Vitamin D - Physiology, Molecular Biology, and Clinical Applications

Dedication

In Memoriam

Series Editor Introduction

Preface

ACKNOWLEDGMENTS

Contents

Contributors

Part I Introduction and Basic Biology

1 Vitamin D and Health: Evolution, Biologic Functions,and Recommended Dietary Intakes for Vitamin D

1 Evolutionary Perspective

1.1 The Calcium Connection

1.2 Photosynthesis of Vitamin D in the Skin

1.3 Metabolism of Vitamin D

2 Vitamin D Deficiency And Sources Of Vitamin D

2.1 Consequences of Vitamin D Deficiency on Skeletal Health

2.2 Sources of Vitamin D

2.3 Definition of Vitamin D Deficiency, Insufficiency, and Sufficiency

2.4 The Vitamin D Deficiency Pandemic

3 Recommended Adequate Dietary Intake Of Vitamin D

3.1 Birth to 6 Months

3.2 Ages 6--12 Months

3.3 Ages 1--8 Years

3.4 Ages 9--18 Years

3.5 Ages 19--50 Years

3.6 Ages 51--70 Years

3.7 Age 71 Years and Older

3.8 Pregnancy

3.9 Lactation

3.10 Tolerable Upper Intake Levels

4 Causes Of And Treatment Strategies For Vitamin D Deficiency

4.1 Causes

4.2 Strategies for Preventing and Treating Vitamin D Deficiency

5 Myths

5.1 Vitamin D Treatment Will Worsen Hypercalcemia in Hyperparathyroid Patients

5.2 Treatment with Vitamin D Will Increase Risk of Kidney Stones

5.3 Patients with Chronic Kidney Disease Do Not Need to Be Treated with Vitamin D Since They Cannot Activate It

5.4 Treatment with 50,000 IU of Vitamin D Long-Term Will Cause Vitamin D Intoxication

6 Conclusion

Acknowledgments

References

2 Photobiology of Vitamin D

1 Introduction

2 Historical Perspective

3 Vitamin D Fortification In Milk

4 Photosynthesis Of Previtamin D 3 In The Skin

4.1 Photoconversion of 7-DHC to Previtamin D 3

4.2 Conversion of Previtamin D 3 to Vitamin D 3

4.3 Translocation of Vitamin D 3 from the Skin into the Circulation

4.4 Photodegradation of Vitamin D 3

4.5 Photoisomers of Vitamin D 3

5 Regulation Of The Cutaneous Synthesis Of Previtamin D 3

5.1 Role of Melanin Pigmentation

5.2 Influence of Altitude, Latitude, Time of Day, and Weather Conditions on Previtamin D 3 Production

5.3 Effect of Aging on the Cutaneous Production of Previtamin D 3

5.4 Effect of Sunscreen Use and Clothing on Previtamin D 3 Formation

5.5 Influence of Season on 25(OH)D Levels in Nursing Home and Home Care Elderly

5.6 Tanning Bed Irradiation Enhances Vitamin D Status and Bone Mineral Density

6 SUMMARY

Acknowledgments

References

3 The Functional Metabolism and Molecular Biology of Vitamin D Action

1 Introduction

2 Overall Role Of The Vitamin D Hormone In Calcium And Phosphorus Homeostasis

3 Functional Metabolism

4 Regulation Of The Production And Catabolism Of 1,25(OH) 2 D

5 Molecular Mechanism Of Vitamin D Action

6 Analogs: Mechanisms Of Action

7 Function Of Vitamin D Not Related To Calcium And Phosphate Homeostasis

8 Vitamin D In Public Health

Bibliography

4 Metabolism and Catabolism of Vitamin D, Its Metabolites and Clinically Relevant Analogs

1 Metabolism Of Vitamin D 3 AND 25(OH)D 3

1.1 25- and 1-Hydroxylation

1.2 24-Hydroxylation

1.3 26-Hydroxylation and 26,23-Lactone Formation

2 CATABOLISM of 1,25(OH)2D3

2.1 C-24 Oxidation Pathway to Calcitroic Acid

3 Metabolism And Catabolism Of The Analogs Of Vitamin D

3.1 Activation of Prodrugs

3.2 Vitamin D 2

3.2.1 Dihydrotachysterol

3.2.2 1(OH)D2 and 1(OH)D 3

3.3 Metabolism-Sensitive Analogs

3.3.1 Cyclopropane Ring Containing Analogs of Vitamin D

3.3.2 Oxa-Group-Containing Analogs

3.4 Metabolism-Resistant Analogs

3.4.1 F 6 -1,25-(OH) 2 D

3.4.2 Unsaturated Analogs

4 Important Implications Derived From Metabolism Studies

4.1 Relative Importance of Metabolism in the Mechanism of Action of Vitamin D Analogs

4.2 Future Directions

4.2.1 Structural Aspects of Vitamin D-Related Cytochrome P450s

4.2.2 Hydroxylase Gene Knockouts

4.2.3 Future Vitamin D Analog Design and Development

Acknowledgements

References

5 The Molecular Biology of the Vitamin D Receptor

1 INTRODUCTION

2 The Vitamin D Receptor Gene

3 Molecular Analysis Of The Functional Domains Of The Vdr

3.1 The DNA-Binding Domain (DBD)

3.2 The Multifunctional C-terminal Domain

4 Molecular Mechanism Of Transcriptional Control By Vdr

4.1 VDR Interaction with Vitamin D-Responsive Elements

4.1.1 Vitamin D-Responsive Elements

4.1.2 A R ole for the 1,25(OH) 2 D L igand

4.1.3 Gene Regulation Through Negative Response Elements

