED DAILY ALLOWANCES

Chapter 63: Vitamin D and the Pathogenesis of Rickets and Osteomalacia

I. INTRODUCTION

II. MORPHOLOGIC AND BIOCHEMICAL ASPECTS OF MINERALIZATION

III. PROCESSES LEADING TO ACCUMULATION OF UNMINERALIZED TISSUE

IV. EVOLUTION OF VITAMIN D RELATED BONE DISEASE

V. ASPECTS OF VITAMIN D METABOLISM RELEVANT TO RICKETS AND OSTEOMALACIA

VI. VITAMIN D AND THE PATHOGENESIS OF IMPAIRED MINERALIZATION

Chapter 64: The Hypocalcemic Disorders: Differential Diagnosis and Therapeutic Use of Vitamin D

I. PHYSIOLOGY

II. DIFFERENTIAL DIAGNOSIS OF HYPOCALCEMIA

III. THERAPY FOR HYPOCALCEMIA

Acknowledgments

Chapter 65: Vitamin D Deficiency and Nutritional Rickets in Children

I. INTRODUCTION

II. HISTORICAL PERSPECTIVE

III. THE EPIDEMIOLOGY OF VITAMIN D DEFICIENCY AND NUTRITIONAL RICKETS

IV. CLINICAL PRESENTATION

V. BIOCHEMICAL ABNORMALITIES

VI. RADIOLOGIC CHANGES

VII. TREATMENT AND PREVENTION

VIII. DIETARY CALCIUM DEFICIENCY

IX. THE PATHOGENETIC SPECTRUM OF NUTRITIONAL RICKETS

X. CONCLUSIONS

Chapter 66: Vitamin D Insufficiency in Adults and the Elderly

I. INTRODUCTION

II. DEFINITION OF VITAMIN D DEFICIENCY AND INSUFFICIENCY

III. DETERMINANTS OF VITAMIN D INSUFFICIENCY

IV. CONSEQUENCES OF LOW VITAMIN D STATUS

V. PREVALENCE OF VITAMIN D INSUFFICIENCY

VI. PREVENTIVE MEASURES: CORRECTION OF LOW VITAMIN D STATUS

VII. CONCLUSIONS

Chapter 67: Vitamin D and Osteoporosis

I. INTRODUCTION

II. EFFECT OF AGE ON LEVELS OF 25OHD

III. EFFECT OF AGE ON LEVELS OF 1,25(OH)2D

IV. THE EFFECT OF AGE ON CALCIUM INTAKE AND ABSORPTION

V. AGE AND PARATHYROID HORMONE

VI. INTERRELATIONSHIPS BETWEEN AGE-RELATED BONE LOSS, ESTROGEN, PTH, AND VITAMIN D METABOLISM

VII. SUMMARY OF CHANGES IN VITAMIN D WITH AGING

VIII. TREATMENT OF ESTABLISHED OSTEOPOROSIS WITH VITAMIN D

C. Meta-analysis of the Clinical Trials of Vitamin D

D. Safety

IX. CONCLUSIONS

Chapter 68: Genetic Vitamin D Receptor Polymorphisms and Risk of Disease

I. Introduction

II. STRUCTURE AND POLYMORPHISM OF THE VDR GENE

III. ASSOCIATION ANALYSIS IN DISEASE STATES

IV. CONCLUSIONS

Chapter 69: Clinical Disorders of Phosphate Homeostasis

I. Introduction

II. DISORDERS OF PHOSPHATE HOMEOSTASIS

III. DISORDERS RELATED TO AN ALTERED PHOSPHATE LOAD

Chapter 70: Disorders of Phosphate Metabolism: Autosomal Dominant Hypophosphatemic Rickets, Tumor Induced Osteomalacia, Fibrous Dysplasia, and the Pathophysiological Relevance of FGF23

I. INTRODUCTION

II. ADHR

III. TUMOR INDUCED OSTEOMALACIA

IV. FIBROUS DYSPLASIA

V. THE ROLE OF FGF23 IN XLH

VI. FGF23 IN HEALTH AND ITS POTENTIAL ROLE IN MAINTENANCE OF NORMAL PHOSPHATE AND VITAMIN D HOMEOSTASIS

VII. SUMMARY

Acknowledgements

Chapter 71: Vitamin D Pseudodeficiency

I. INTRODUCTION

II. CLINICAL MANIFESTATIONS

III. BIOCHEMICAL FINDINGS

IV. PLACENTA STUDIES

V. GENETIC STUDIES

VI. MOLECULAR DEFECT

VII. TREATMENT

VIII. CONCLUSION

Chapter 72: Hereditary 1,25-Dihydroxyvitamin D—Resistant Rickets

I. INTRODUCTION

II. THE CLINICAL FEATURES OF HVDRR

III. MECHANISM OF 1,25(OH)2D ACTION

IV. CELLULAR BASIS OF HVDRR

V. MOLECULAR BASIS FOR HVDRR

VI. THERAPY OF HVDRR

VII. ALOPECIA

VIII. CONCLUDING REMARKS

Chapter 73: Glucocorticoids and Vitamin D

I. INTRODUCTION

II. STEROID RECEPTORS AND ACTIONS IN BONE

III. EFFECT OF GLUCOCORTICOIDS ON VITAMIN D METABOLISM

IV. VITAMIN D AS A TREATMENT FOR GIO

V. SUMMARY

Chapter 74: Drug and Hormone Effects on Vitamin D Metabolism

I. INTRODUCTION

II. HORMONE EFFECTS ON VITAMIN D METABOLISM

III. DRUG EFFECTS ON VITAMIN D METABOLISM

IV. CONCLUSION

Chapter 75: Bone Disorders Associated with Gastrointestinal and Hepatobiliary Disease