4.1.4 A Role for the Unliganded VDR in Transcriptional Regulation

4.2 Communication Between VDR and the Transcriptional Machinery

REFERENCES

6 VDR and RXR Subcellular Trafficking

1 Significance Of Receptor Localization

2 Spatial And Temporal Control Of Nuclear Receptor Functions

3 Nuclear Import Mechanisms For Vdr And Rxr

4 Nuclear Export Mechanisms For Vdr And Rxr

5 Intranuclear Trafficking Of Vdr And Rxr

6 Summary And Conclusion

REFERENCES

7 Mechanism of Action of 1,25-Dihydroxyvitamin D3 on IntestinalCalcium Absorption and Renal Calcium Transport

1 Introduction

2 Intestinal Calcium Absorption

2.1 Overview

2.2 Effect of 1,25-Dihydroxyvitamin D 3 on Saturable, Transcellular Intestinal Calcium Absorption

2.2.1 Role of 1,25(OH) 2 D on the Entry of Calcium Across the Brush Border Membrane

2.2.2 Role of 1,25(OH) 2 D on Transcellular Movement of Calcium

2.2.3 Role of 1,25(OH) 2 D on Calcium Extrusion from the Intestinal Cell

2.3 Other Models of Intestinal Calcium Transport -- Nonsaturable, Paracellular Intestinal Calcium Absorption

2.4 1,25(OH) 2 D and Intestinal Phosphorus Absorption

3 Renal Calcium Transport

3.1 Overview

3.2 Effect of 1,25(OH) 2 D on Renal Calcium Transport

3.2.1 Current Understanding of the Role of 1,25(OH) 2 D

3.2.2 Role of Vitamin D-Dependent Calcium-Binding Proteins and TRPV5 in Renal Calcium Transport

3.2.3 Role of the Plasma Membrane Calcium Pump and the Na + /Ca 2+ Exchanger

3.3 Other Effects of 1,25(OH) 2 D in the Kidney

4 Summary

References

8 Biological and Molecular Effects of Vitamin D on Bone

1 Introduction

2 A Spectrum of Cellular Activities of 1,25(OH) 2 D Contributing to Bone Formation

2.1 Bone Tissue Organization, Vitamin D, and Osteoblasts

2.2 Skeletal Development

2.3 Vitamin D3 Promotes Cell Differentiation at Multiple Levels

3 The Role of Vitamin D in Coupling Osteoblast Activity to Osteoclast Differentiation for Bone Resorption

4 Vitamin D Regulation of Gene Expression During Bone Formation

4.1 Components of Vitamin D-Dependent Regulatory Complexes

4.2 Vitamin D-Mediated Gene Expression Within the Three-Dimensional Context of Nuclear Structure in Bone Cells

4.3 Vitamin D Receptor Coregulatory Factors Provide Gene-Specific Regulation

5 Conclusions and Future Directions

Acknowledgments

References

9 Biological and Molecular Effects of Vitamin D on the Kidney

1 The Kidney, The Vitamin D Endocrine System, And Disease Prevention

2 Essential Role Of The Kidney In Vitamin D Biological Actions

2.1 Renal Regulation of Systemic Calcitriol

2.1.1 Calcitriol Synthesis

2.1.2 Calcitriol Catabolism

2.2 Abnormal Calcitriol Production in CKD

3 Renal Uptake Of 25(Oh)D: Relevance In The Maintenance Of Normal Vitamin D Status

3.1 Essential Contribution of Megalin-Mediated Endocytosis to Calcitriol Production

3.2 Abnormal Uptake of 25(OH)D in CKD

3.3 Abnormal Renal 25(OH)D Uptake in CKD Contributes to Impaired Extrarenal Calcitriol Production

4 Renal Regulation Of Vdr Expression And Function

4.1 Calcitriol Regulation of VDR Expression

4.2 Abnormal Regulation of VDR Expression and Function in CKD

4.3 Impaired VDR Function in CKD

5 Vitamin D Regulation Of Kidney Function

5.1 Mineral Homeostasis

5.1.1 Calcitriol/VDR Regulation of Calcitriol Homeostasis

5.1.2 Calcitriol/VDR Control of Renal Handling of Calcium and Phosphate

5.2 Renal Calcitriol/VDR Actions Affecting the Cardiovascular System

5.3 Calcitriol/VDR Renoprotective Actions

Acknowledgments

References

10 Vitamin D and the Parathyroids

1 INTRODUCTION

2 THE PARATHYROID HORMONE GENE

2.1 The PTH Gene

2.2 The PTH mRNA

3 DEVELOPMENT OF THE PARATHYROID AND TISSUE-SPECIFIC EXPRESSION OF THE PTH GENE

4 PROMOTER SEQUENCES

5 REGULATION OF PTH GENE EXPRESSION

5.1 1,25-Dihydroxyvitamin D

5.1.1 Calreticulin and the Action of 1,25(OH)2D on the PTH Gene

5.1.2 Studies on Mice with VDR Gene Deletion

5.2 Calcium

5.2.1 Mechanisms of Regulation of PTH mRNA by Caclium

5.3 Phosphate

5.3.1Phosphate Regulates the Parathyroid Independently of Calcium and 1,25(OH)2D

5.4 Protein--PTH mRNA Interactions Determine the Regulation of PTH Gene Expression by Serum Calcium and Phosphate

5.4.1 Identification of the PTH mRNA 30 -UTR-Binding Proteins that Determine PTH mRNA Stability

5.4.2 A Conserved Sequence in the PTH m RNA 30-UTR Binds Parathyroid Cytosolic Proteins and Determines m RNA Stability in Response to Changes in Calcium and Phosphate

6 FIBROBLAST GROWTH FACTOR 23 AND THE PARATHYROID

7 SUMMARY

Acknowledgments

References

11 Diversity of Vitamin D Target Genes

1 INTRODUCTION

2 VDR IS A NUCLEAR RECEPTOR

2.1 The Nuclear Receptor Superfamily

2.2 Modular Structure of Nuclear Receptors

2.3 The VDR

3 VDR-BINDING SITES

3.1 DR3-Type VDREs

3.2 Other Types of VDREs

3.3 Chromatin and Co-factors

3.4 VDREs in the Chromatin Context

3.5 Negative VDREs

4 VDR TARGET GENES

4.1 Classical VDR Targets

4.2 VDR Targets in Cell Cycle Regulation

4.3 Relative Expression of VDR Target Genes

5 VDR TARGET GENE ANALYSIS

5.1 Transcriptome Analysis

5.2 ChIP Analysis

5.3 ChIP-Chip Assays

5.4 In Silico Screening of VDREs

6 CONCLUSIONS

Acknowledgments

REFERENCES

Part II Non-skeletal/Functions of Vitamin D

12Extrarenal Synthesis of 1,25-Dihydroxyvitamin D and Its Health Implications

1 INTRODUCTION

2 TISSUE DISTRIBUTION OF CYP27B1

3 REGULATION OF EXTRARENAL CYP27 b 1 EXPRESSION

4 FUNCTION OF EXTRARENAL CYP27B1

4.1 Regulation of Proliferation and Differentiation

4.2 Regulation of Hormone Secretion

4.3 Regulation of Immune Function

5 SUMMARY

REFERENCES

13 Vitamin D and the Innate Immunity

1 TUBERCULOSIS

1.1 Tuberculosis Overview

1.1.1 Innate Immunity

1.1.2 Toll-Like Receptors

1.1.3 Immunoactivity of 1,25-Dihydroxyvitamin D

1.1.4 Antimicrobial Peptides

1.2 Vitamin D Pathway and Tuberculosis

1.2.1 Role of 25-HydroxyvitaminD on the Innate Immune Response

1.2.2 History of Vitamin D, Sunshine, and Tuberculosis

1.2.3 Treatment of Tuberculosis with Vitamin D

REFERENCES

14 Vitamin D and Colon Cancer

1 INTRODUCTION

1.1 Colorectal Cancer Prevention by Vitamin D and Calcium: Molecular and Cellular Mechanisms

2 RELEVANCE OF ENDOGENOUS 1,25(OH)2 D SYNTHESIS FOR GROWTH CONTROL OF NORMAL AND NEOPLASTIC COLON EPITHELIAL CELLS

3 EXPRESSION OF CYP27B1 DURING INFLAMMATION AND TUMOR PROGRESSION

4 REGULATION OF VITAMIN D HYDROXYLASES, CYP27B1 AND CYP24A1

4.1 Regulation of Vitamin D Metabolism in the Gut Mucosa by Calcium

4.2 Regulation of the Vitamin D System by Estrogenic Compounds

4.3 Effect of Folate on CYP24A1 Expression

4.4 Epigenetic Regulation of CYP24A1 and CYP27B1 Activity

4.5 Regulation of CYP24A1 and CYP27B1 and Prevention of Colon Cancer

REFERENCES

15Mechanisms of Resistance to Vitamin D Action in Human Cancer Cells

Acknowledgments

REFERENCES

16Vitamin D and the Brain: A Neuropsychiatric Perspective

1 INTRODUCTION

2 Vitamin D And Brain Development

3 Brain Development In The Developmental Vitamin D (Dvd)-Deficient Rodent

4 Behaviour In The Dvd-Deficient Rat And Mouse

5 Vitamin D And Neuropsychiatric Disorders: Clues From Epidemiology

6 CONCLUSIONS

REFERENCES

17 Vitamin D Modulation of Adipocyte Function

1 INTRODUCTION

2 Ca2+ SIGNALING

3 Role Of The Nuclear Vitamin D Receptor

4 Calcitriol Regulation Of Adipocyte Apoptosis

5 Calcitriol Modulation Of Adipocyte Glucocorticoid Production

6 Calcitriol Regulation Of Cross Talk Between Adipocyte And Skeletal Muscle In Energy Metabolism

7 Calcitriol Regulation Of Adipocyte Oxidative Stress

8 Calcitriol Regulation Of Adipocyte Inflammatory Cytokine Production

9 Calcitriol Regulation Of AdipocyteMacrophage Cross Talk In Inflammation

10 CONCLUSION

REFERENCES

Part III Vitamin D Status Global Analysis

18 Determinants of Vitamin D Intake

1 INTRODUCTION

2 Dietary Guidelines: Past, Present, And Future Considerations

3 History And Use Of Dietary Reference Intakes For Vitamin D

4 The Tolerable Upper Intake Level

5 Estimated Vitamin D Intakes In Canada And The United States

6 Food Patterns And Dietary Sources Of Vitamin D

7 Vitamin D Fortification Of Food

8 Vitamin D Supplementation

9 Considerations For Public Health Action

REFERENCES

19 25-Hydroxyvitamin D Assays and Their Clinical Utility

1 INTRODUCTION

2 Vitamin D Physiology

3 Currently Available 25(Oh)D Assays

3.1 Chromatographic Assays

3.2 Immunochemical and Competitive Protein Binding Assays (CPBA)

3.3 Specimen Stability

3.4 Proficiency Testing and Assay Quality

3.5 Current Status of 25(OH)D Result Agreement

3.6 25(OH)D Variability

3.7 Definition of Low Vitamin D Status/Reporting of Circulating 25(OH)D Results

3.8 When Should 25(OH)D Be Measured?

4 CLINICAL UTILITY of 25(OH)D MEASUREMENT

5 CONCLUSIONS

REFERENCES

20 Health Disparities and Vitamin D

1 Introduction

2 Infant Mortality

3 Cardiovascular Disease

4 Cancer

5 Total Mortality

6 Diabetes

7 Tuberculosis