I. INTRODUCTION

II. METABOLIC DISTURBANCES IN GASTROINTESTINAL DISEASE

III. ACQUIRED BONE DISEASE IN GASTROINTESTINAL DISORDERS

IV. GASTROINTESTINAL CONDITIONS ASSOCIATED WITH BONE DISORDERS

V. LIVER DISEASE

VI. SUMMARY

Chapter 76: Vitamin D and Renal Failure

I. INTRODUCTION

II. ALTERATIONS IN VITAMIN D BIOACTIVATION TO 1,25(OH)2D

III. ALTERATIONS IN 1,25(OH)2D/VDR ACTION

IV. TISSUE SPECIFIC EFFECTS OF LOW CALCITRIOL AND ABNORMAL VDR FUNCTION

V. VITAMIN D THERAPY IN CHRONIC RENAL FAILURE

VI. SUMMARY

Chapter 77: Idiopathic Hypercalciuria and Nephrolithiasis

I. INTRODUCTION

II. IDIOPATHIC HYPERCALCIURIA

III. GENETIC HYPERCALCIURIC RATS

IV. CURRENT VIEW OF HUMAN GENETIC HYPERCALCIURIA

V. THERAPEUTICS OF IDIOPATHIC HYPERCALCIURIA AND EFFECTS ON CALCIUM METABOLISM

VI. RISK OF STONE FORMATION USING VITAMIN D ANALOGS

VII. SUMMARY

Chapter 78: Hypercalcemia Due to Vitamin D Toxicity

I. INTRODUCTION

II. FORMS OF EXOGENOUS VITAMIN D TOXICITY

III. FORMS OF ENDOGENOUS VITAMIN D TOXICITY

IV. MECHANISMS OF VITAMIN D TOXICITY

V. CLINICAL MANIFESTATIONS

VI. Diagnosis of Vitamin D Toxicity

VII. Treatment of Vitamin D Toxicity

VIII. EVIDENCE FOR BENEFITS OF HIGHER VITAMIN D LEVELS

IX. SUMMARY AND CONCLUSIONS

Acknowledgment

Chapter 79: Extra-renal 1α-Hydroxylase Activity and Human Disease

I. INTRODUCTION

II. VITAMIN D AND GRANULOMA-FORMING DISEASE: HISTORICAL PERSPECTIVE

III. PATHOPHYSIOLOGY OF DISORDERED CALCIUM BALANCE IN SARCOIDOSIS: A MODEL FOR THE EXTRA-RENAL PRODUCTION OF AN ACTIVE VITAMIN D METABOLITE IN HUMAN DISEASE

IV. LOCAL IMMUNOREGULATORY EFFECTS OF ACTIVE VITAMIN D METABOLITES

V. HUMAN DISEASES ASSOCIATED WITH THE EXTRA-RENAL OVERPRODUCTION OF ACTIVE VITAMIN D METABOLITES (see Table I)

VI. DIAGNOSIS, PREVENTION, AND TREATMENT OF THE PATIENT WITH ENDOGENOUS VITAMIN D INTOXICATION

SECTION VIII: NEW VITAMIN D ANALOGS

Introduction to Vitamin D Analogs: An Overview

Chapter 80: Overview: Rational Design of 1α,25-Dihydroxyvitamin D3 Analogs (Deltanoids)

I. INTRODUCTION

II. RATIONALE BASED ON METABOLISM

III. RATIONALE BASED ON MOLECULAR BIOLOGY

IV. RATIONALE BASED ON ORGANIC CHEMISTRY

V. Conclusions

Chapter 81: Analog Metabolism

I. GENERAL CONSIDERATIONS

II. EXAMPLES OF THE METABOLISM OF ANALOGS OF VITAMIN D

III. IMPORTANT IMPLICATIONS DERIVED FROM ANALOG METABOLISM STUDIES

Acknowledgements

Chapter 82: Mechanisms for the Selective Actions of Vitamin D Analogs

I. IDENTIFICATION OF SELECTIVE VITAMIN D ANALOGS

II. THE IN VIVO SELECTIVITY OF VITAMIN D ANALOGS IS DETERMINED BY MULTIPLE PROTEIN INTERACTIONS

III. CONCLUDING REMARKS

Chapter 83: Molecular Basis for Differential Action of Vitamin D Analogs

I. INTRODUCTION

II. STRUCTURAL REQUIREMENTS FOR TRANSACTIVATION OF THE VDR BY ITS NATURAL LIGAND, 1,25(OH)2D3

III. DIFFERENTIAL ACTIVATION OF THE VDR BY SYNTHETIC ANALOGS

IV. CLINICAL SIGNIFICANCE FOR SELECTIVE MODULATION OF THE VDR BY VITAMIN D ANALOGS

Chapter 84: Development of New Vitamin D Analogs

I. INTRODUCTION

II. STRATEGY FOR DEVELOPMENT OF NEW VITAMIN D ANALOGS

III. STRUCTURE-ACTIVITY RELATIONSHIPS

IV. BIOLOGICAL ACTIVITIES

V. CLINICAL DEVELOPMENT OF LEO ANALOGS

Chapter 85: Gemini: The 1,25-dihydroxy Vitamin D Analogs with Two Side-Chains

I. INTRODUCTION

II. SYNTHESIS OF GEMINI

III. 24R-HYDROXY GEMINI METABOLITE

IV. THE 23-YNE-26,27-HEXAFLUORO GEMINI ANALOGS

V. GEMINI ANALOGS AS RENIN INHIBITORS

VI. INHIBITION OF ACUTE ALLOGRAFT REJECTION BY GEMINI ANALOGS

VII. RATIONALE FOR USING GEMINI ANALOGS TO TREAT COLON CANCER

Chapter 86: Development of OCT and ED-71

I. INTRODUCTION TO OCT AND ED-71

II. DEVELOPMENT OF OCT FOR SECONDARY HYPERPARATHYROIDISM AND PSORIASIS VULGARIS

III. DEVELOPMENT OF ED-71 FOR OSTEOPOROSIS

Acknowledgments

Chapter 87: 2-Carbon-Modified Analogs of 19-Nor-1α,25-Dihydroxyvitamin D3

I. INTRODUCTION

II. 19-NOR-AND 10,19-SATURATED DERIVATIVES OF 1,25(OH)2D3

III. EPIMERIZATION OF THE 20-CARBON

IV. EARLY 2-CARBON ANALOGS OF 19-NOR-1,25(OH)2D3 AND 25-OH-D3

V. 2-METHYLENE AND 2α-METHYL AND 2β-METHYL DERIVATIVES OF 1,25(OH)2D3

VI. 2-METHYLENE-19-NOR-(20S) -1,25(OH)2D3 (2MD) AND 2α-METHYL-19-NOR-(20S)-1,25(OH)2D3: ANALOGS THAT POSSESS ANABOLIC ACTIVITY ON THE SYNTHESIS OF BONE AND APPEAR TO BE BONE SELECTIVE ANALOGS OF 1,25(OH)2D3

VII. 2-METHYLENE-19-NOR-(20S)-1,25(OH)2D3: MOLECULAR MECHANISMS OF TISSUE SELECTIVITY AND ENHANCED POTENCY

VIII. 2-METHYLENE-19-NOR-1α-HYDROXYPREGNACALCIFEROL (2MPREGNA), 2-METHYLENE-19-NOR-1α-HYDROXYHOMOPREGNACALCIFEROL (2MP) AND 2-METHYLENE-19-NOR-(20S)-1α-HYDROXYBISHOMOPREGNA-CALCIFEROL (2MBISP)

IX. 2-METHYLENE-19-NOR-PREGNACALCIFEROL (2MPREGNA), 2-METHYLENE-19-NOR-1α-HYDROXYHOMOPREGNACALCIFEROL (2MP) AND 2-METHYLENE-19-NOR-(20S)-1α-HYDROXYBISHOMOPREGNA-CALCIFEROL (2MBISP): MOLECULAR MECHANISMS OF TISSUE SELECTIVITY

X. SUMMARY

Chapter 88: Nonsteroidal Analogs

I. INTRODUCTION

II. NONSECOSTEROID BISPHENOL COMPOUNDS

III. BISPHENOL ANALOGS AS SELECTIVE AGONISTS OF MUTANT VDR

IV. NON-SECOSTEROID CD RING MODIFICATIONS

V. PERSPECTIVES

Acknowledgments

SECTION IX: VITAMIN D AND CANCER

Chapter 89: Vitamin D: Cancer and Differentiation

I. INTRODUCTION

II. VITAMIN D AND CANCER

III. VITAMIN D EFFECTS ON TUMOR CELLS

IV. COMBINATION THERAPY

V. RESISTANCE AND VITAMIN D METABOLISM

VI. STIMULATION OF PROLIFERATION

VII. CONCLUSIONS

Chapter 90: Vitamin D, Sunlight, and the Natural History of Prostate Cancer

I. INTRODUCTION AND BACKGROUND

II. PROSTATE CANCER AND THE VITAMIN D HYPOTHESIS

III. OBSERVATIONAL STUDIES

IV. EXPERIMENTAL STUDIES OF THE VITAMIN D HYPOTHESIS

V. 1,25(OH)2D IS AN AUTOCRINE HORMONE IN THE PROSTATE

VI. VITAMIN D HYPOTHESIS: CONCLUSIONS

Acknowledgments

Chapter 91: Epidemiology of Cancer Risk: Vitamin D and Calcium

I. INTRODUCTION

II. COLORECTAL NEOPLASMS

III. PROSTATE CANCER

IV. CONCLUSION

Chapter 92: Differentiation and the Cell Cycle

I. INTRODUCTION

II. INDUCTION OF DIFFERENTIATION BY 1,25(OH)2D3 AND ANALOGS (DELTANOIDS)

III. CELL CYCLE CONSEQUENCES OF DELTANOID-INDUCED DIFFERENTIATION

IV. CELL-TYPE SPECIFICITY OF INHIBITION OF CELL PROLIFERATION BY DELTANOIDS WITHOUT EVIDENCE OF DIFFERENTIATION

V. CONCLUSIONS

Acknowledgments

Chapter 93: Vitamin D and Breast Cancer

I. INTRODUCTION

II. Vitamin D Actions on Breast Cancer Cells

III. DETERMINANTS OF BREAST CANCER SENSITIVITY TO VITAMIN D

IV. VITAMIN D ANALOGS: PRECLINICAL AND CLINICAL TRIALS

V. VITAMIN D AND PREVENTION OF BREAST CANCER

VI. SUMMARY AND OUTSTANDING RESEARCH QUESTIONS

Chapter 94: Vitamin D and Prostate Cancer

I. INTRODUCTION

II. PROSTATE AS A TARGET FOR VITAMIN D

III. INHIBITION OF PROSTATE CANCER GROWTH BY VITAMIN D

IV. VITAMIN D ANALOGS

V. MECHANISMS OF VITAMIN D–MEDIATED GROWTH INHIBITION

VI. VITAMIN D IN COMBINATION WITH OTHER AGENTS

VII. CLINICAL TRIALS

VIII. SUMMARY AND CONCLUSIONS

Chapter 95: Vitamin D and Colon Cancer

I. INTRODUCTION

II. MOLECULAR BASIS OF VITAMIN D ACTION ON NEOPLASTIC COLONOCYTES

III. VITAMIN D METABOLISM IN NORMAL AND NEOPLASTIC COLON CELLS

IV. NUTRITIONAL REGULATION OF CYP27B1 AND CYP24

V. CONCLUSION

Acknowledgment

Chapter 96: Vitamin D and Hematological Malignancy

I. OVERVIEW OF HEMATOPOIESIS

II. VITAMIN D RECEPTORS IN BLOOD CELLS

III. EFFECTS OF VITAMIN D COMPOUNDS ON NORMAL HEMATOPOIESIS

IV. EFFECTS OF VITAMIN D COMPOUNDS ON LEUKEMIC CELL LINES

V. VITAMIN D ANALOGS EFFECTIVE AGAINST LEUKEMIC CELLS

VI. SUMMARY AND CONCLUSIONS

Chapter 97: Clinical Development of Calcitriol and Calcitriol Analogs in Oncology: Progress and Considerations for Future Development

I. INTRODUCTION

II. CLINICAL TRIALS

III. LABORATORY-CLINICAL EXTRAPOLATIONS OF CALCITRIOL EXPOSURE

IV. HIGH DOSE INTERMITTENT CALCITRIOL

V. CALCITRIOL + CYTOTOXIC AGENT COMBINATIONS

VI. CALCITRIOL ANALOGS

VII. THE FUTURE

SECTION X: EMERGING USES

Chapter 98: Vitamin D3: Autoimmunity and Immunosuppression

I. INTRODUCTION

II. AUTOIMMUNITY

Chapter 99: Vitamin D and Diabetes

I. INTRODUCTION

II. VITAMIN D AND THE β CELL

III. VITAMIN D AND THE IMMUNE SYSTEM IN TYPE 1 DIABETES MELLITUS

IV. VITAMIN D RECEPTOR POLYMORPHISM AND THE RISK FOR DIABETES

V. CLINICAL PERSPECTIVES

Chapter 100: Vitamin D, A Neuroactive Hormone: From Brain Development to Pathological Disorders

I. INTRODUCTION

II. VITAMIN D RECEPTOR AND TARGETS IN THE CENTRAL NERVOUS SYSTEM

III. VITAMIN D ACTIONS IN THE CENTRAL NERVOUS SYSTEM

IV. 1,25(OH)2D3 AND BRAIN TUMORS

V. 1,25(OH)2D3, A MEDIATOR OF NEURO-IMMUNE INTERACTIONS

VI. CONCLUSION

Chapter 101: Psoriasis and Other Skin Diseases

I. INTRODUCTION

II. PATHOGENESIS OF PSORIASIS

III. THE VITAMIN D SYSTEM IN NORMAL AND PSORIATIC SKIN

IV. PHYSIOLOGICAL AND PHARMACOLOGICAL ACTIONS OF VITAMIN D ANALOGS IN NORMAL AND PSORIATIC SKIN

V. CLINICAL USE OF 1,25(OH)2D3 AND ITS ANALOGS IN PSORIASIS

VI. VITAMIN D ANALOG THERAPY IN OTHER SKIN DISEASES

VII. PERSPECTIVES FOR THE DEVELOPMENT OF NEW VITAMIN D ANALOGS WITH LESS CALCEMIC ACTIVITY FOR THE TREATMENT OF HYPERPROLIFERATIVE SKIN DISORDERS