8 HIV/AIDS

9 Conclusion

ReferenceS

21 Vitamin D Deficiency in Canada

1 INTRODUCTION

2 Dietary Studies Of Vitamin D In Canadians

3 Studies Of Canadians Utilizing Measurements Of Serum 25(OH)D

3.1 Healthy Ambulatory Adults

3.2 Children

3.3 Aboriginal (First Nations and Inuit) Peoples

4 CONCLUSIONS

REFERENCES

22 Vitamin D Deficiency and Its Health Consequences in Northern Europe

1 INTRODUCTION

2 DEFINITION OF VITAMIN D INSUFFICIENCY AND DEFICIENCY

3 GEOGRAPHY AND SOLAR UV RADIATION

4 OVERVIEW OF VITAMIN D STATUS IN EUROPE

5 WHAT IS THE EFFECT OF LATITUDE ON VITAMIN D STATUS IN EUROPE?

6 NATIONAL NUTRITIONAL RECOMMENDATIONS AND DIET

7 FORTIFICATION POLICY IN NORTHERN EUROPE

8 SUPPLEMENTATION

9 INDIVIDUAL LIFESTYLE FACTORS

10 VITAMIN D INTAKES

11 PREVALENCE OF VITAMIN D INSUFFICIENCY

12 VITAMIN D STATUS IN DENMARK

13 CONCLUSION

REFERENCES

23 Vitamin D Deficiency and Consequences for the Health of People in Mediterranean Countries

1 INTRODUCTION

2 VITAMIN D STATUS IN MEDITERRANEAN POPULATIONS IN SPAIN AND OTHER EUROPEAN COUNTRIES

3 VITAMIN D STATUS IN MEDITERRANEAN POPULATIONS OF THE MIDDLE EAST AND NORTH AFRICAN COUNTRIES

REFERENCES

24 Vitamin D Deficiency in the Middle East and Its Health Consequences

1 INTRODUCTION

2 Nutritional Rickets

2.1 Nutritional Rickets in the Middle East

2.2 Non-skeletal Manifestations of Nutritional Rickets

2.3 Rickets in Immigrants from Middle East

3 Hypovitaminosis D

3.1 Mothers--Neonates--Infants

3.2 Children and Adolescents

3.3 Adults

3.4 Immigrants from Middle East

3.5 Impact of Hypovitaminosis D on Musculoskeletal Outcomes

4 Recommendations For Treatment

4.1 Rickets

4.2 Hypovitaminosis D

5 Conclusion

Acknowledgments

References

25Vitamin D Deficiency in the Middle East and Its Health Consequencesfor Adults

1 Introduction

2 Epidemiology

3 Etiology

4 Conclusions

References

26 Vitamin D Deficiency and Its Health Consequences in Africa

1 Introduction

2 The Continent Of Africa

2.1 Geography, Topography, Climate

2.2 Demography

2.3 Ultraviolet Radiation and Skin Pigmentation

2.4 Diet and Foodstuffs

3 Indicators Of Health And Burden Of Disease In Africa Which May Affect Or Be Affected By Vitamin D Status

3.1 Malnutrition

3.2 Vitamin D Intake

3.3 Low Calcium Intake

3.4 Fluorosis

3.5 Tropical Enteropathy

3.6 Malaria

3.7 HIV/AIDS

3.8 Tuberculosis

3.9 Non-communicable Disease

4 Health Consequences Of Poor Vitamin D Status In Africa

4.1 Rickets and Osteomalacia

4.2 Tuberculosis

4.3 HIV/AIDS

5 Studies Of Vitamin D Status In Africa

6 Conclusions

REFERENCES

27 Vitamin D Deficiency and Its Health Consequences in India

1 Introduction

2 Historical Background

3 Vitamin D Status In Adults

3.1 Vitamin D Deficiency and Bone Mineral Density

4 Vitamin D Status In Pregnancy And Lactation

5 Vitamin D Status In Neonates And Infants

6 Vitamin D Status In Indian Children

6.1 Clinical Evidence of Rickets

7 Serum 25(Oh)D Levels

7.1 Vitamin D Deficiency and Bone Mineral Density

7.2 Do We Have Protective Bioadaptation to Vitamin D Deficiency?

7.3 How to Tackle Vitamin D Deficiency

8 Conclusion

References

28 Vitamin D Deficiency, Rickets, and Fluorosis in India

1 Vitamin D Deficiency In India

2 Nutritional Rickets In India

2.1 Skeletal Fluorosis in India: An Endemic Disease

3 Pathogenesis Of Fluorotoxic Bone Disease

4 Calcium Vitamin DFluoride Interactions

REFERENCES

29 Vitamin D in Asia

1 Vitamin D In Asia

2 Northern Asia

2.1 Vitamin D Status

2.2 Consequences

2.3 Causes of Vitamin D Deficiency

3 Middle East

3.1 Vitamin D Status

3.2 Consequences

3.3 Causes of Vitamin D Deficiency

4 Southern Asia

4.1 Vitamin D Status

4.2 Consequences

4.3 Causes of Vitamin D Deficiency

5 Strategies To Improve Vitamin D Status

6 CONCLUSION

References

30 Vitamin D Deficiency and Its Health Consequences in New Zealand

1 INTRODUCTION

2 New Zealand Location, Climate, And Uv Exposure

3 Prevalence Of Low 25(Oh)D Levels

4 Determinants Of 25(Oh)D Levels

5 The Effects Of Seasonal Variation Of 25(Oh)D And Fat Mass On The Diagnosis Of Vitamin D Sufficiency

6 CONCLUSION

References

31 Toxicity of Vitamin D

1 Signs And Symptoms

2 Treatment

3 Mechanisms Of Toxicity

3.1 Hypersensitivity to Vitamin D

4 Mandated Safety Levels

5 Theoretical Noncalcemic Risks Of Vitamin D

6 Conclusion

References

Part IV Health Consequences of Vitamin D Deficiency and Resistance on Musculoskeletal Health