Chapter 102: Muscles and Falls

I. INTRODUCTION

II. HYPOVITAMINOSIS D MYOPATHY (HDM): SYMPTOMS AND SIGNS

III. MUSCLE PHYSIOLOGY IN RELATION TO HDM

IV. EXPERIMENTAL STUDIES ON THE EFFECTS OF VITAMIN D ON STRIATED MUSCLE

V. CLINICAL STUDIES ON HYPOVITAMINOSIS D MYOPATHY

VI. CLINICAL STUDIES ON THE RISK OF FALLS AND VITAMIN D STATUS

VII. IS HDM CAUSED BY LOW LEVELS OF 25OHD, 1,25(OH)2D OR ELEVATED PTH?

VIII. OTHER POSSIBLE MUSCULAR EFFECTS OF VITAMIN D

IX. SUMMARY

Chapter 103: Renal Failure and Secondary Hyperparathyroidism

I. ROLE OF VITAMIN D IN THE DEVELOPMENT OF HYPERPARATHYROIDISM IN RENAL FAILURE

II. RESISTANCE TO 1,25(OH)2D AS A CAUSE OF SEVERE SECONDARY HYPERPARATHYROIDISM IN CHRONIC RENAL FAILURE

III. MANAGEMENT OF SEVERE HYPERPARATHYROIDISM REFRACTORY TO MEDICAL THERAPY

IV. FUTURE ROLES OF VITAMIN D ANALOGS IN CHRONIC RENAL FAILURE

Acknowledgements

Chapter 104: Inhibition of Benign Prostatic Hyperplasia by Vitamin D Receptor Ligands

I. INTRODUCTION

II. PATHOGENESIS OF BPH

III. EFFECTS OF ANDROGENS AND GROWTH FACTORS ON HUMAN BPH CELLS

IV. VITAMIN D RECEPTOR EXPRESSION IN PROSTATE CELLS

V. ANTIPROLIFERATIVE EFFECTS OF BXL-353 ON HUMAN BPH CELLS

VI. INHIBITION OF IN VIVO PROSTATE GROWTH BY BXL-353

VII. CONCLUSIONS

Index

Copyright

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List of Contributors

Numbers in parentheses indicate the page(s) on which the authors’ contributions begin.

Steven A. Abrams (811),      USDA/ARS Children’s Nutrition Research Center, Houston, Texas 77030, USA

John S. Adams(341, 1379),      Division of Endocrinology, Diabetes, and Metabolism, University of California, 8700 Beverly Blvd, Los Angeles, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA

Judith E. Adams (967),      Clinical Radiology, Imaging Science and Biomedical Engineering, Stopford Building, The University, Manchester M13 9PT, United Kingdom

Luciano Adorini (631, 1511, 1833),      BioXell SpA, 20132 Milano, Italy

Paul H. Anderson (711),      Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia

Gerald J. Atkins (711),      Hanson Institute, Adelaide, South Australia, Australia

Jane E. Aubin (649),      Department of Molecular and Medical Genetics, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Isabelle Bailleul-Forestier (599),      INSERM E110, Université Paris VII, IFR58, Cordeliers Biomedical Institute, 75270 Paris Cedex 06, France

Julia Barsony (363),      Laboratory of Cellular Biochemistry and Biology, NIDDK/NIH, Bethesda, Maryland 20892-0850, USA

Thomas K. Barthel (219),      Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, Arizona 85721, USA

Norman H. Bell (789),      Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA

Ariane Berdal (599),      INSERM E110, Université Paris VII, IFR58, Cordeliers Biomedical Institute, 75270 Paris Cedex 06, France

Joel J. Bergh (751),      Department of Biological Sciences, University of Delaware, Newark, Delaware 19716, USA

Jacqueline L. Berry (1293),      University of Manchester, Vitamin D Research Group, Department of Medicine, Manchester Royal Infirmary, Manchester M13 9WL, UK

Daniel D. Bikle (609),      Endocrine Research Unit, Veterans’ Affairs Medical Center, University of California-San Francisco, San Francisco, California 94121-1598, USA

John P. Bilezikian (1355),      Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA

Ernst Binderup (1489),      Biological Research, Leo Pharma, DK-2750 Ballerup, Denmark

Lise Binderup (1489),      Biological Research, Leo Pharma, DK-2750 Ballerup, Denmark

Nicholas J. Bishop (803),      Academic Department of Child Health, University of Sheffield, Sheffield Children’s Hospital, Sheffield S10 2TH, United Kingdom

Ilse Bogaerts (135),      Laboratory Analytische Chemie, Van Evenstraat 4; B-3000 Leuven, Belgium

Ricardo L. Boland (883),      Department de Biología, Bioquímica & Farmacía, Universidad Nacional del Sur, San Juan 670, (8000) Bahía Blanca, Argentina

Adele L. Boskey (477),      Mineralized Tissues Laboratory, Hospital for Special Surgery, Affiliated with Weil College of Cornell Medical School, New York, New York 10021, USA

Roger Bouillon (135, 429, 1763),      Legendo, Onderwijs en Navorsing 902, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium

Barbara D. Boyan (575),      Department of Biomedical Engineering at Georgia Tech and Emory University, Georgia Institute of Technology, Atlanta, Georgia 30332, USA

Philippe Brachet (1779),      INSERM U 643, Centre Hospitalier Universitaire, 30 bd Jean Monnet, 44093 Nantes, France

Alex J. Brown (1313, 1449),      Renal Division, Washington University School of Medicine, St. Louis, Missouri 63110, USA

Edward M. Brown (551),      Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

Carsten Carlberg (313),      Department of Biochemistry, University of Kuopio, PFIN-70211 Kuopio, Finland

Geert Carmeliet (429),      Legendo, Onderwijs en Navorsing 902, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium

Thomas O. Carpenter (1049),      Department of Pediatrics, Yale University, School of Medicine, New Haven, Connecticut 06520-8064, USA

Marie-Claire Chapuy (1085),      INSERM Unit 403, Faculty Laennec and Department of Rheumatology and Bone Disease, Edouard Herriot Hosptial, Lyon, France