32 Vitamin D Deficiency in Pregnancy and Lactation and Health Consequences

1 Introduction

2 Maternal/Infant Calcium Homeostasis In Pregnancy

3 Contemporary Maternal Vitamin D Status In Pregnancy

4 Clinical Trials Of Vitamin D Supplementation In Pregnancy

5 Vitamin D And Fetal Development

6 Fetal Vitamin D Exposure And Immune Function

7 Fetal Vitamin D Exposure And Cardiac Development

8 Vitamin D And Pregnancy Health

9 Vitamin D Requirements For Mother And Infant During Lactation

10 The Mechanism Of Vitamin D In Human Milk

11 Maternal Vitamin D Supplementation During Lactation

12 Infant Vitamin D Supplementation During Lactation

13 Consequences Of Infant Vitamin D Status

14 Conclusion

References

33 Vitamin D Deficiency in Children and Its Health Consequences

1 Introduction

2 Prevalence Data

2.1 Newborns, Infants, and Toddlers

2.2 Older Children and Adolescents

2.3 Factors Influencing Vitamin D Status Throughout Childhood

3 Prevalence Of Vitamin D Deficiency In At-Risk Groups

3.1 Overweight

3.2 Epilepsy and Other Neurological Disorders

3.3 Inflammatory Bowel Disease, Celiac Disease, and Cystic Fibrosis

3.4 Hereditary Predisposition

4 Assessment Of Vitamin D Status

5 Supplementation

5.1 Supplementation in Infants

5.2 Supplementation in Children and Adolescents

6 Treatment

7 Conclusions

REFERENCES

34Dietary Calcium Deficiency and Rickets

1 INTRODUCTION

2 Calcium Homeostasis

3 Dietary Calcium Deficiency Rickets

3.1 Dietary Calcium Intakes

3.2 Intestinal Calcium Absorption

3.3 Vitamin D Requirements

3.4 Possible Genetic Influences

4 CONCLUSIONS

REFERENCES

35 Vitamin D in Fracture Prevention and Muscle Function and Fall Prevention

1 Introduction

2 Vitamin D: Its Role In Muscle Health

3 Desirable 25-Hydroxyvitamin D Status For Better Function And Lower Risk Of Sarcopenia

4 Vitamin D And Muscle Weakness

5 Vitamin D And Fall Prevention

6 Desirable 25-Hydroxyvitamin D Status For Better Bone Health

7 Importance Of Dose In Anti-Fracture Efficacy With Vitamin D

8 Summary

REFERENCES

36 Inherited Defects of Vitamin D Metabolism

1 Introduction

2 Pseudovitamin D Deficiency Rickets

3 Hereditary Vitamin D-Resistant Rickets

4 25-Hydroxylase Deficiency

REFERENCES

37Molecular Defects in the Vitamin D Receptor Associatedwith Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets (HVDRR)

1 Introduction

2 Hereditary 1,25-Dihydroxyvitamin D-Resistant Rickets (Hvdrr)

3 The Vitamin D Receptor

4 Cellular Basis Of Hvdrr

5 Molecular Basis For Hvdrr

5.1 Mutations in the VDR DNA-Binding Domain (DBD)

5.2 Mutations Causing Premature Termination of the VDR

5.2.1 Premature Stop Mutations

5.2.2 Splicing Mutations

5.3 Mutations in the VDR Ligand-Binding Domain (LBD)

5.3.1 Mutations That Affect 1,25(OH)2D Binding

5.3.2 Mutations That Affect VDR0RXR Heterodimerization

5.3.3 Mutations That Affect Coactivator Binding

5.4 Compound Heterozygous Mutations in the VDR

5.5 Other Mutations in the VDR

6 Therapy Of Hvdrr

6.1 General

6.2 Treatment with Vitamin D

6.3 Calcium Therapy

6.4 Lessons from the Therapy of HVDRR Cases

7 Alopecia

8 Concluding Remarks

References

38Receptor-Independent Vitamin D Resistance in Subhumanand Human Primates

1 Early Primate Evolution

2 Simian Bone Disease

3 Steroid Hormone Resistance In New World Primates

4 Outbreak Of Rickets in The New World Primate Colonies of the Los Angeles Zoo

5 Investigating the Biochemical Nature of Vitamin D Resistance in New World Primates

6 Vitamin D Response Element-Binding Protein

7 hn RNPC-Related Proteins as Multifunctional Regulators of Gene Expression: Beyond Transcription