Fredriech K.W. Chan (1355),      Department of Medicine, Queen Elizabeth Hospital, Hong Kong

Tai C. Chen (1599),      Vitamin D, Skin, and Bone Research Laboratory, Boston University Medical Center, Boston, Massachusetts 02188, USA

Sylvia Christakos (721),      Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA

Margaret Clagett-Dame (1543),      Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706, USA

Thomas L. Clemens (899),      Department of Cell Biology and Physiology, Department of Internal Medicine, University of Cincinnati School of Medicine, Cincinnati, Ohio 45276, USA

Je-Yong Choi (327),      Department of Biochemistry, Kyungpook National University, Daegu, Korea

Fredric L. Coe (1339),      Nephrology Section, The University of Chicago Pritzker School of Medicine, Chicago, Illinois 60637, USA

Kay Colston (1663),      Department OGEM, St. George’s Hospital Medical School, London, SW17 0RE, United Kingdom

Juliet E. Compston (951),      Department of Medicine, Level 5, University of Cambridge, School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, England CB2 2QQ, United Kingdom

Nancy E. Cooke (117),      Department of Genetics and Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6149, USA

Clara Crescioli (1833),      Endocrinology Unit, Department of Clinical Physiopathology, University of Florence, Florence 50139, Italy

Heide S. Cross (1709),      Department of Pathophysiology, Medical, University of Vienna, A-1090 Vienna, Währingergürtel 18-20, Austria

Michael Danilenko (1635),      Department of Clinical Biochemistry, Faculty of Health Science, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel

Jean-Luc Davideau (599),      INSERM E110, Université Paris VII, IFR58, Cordeliers Biomedical Institute, 75270 Paris Cedex 06, France

Michael Davies (1293),      Vitamin D Research Group, University Department of Medicine, Manchester Royal Infirmary, Manchester, M13 9WL, United Kingdom

Hector F. DeLuca (3, 1543),      Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706, USA

Marie B. Demay (341),      Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA

Puneet Dhawan (721),      Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA

Carlos Encinas Dominguez (219),      Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, Arizona 85721, USA

Diane R. Dowd (291),      Department of Pharmacology–W334, Case Western Reserve University, Cleveland, Ohio 44106, USA

Marc K. Drezner (1159),      Department of Medicine, Endocrinology, Diabetes, and Metabolism Section, University of Wisconsin–Madison, Madison, Wisconsin 53792, USA

Thomas W. Dunlop (313),      Department of Biochemistry, University of Kuopio, PFIN-70211 Kuopio, Finland

Adriana S. Dusso (1313),      Renal Division, Washington University School of Medicine, St. Louis, Missouri 63110, USA

Richard Eastell (1101),      University of Sheffield Clinical Sciences Centre, Northern General Hospital, Sheffield South Yorkshire S5 7AU, United Kingdom

Michael J. Econs (1189),      Indiana University School of Medicine, Department of Medicine and Medical and Molecular Genetics, Indianapolis, Indiana 46202, USA

John Eisman (193),      Bone and Mineral Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, New South Wales 2010, Australia

Sol Epstein (1253),      Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA

Erik Fink Eriksen (1805),      Osteoporosis Team of Lilly Research Laboratories, Lilly Corp Center, Indianapolis, Indiana 46285, USA

Luis M. Esteban (193),      Bone and Mineral Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, New South Wales 2010, Australia

Dan Faibish (477),      Mineralized Tissues Laboratory, Hospital for Special Surgery, Affiliated with Weil College of Cornell Medical School, New York, New York 10021, USA

Yue Fang (1121),      Department of Internal Medicine, Genetic Laboratory, Erasmus Medical Centre, NL-3015 GE Rotterdam, The Netherlands

Mary C. Farach-Carson (751),      Department of Biological Sciences, University of Delaware, Newark, Delaware 19716, USA

Murray J. Favus (1339),      Section of Endocrinology, University of Chicago, Chicago, Illinois 60637, USA

David Feldman (1207, 1679),      Stanford University School of Medicine, Division of Endocrinology, Stanford, California 94305-5103, USA

David Findlay (711),      Department of Orthopedic Surgery and Trauma, University of Adelaide, Adelaide 5000, South Australia, Australia

Christian Frank (313),      Department of Biochemistry, University of Kuopio, PFIN-70211 Kuopio, Finland

Leonard P. Freedman (263),      Department of Molecular Endocrinology and Bone Biology, Merck Research Laboratories, West Point, Pennsylvania 19486-0004, USA

Ryuji Fujiki (305),      University of Tokyo, Institute of Molecular and Cellular Biosciences, 1-1-1 Yayoi-cho, Bunkyo-ku, Tokyo, 113-0032, Japan

Masafumi Fukagawa (1821),      Division of Nephrology and Dialysis Center, Kobe University School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan

Robert F. Gagel (687),      Section of Endocrinology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Emmanuel Garcion (1779),      INSERM U 646, 10 rue André Boquel, 49100 Angers, France

Edith M. Gardiner (193),      Bone and Mineral Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, New South Wales 2010, Australia

Marielle Gascon-Barré (47),      Département de Pharmacologie, Faculté de Médecine, Université de Montréal, and Centre de recherche de l’Université de Montréal, Montréal, Québec H2X 1P1, Canada

Edward Giovannucci (1617),      Harvard School of Public Health, Department of Nutrition, Boston, Massachusetts 02115, USA

Henning Glerup (1805),      Aarhus Kommunehospital, Dept V, Noerrebrogade 44, DK-8000 Aarhus C, Denmark

Francis H. Glorieux (1197),      Genetics Unit, Shriners Hospital for Children, Departments of Surgery, Pediatrics, and Human Genetics, McGill University, Montréal, Québec H3G 1A6, Canada

Wagn O. Godtfredsen (1489),      Medicinal Chemistry, Leo Pharma, DK-2750 Ballerup, Denmark

David Goltzman (737),      Department of Medicine, McGill University and McGill University Health Center, Montréal, Québec H3A 1A1, Canada

Soraya Gutierrez (327),      Departamento de Biología Molecular, Universidad de Concepción, Concepción, Chile

Conny Gysemans (1763),      Legendo, Onderwijs en Navorsing 902, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium

Bernard P. Halloran (823),      Division of Endocrinology, Veterans Affairs Medical Center, San Francisco, California 94121, USA

Carol A. Haussler (219),      Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, Arizona 85721, USA

Mark R. Haussler (219),      Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, Arizona 85721, USA

Robert P. Heaney (773),      Creighton University, Omaha, Nebraska 68131, USA

Johan Heersche (649),      Faculty of Dentistry, University of Toronto, Toronto M5S 1A8, Ontario, Canada