8 Intracellular Vitamin D-Binding Protein

9 Summary

Acknowledgments

References

3925-Hydroxyvitamin D-1-Hydroxylase: Studies in Mouse Modelsand Implications for Human Disease

1 Introduction

2 Skeletal and Mineral Modulating Actions of 25-Hydroxyvitamin D 3 -1 -Hydroxylase as Determined by Genetic Mouse Models

2.1 Regulation of Calcium Absorption

2.2 Regulation of the 1(OH)ase and of the 24(OH)ase Enzymes

2.3 Parathyroid Gland Function

2.4 Development of the Cartilaginous Growth Plate

2.5 Bone and Cartilage Remodeling

2.6 Mineralization of Bone

2.7 1,25 Dihydroxyvitamin D as a Bone Anabolic Agent

2.7.1 1anabolic Effects in Older Animals

2.7.2 Anabolic Effects in Neonatal Animals

2.7.3 Anabolic Effects of Exogenous 1, 25(OH)2D

2.7.4 Interaction of Exogenous PTH and Endogenous 1,25(OH)2D in Exerting a Bone Anabolic Effect

3 Role of 25-Hydroxyvitamin D 3 -1 -Hydroxylase in Extra-Skeletal Actions of 1,25(OH) 2 D as Determined by Genetic Mouse Models

Acknowledgments

References

Part V Sunlight, Vitamin D and Cancer

40The Health Benefits of Solar Irradiance and Vitamin Dand the Consequences of Their Deprivation

1 Introduction

2 Scientific Methods Utilized

3 Application to Specific Health Conditions

3.1 Bone Health

3.2 Cancer

3.3 Infectious Diseases

3.4 Autoimmune Diseases

3.5 Metabolic Diseases

3.6 Cardiovascular Diseases

3.7 Alzheimer's Disease

3.8 Life Expectancy

3.9 Historical Review

4 Summary and Conclusion

References

41 Vitamin D Status, Solar Radiation and Cancer Prognosis

1 INTRODUCTION

2 skin synthesis and activation of vitamin d

3 Calculation Of Seasonal And Latitudinal Variations In Vitamin D Status

4 Serum Measurements Of Vitamin D Metabolites

5 Epidemiological Investigations Of Relative Risk Of Death From Breast, Colon And Prostate Cancer

6 Anti-Neoplastic Mechanisms Of Action

7 Summary

References

42 The Epidemiology of Vitamin D and Cancer Risk

1 Introduction

2 Colorectal Cancer

2.1 25(OH)D Level

2.2 Predicted 25(OH)D Level

2.3 Dietary Intake

2.4 Sun Exposure

2.5 Randomized Controlled Trial

3 Prostate Cancer

3.1 25(OH)Vitamin D

3.2 Predicted 25(OH)D Level

3.3 Vitamin D Intake

3.4 Sun Exposure

4 Breast Cancer

4.1 25(OH)Vitamin D

4.2 Vitamin D Intake

4.3 Sun Exposure

5 Pancreatic Cancer

5.1 25(OH)D Level

5.2 Predicted 25(OH)D

5.3 Vitamin D Intake

6 Esophageal And Gastric Cancers

6.1 25(OH)D Level

7 Ovarian Cancer

7.1 25(OH)D

7.2 Sun Exposure

8 Non-Hodgkin's Lymphoma (NHL)

8.1 Sun Exposure

9 Total Cancer

9.1 Circulating 25(OH)D

9.2 Predicted 25(OH)D

9.3 Randomized Trials (RCT)

10 Synthesis And Summary

REFERENCES

43 Vitamin D Deficiency and the Epidemiology of Prostate Cancer

1 INTRODUCTION

2 Prostate Cancer, Clinical Considerations

3 Synthesis Of Vitamin D Metabolites

4 Prostate Cancer And The Vitamin D Hypothesis

5 1,25(OH) 2 D Is Synthesized By Normal Prostate Cells

6 PROSTATE CANCER CELLS EXPRESS VDR BUT LOSE EXPRESSION OF 1 -OH ase

7 Vdr Polymorphisms

8 Serological Studies Of The Vitamin D Deficiency Hypothesis

9 Epidemiologic Studies Of Solar Exposure

10 Vitamin D Deficiency And Prostate Cancer: Potential Mechanisms

11 Serum Calcium And Prostate Cancer Risk

REFERENCES

44Vitamin D for Cancer Prevention and Survival

1 Introduction

2 Serum 25-Hydroxyvitamin D and Risk of Breast Cancer

3 Serum 25-Hydroxyvitamin D and Risk of Colon Cancer

4 Latitude, Ultraviolet B, Serum 25-Hydroxyvitamin D and Risk of Cancer of the Ovary

5 Vitamin D and Cancer of Other Sites

6 Randomized Trials

7 Future Potential For Cancer Prevention

8 Serum 25-Hydroxyvitamin D And Cancer Survival

9 Vitamin D And Global Cancer Prevention

10 DisjunctionNatural SelectionInvasion (Dni) Model

10.1 Natural Selection: Basis of Pathogenesis

10.2 Invasion

10.3 Role of Calcium and Dietary Factors

10.4 Implications for Cancer Treatment

11 Safety of Vitamin D for Cancer Prevention and As an Adjunct to Treatment

12 Geographic Distribution of Cancer and Environmental Factors

13 Summary

Acknowledgments

References

45 The Anti-cancer Effect of Vitamin D: What Do the Randomized Trials Show?

1 INTRODUCTION

2 Potential Mechanism Of Vitamin D Anti-Cancer Effects