Helen L. Henry (69),      Department of Biochemistry, University of California–Riverside, Riverside, California 92521, USA

Pamela A. Hershberger (1741),      Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA

Martin Hewison (1379),      Division of Medical Sciences, The University of Birmingham, Queen Elizabeth Medical Centre, Birmingham, B15 2TH, United Kingdom

Richard A. Heyman (1557),      X-Ceptor Therapeutics, San Diego, California 92121, USA

Kanji Higashio (665),      Research Center for Genomic Medicine, Saitama Medical School, Saitama, 350-1241, Japan

Michael F. Holick (37, 1511, 1791),      Vitamin D, Skin, and Bone Research Laboratory; Department of Medicine; Endocrinology, Nutrition and Diabetes Section; Boston Medical Center and Boston University School of Medicine, Boston, Massachusetts 02118, USA

Bruce W. Hollis (931),      Departments of Pediatrics, Biochemistry, and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425, USA

Ronald L. Horst (15),      U.S. Department of Agriculture, Agricultural Research Service, National Animal Disease Center, Ames, Iowa 50010-0070, USA

Jui-Cheng Hsieh (219),      Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, Arizona 85721, USA

Karl L. Insogna (1049),      Department of Medicine, Yale University School of Medicine, New Haven, CT 06520-8064, USA

Elizabeth T. Jacobs (219),      College of Medicine, University of Arizona, Tucson, Arizona 85721, USA

Amjad Javed (327),      Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA

Glenville Jones (1423),      Department of Biochemistry, Queen’s University, Kingston, Ontario K7L 3N6, Canada

Candace S. Johnson (1741),      Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA

Peter W. Jurutka (219),      Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, Arizona 85721, USA

Mehmet Kahraman (1405),      Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218-2685, USA

S. Kaleem Zaidi (327),      Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA

Heidi J. Kalkwarf (839),      Division of General and Community Pediatrics, Children’s Hospital Medical Center, Cincinnati, Ohio 45229, USA

Shigeaki Kato (305),      University of Tokyo, Institute of Molecular and Cellular Biosciences, 1-1-1 Yayoi-cho, Bunkyo-ku, Tokyo, 113-0032, Japan

Anne-Marie Kissmeyer (1489),      Biological Research, Leo Pharma, DK-2750 Ballerup, Denmark

Hirochika Kitagawa (305),      University of Tokyo, Institute of Molecular and Cellular Biosciences, 1-1-1 Yayoi-cho, Bunkyo-ku, Tokyo, 113-0032, Japan

Lilia M.C. Koberle (1355),      Health Sciences Department, Federal University, Sao Carlos, Brazil

H. Phillip Koeffler (1727),      Hematology/Oncology Division, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA

Ruth Koren (761),      Felsenstein Medical Research Center, Beilinson Campus, Rabin Medical Center, Petah Tikva 49100, Israel

Barbara E. Kream (703),      Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030-1850, USA

Richard Kremer (737),      Department of Medicine, McGill University and McGill University Health Center, Montréal, Québec H3A 1A1, Canada

Aruna V. Krishnan (1679),      Stanford University School of Medicine, Division of Endocrinology, Stanford, California 94305-5103, USA

Noboru Kubodera (1525),      Department of Product Planning, Chugai Pharmaceutical Co. Ltd., 2-1-9 Kyobashi, Chuo-ku, Tokyo, 104-8301, Japan

Rajiv Kumar (515),      Departments of Medicine, Biochemistry and Molecular Biology and Mayo Proteomics Research Center, Divisions of Nephrology, and Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic and Foundation, Rochester, Minnesota 55905-0002, USA

Kiyoshi Kurokawa (1821),      Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

Christopher J. Laing (117),      Department of Genetics and Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6144, USA

Jacques Lemire (1753),      Pediatric Nephrology, University of California-San Diego, La Jolla, California 92093-0831, USA

Frédéric Lézot (599),      INSERM E110, Université Paris VII, IFR58, Cordeliers Biomedical Institute, 75270 Paris Cedex 06, France

Yan Chun Li (721, 871, 1511),      Department of Medicine/GI Section, University of Chicago, Chicago, Illinois 60637, USA

Jane B. Lian (327),      Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA

Alexander C. Lichtler (703),      Department of Genetics and Developmental Biology, The University of Connecticut Health Center, Farmington, Connecticut 06030, USA

Paul Lips (1019),      Department of Endocrinology, Vrijie University Medical Center, Amsterdam, 1007 MB, The Netherlands

Yan Liu (721),      Department of Biochemistry and Molecular Biology, New Jersey Medical School, Newark, New Jersey 07103, USA

Paul MacDonald (291),      Department of Pharmacology–W334, Case Western Reserve University, Cleveland, Ohio 44106, USA

Hubert Maehr (1511),      BioXell, Inc., Hoffmann-La Roche, Inc., Nutley, New Jersey 07110-1199, USA

Mario Maggi (1833),      Andrology Unit, Department Clinical Physiopathology, University of Florence, 50139 Florence, Italy

Peter J. Malloy (1207),      Stanford University School of Medicine, Division of Endocrinology, Stanford, California 94305-5103, USA

David J. Mangelsdorf (863),      Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9050, USA

Chantal Mathieu (1763),      Legendo, Onderwijs en Navorsing 902, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium

Brian May (85),      School of Molecular and Biomedical Science, University of Adelaide, South Australia 5005, Australia

Andrew P. Mee (1293),      Vitamin D Research Group, University Department of Medicine, Manchester Royal Infirmary, Manchester, M13 9WL, United Kingdom

Pierre J. Meunier (1085),      INSERM Unit 403, Faculty Laennec and Department of Rheumatology and Bone Disease, Edouard Herriot Hospital, Lyon, France

Toshimi Michigami (851),      Department of Environmental Medicine, Osaka Medical Center and Institute for Maternal and Child Health, Osaka, Japan

Martin Montecino (327),      Departamento de Biología Molecular, Universidad de Concepción, Concepción, Chile

Dino Moras (279),      Département de Biologie et de Génomique Structurales, CNRS/INSERM/Université Louis Pasteur 1, BP 10142, 67404 Illkirch Cedex, France

Roberta Morosetti (1727),      Pediatric Oncology Division, Catholic University of Rome, Rome, Italy

Howard A. Morris (711),      Hanson Institute, Adelaide, South Australia, Australia

Daniel L. Motola (863),      Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9050, USA

Josephia Muindi (1741),      Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA

Shigeo Nakajima (851),      Department of Developmental Medicine (Pediatrics), D-5, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan

Tally Naveh-Many (537),      Minerva Center for Calcium and Bone Metabolism, Hebrew University Hadassah Medical Center, Ein Karem, Jerusalem, 91120, Israel

Philippe Naveilhan (1779),      INSERM U 643, Centre Hospitalier Universitaire, 30 bd Jean Monnet, 44093 Nantes, France

Isabelle Neveu (1779),      INSERM U 643, Centre Hospitalier Universitaire, 30 bd Jean Monnet, 44093 Nantes, France

Anthony W. Norman (381),      Department of Biochemistry, University of California, Riverside, Riverside, California 92521-0129, USA

Anders Nykjaer (153),      Institute of Medical Biochemistry, University of Aarhus, Ole Worms Allee, DK-8000 Aarhus C, Denmark

James O’Kelly (1727),      Hematology/Oncology Division, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA

John L. Omdahl (85),      Office of Research, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131-5166, USA

Peter Ordentlich (1557),      X-Ceptor Therapeutics, San Diego, California 92121, USA

Keiichi Ozono (851),      Department of Developmental Medicine (Pediatrics), D-5, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan

A. Michael Parfitt (497, 1029),      Division of Endocrinology and Center for Osteoporosis and Metabolic Bone Disease, University of Arkansas for Medical Science, Little Rock, Arkansas 72205, USA

Donna M. Peehl (1679),      Stanford University School of Medicine, Division of Endocrinology, Stanford, California 94305-5103, USA

Sara Peleg (1471),      Department of Endocrine Neoplasia and Hormonal Diseases, Unit 435, University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA

Xiaorong Peng (721),      Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA

John M. Pettifor (1065),      Department of Pediatrics, Chris Hani Baragwanath Hospital, Mineral Metabolism Research Unit, P.O. Bertsham, Johannesburg, Gauteng 2013, South Africa

J. Wesley Pike (167, 1207, 1403, 1543),      Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706, USA

Elizabeth A. Platz (1617),      Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA

Lori A. Plum (1543),      Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706, USA

Shirwin Pockwinse (327),      Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA

Huibert A.P. Pols (1121, 1571),      Department of Internal Medicine, Erasmus Medical Centre, NL-3015 GD Rotterdam, The Netherlands

Anthony A. Portale (453, 823),      Department of Pediatrics, University of California – San Francisco, San Francisco, California 94121, USA

Gary H. Posner (1405),      Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218-2685, USA

Mehrdad Rahmaniyan (789),      Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA

Amiram Ravid (761),      Felsenstein Medical Research Center, Beilinson Campus, Rabin Medical Center, Petah Tikva 49100, Israel

G. Satyanarayana Reddy (15, 1511),      Brown University, Department of Chemistry, Providence, Rhode Island, USA

Jörg Reichrath (1791),      The Saarland University Hospital, Department of Dermatology, Kirrberger Str., 66421 Homburg/Saar, Germany

Timothy A. Reinhardt (15),      U.S. Department of Agriculture, Agricultural Research Service, National Animal Disease Center, Ames, Iowa 50010-0070, USA

Alfred A. Reszka (263),      Department of Molecular Endocrinology and Bone Biology, Merck Research Laboratories, West Point, Pennsylvania 19486-0004, USA

B. Lawrence Riggs (1101),      Division of Endocrinology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA

Natacha Rochel (279),      Département de Biologie et de Génomique Structurales, CNRS/INSERM/Université Louis Pasteur 1, BP 10142, 67404 Illkirch Cedex, France

Mishaela R. Rubin (1355),      Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10027, USA

Andrew F. Russo (687),      Department of Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242, USA

Philip Sambrook (1239),      Institute of Bone & Joint Research, University of Sydney, Royal North Shore Hospital, Sydney 2065, Australia

Adina E. Schneider (1253),      Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA

Gary G. Schwartz (1599),      Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA

Zvi Schwartz (575),      Department of Periodontics, Hebrew University Hadassah Faculty of Dental Medicine, Jerusalem, Israel

Jiali Shen (327),      Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA

Nirupama K. Shevde (167, 1543),      Department of Biochemistry, University of Wisconsin–Madison, Madison, Wisconsin 53706, USA

Rafal R. Sicinski (1543),      Department of Chemistry, University of Warsaw, ul. L. Pasteura 2, Warsaw 02-093, Poland

Justin Silver (537),      Minerva Center for Calcium and Bone Metabolism, Hebrew University Hadassah Medical Center, Ein Karem, Jerusalem, 91120, Israel

Eduardo A. Slatopolsky (1313, 1449),      Renal Division, Washington University School of Medicine, St. Louis, Missouri 63110, USA

Bonny L. Specker (839),      Martin Program in Human Nutrition, South Dakota State University, Brookings, South Dakota 57007, USA

René St-Arnaud (105, 1197),      Genetics Unit, Shriners Hospital for Children, Montréal, Quebec H3G 1A6, Canada

Gary S. Stein (327),      Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA

Janet L. Stein (327),      Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA

Paula H. Stern (565),      Department of Molecular Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA

George P. Studzinski (1635),      UMD-New Jersey Medical School, Newark, New Jersey 07103, USA

Tatsuo Suda (665),      Research Center for Genomic Medicine, Saitama Medical School, Hidaka-shi, Saitama 350-1241, Japan

Amelia L.M. Sutton (291),      Department of Pharmacology–W334, Case Western Reserve University, Cleveland, Ohio 44106, USA

Peter Tebben (515),      Departments of Medicine, Biochemistry and Molecular Biology and Mayo Proteomics Research Center, Divisions of Nephrology, and Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic and Foundation, Rochester, Minnesota 55905-0002, USA

Harriet S. Tenenhouse (453),      Departments of Pediatrics and Human Genetics, McGill University and Montréal Children’s Hospital Research Institute, Montréal, Québec, H3Z 2Z3, Canada

Michelle L. Thatcher (219),      Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, Arizona 85721, USA

Susan Thys-Jacobs (1355),      Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10027, USA

Dwight A. Towler (899),      Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA

Donald L. Trump (1741),      Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263, USA

André G. Uitterlinden (1121),      Genetic Laboratory, Department of Internal Medicine, Erasmus Medical Centre, NL-3015 GD Rotterdam, The Netherlands

Milan R. Uskoković (1511),      BioXell, Inc., Nutley, New Jersey 07110-1199, USA

Sami Väisänen (313),      Department of Biochemistry, University of Kuopio, PFIN-70211 Kuopio, Finland

Hugo Van Baelen (135),      Legendo, Onderwijs en Navorsing 902, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium

Sophie Van Cromphaut (429),      Legendo, Onderwijs en Navorsing 902, U.Z. Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium

Johannes P.T.M. van Leeuwen (1571),      Department of Internal Medicine, Erasmus MC, 3000 DR Rotterdam, The Netherlands

Joyce B.J. van Meurs (1121),      Genetic Laboratory, Department of Internal Medicine, Erasmus Medical Centre, NL-3015 GD Rotterdam, The Netherlands

Andre J. van Wijnen (327),      Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA

Christel Verboven (135),      Laboratory Analytische Chemie, Van Evenstraat 4; B-3000 Leuven, Belgium

Reinhold Vieth (995),      Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada

Robert H. Wasserman (411),      Department of Biomedical Sciences, VRT-08-20, Cornell University, Ithaca, New York 14853, USA

JoEllen Welsh (1663),      Department Biological Science, University Notre Dame, Notre Dame, Indiana 46556, USA

G. Kerr Whitfield (219),      Department of Biochemistry and Molecular Biophysics, University of Arizona, Tucson, Arizona 85721, USA

Michael P. Whyte (913),      Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri 63131, USA and Division of Bone and Mineral Diseases, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri 63110, USA

Thomas Willnow (153),      Division of Molecular Cardiovascular Research, Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Strasse 10, D-13125 Berlin, Germany

Didier Wion (1779),      INSERM U318, Centre Hospitalier Michallon, 38043 Grenoble cedex 09, France

Hisataka Yasuda (665),      Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

Daniel Young (327),      Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA

Chi Zhang (291),      Department of Pharmacology–W334, Case Western Reserve University, Cleveland, Ohio 44106, USA

Preface to the 2nd Edition

Those interested in the vitamin D field will not be surprised that this second edition is considerably larger than the first edition. A great deal of progress has been made since the first edition was published in 1997. However, our goal in planning this updated version remains the same. We have endeavored to provide investigators, clinicians, and students with a comprehensive, definitive, and up-to-date compendium of the diverse scientific and clinical aspects of vitamin D, each area covered by experts in the field. Our hope for the second edition is that this book will continue to serve as both a resource for current researchers, as well as a guide to assist those in related disciplines to enter the realm of vitamin D research. We hope that this book will illuminate the vitamin D field and help investigators identify areas where new research is needed as well as educate them about what is currently known. We believe that the first edition succeeded in stimulating interactions between researchers and clinicians from different disciplines and that it facilitated collaborations. As we move from basic science and physiology to the use of vitamin D and its analogs as pharmacological agents to treat various diseases, the need for cross-collaborations between researchers and clinicians from different disciplines will increase. We hope that this new volume will continue to be a valuable resource that plays a role in this advancement and stimulates and facilitates these interactions.

Enormous progress in the study of vitamin D has been made in the approximately eight years since the first edition was written and we hope that this book has contributed in some way to this progress. The first edition proved to be highly valuable to its readers and the chapters have been cited frequently as authoritative reviews of the field. However, it became clear to us that the time was ripe to organize a second edition. Building on the original, we hope this second edition will incorporate all of the progress made in the field since the first edition was published so that our objective of an up-to-date compendium containing everything you wanted to know about vitamin D will continue.

The second edition is essentially a new and reinvigorated book. We have changed the symbol on the cover to reflect its updated content and the field’s continued evolution into the molecular world. This new edition now includes 104 chapters. In order to cover the growth of new information on vitamin D, we have had to publish this new edition in two volumes. In addition, the book has undergone some major remodeling. There are 33 completely new chapters and 18 other chapters have had major changes in authorship and are totally rewritten. While approximately half of the chapters have some of the same authors, all have had major updates and many have new co-authors with new perspectives. We have endeavored to attract the leading investigators in each field to author the chapter covering their area. We are especially pleased with the roster of authors who have written for the second edition. They really are the leaders in their respective fields.

We wish to express our thanks to Tari Paschall, Judy Meyer, and Sarah Hajduk as well as the rest of the Elsevier/Academic Press staff for their expertise and indispensable contribution to bringing this revised edition to fruition. Most of all, we thank the authors for their contributions. We hope that our readers will find this updated volume useful and informative and that it will contribute to the burgeoning growth of the vitamin D field.

DAVID FELDMAN, J. WESLEY PIKE and FRANCIS H. GLORIEUX

Preface to the 1st Edition

Our reasons for deciding to publish an entire book devoted to vitamin D can be found in the rapid and extensive advances currently being made in this important field of research. Enormous progress in investigating many aspects of vitamin D, from basic science to clinical medicine, has been made in recent years. The ever-widening scope of vitamin D research has created new areas of inquiry so that even workers immersed in the field are not fully aware of the entire spectrum of current investigation. Our goal in planning this book was to bring the diverse scientific and clinical fields together in one definitive and up-to-date volume. It is our hope that this compendium on vitamin D will serve as both a resource for current researchers and a guide to stimulate and assist those in related disciplines to enter this field of research. In addition, we hope to provide clinicians and students with a comprehensive source of information for the varied and extensive material related to vitamin D.

The explosion of information in the vitamin D sphere has led to new insights into many different areas, and in our treatment of each subject in this book we have tried to emphasize the recent advances as well as the established concepts. The classic view of vitamin D action, as a hormone limited to calcium metabolism and bone homeostasis, has undergone extensive revision and amplification in the past few years. We now know that the vitamin D receptor (VDR) is present in most tissues of the body and that vitamin D actions, in addition to the classic ones, include important effects on an extensive array of other target organs. To cover this large number of subjects, we have organized the book in the following manner: Section I, the enzymes involved in vitamin D metabolism and the activities of the various metabolites; Section II, the mechanism of action of vitamin D, including rapid, nongenomic actions and the role of the VDR in health and disease; Section III, the effects of vitamin D and its metabolites on the various elements that constitute bone and the expanded understanding of vitamin D actions in multiple target organs, both classic and nonclassic; Section IV, the role of vitamin D in the physiology and regulation of calcium and phosphate metabolism and the multiplicity of hormonal, environmental, and other factors influencing vitamin D metabolism and action; and Sections V and VI, the role of vitamin D in the etiology and treatment of rickets, osteomalacia, and osteoporosis and the pathophysiological basis, diagnosis, and management of numerous clinical disorders involving vitamin D.

The recent recognition of an expanded scope of vitamin D action and the new investigational approaches it has generated were part of the impetus for developing this volume on vitamin D. It has become clear that in addition to the classic vitamin D actions, a new spectrum of vitamin D activities that include important effects on cellular proliferation, differentiation, and the immune system has been identified. This new information has greatly expanded our understanding of the breadth of vitamin D action and has opened for investigation a large number of new avenues of research that are covered in Sections VII and VIII of this volume. Furthermore, these recently recognized nonclassic actions have led to a consideration of

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