3 Vitamin D And Calcium In Prevention Of Cancer

4 Randomized Trials Of Vitamin D Supplementation And Cancer

5 Levels Of 25(Oh)d For Cancer Prevention

6 Doses Of Vitamin D Supplementation For Cancer Prevention

7 SUMMARY

REFERENCES

46 Sunlight, Skin Cancer, and Vitamin D

1 The Most Important Negative Health Effect Of Solar Uv Exposure: Induction Of Skin Cancer

1.1 Non-melanoma Skin Cancer, Malignant Melanoma, and Solar UV Exposure

1.2 Photocarcinogenesis of Skin Cancer

2 Recommendations For Sun Protection In Skin Cancer Prevention Campaigns

3 A Challenging Perspective: Understanding And Fighting Vitamin D Deficiency

3.1 Vitamin D Deficiency -- A Serious and Underappreciated Health Problem

3.2 Consequent Sun Protection Increases the Risk of Vitamin D Deficiency

3.3 How Much Vitamin D Do We Need?

4 Conclusions

References

Part VI Vitamin D Deficiency and Chronic Disease

47 Vitamin D and the Risk of Type 1 Diabetes

1 MECHANISMS

2 Ecological Correlations

3 Animal Experiments

4 Studies In Humans

5 Genetic Studies

6 Conclusions

References

48 Vitamin D and Multiple Sclerosis

1 Introduction

2 Ms Epidemiology

3 Sun Exposure, Vitamin D, And Ms Risk

3.1 Database Analyses

3.2 Case--Control Studies

3.3 Longitudinal Studies

4 Seasonal Variations In Birth Patterns

5 Vitamin D And Ms Progression

6 Summary

REFERENCES

49 Vitamin D and Type 2 Diabetes

1 Epidemiology And Burden Of Type 2 Diabetes

2 Vitamin D Metabolism

3 Potential Mechanisms Of Action Of Vitamin D On Glucose Metabolism

3.1 Vitamin D and Pancreatic Beta-Cell Function/Insulin Secretion

3.2 Vitamin D and Insulin Sensitivity

3.3 Vitamin D and Systemic Inflammation

4 Evidence From Observational Human Studies

4.1 Seasonal Variation and Type 2 Diabetes

4.2 Case--Control and Cross-Sectional Studies of Vitamin D and Type 2 Diabetes

4.3 Prospective Studies of Vitamin D and Type 2 Diabetes

4.4 The Role of Calcium Intake and Type 2 Diabetes or the Metabolic Syndrome

4.5 Summary of Evidence from Human Observational Studies

5 Evidence From Intervention Human Studies

5.1 Effect of Vitamin D Supplementation on Type 2 Diabetes

5.2 Effect of Combined Vitamin D and Calcium Supplementation on Type 2 Diabetes

5.3 Summary of Evidence from Intervention Studies

6 Limitations In The Study Of Vitamin D

7 Optimal Intake Of Vitamin D And Calcium In Relation To Type 2 Diabetes

8 Conclusions And Future Directions

REFERENCES

50 Role of Vitamin D for Cardiovascular Health

1 Historical Review

1.1 Adverse Cardiovascular Effects from Very High Intake of vitamin D

1.2 Early Epidemiological Studies

2 Ecological Studies

2.1 Hypothesis That Sunlight and vitamin D Protect Against Cardiovascular Disease

2.2 Winter Excess in Cardiovascular Disease

3 Recent Epidemiological Studies

3.1 Observational Studies

3.2 Experimental Studies

4 Possible Cardio-Preventive Mechanisms Of vitamin D

4.1 Cardiac Function

4.2 Blood Pressure

4.3 Inflammatory Factors

4.4 Summary of Possible Mechanisms

REFERENCES

51 Vitamin D, Renin, and Blood Pressure

1 Introduction

2 Vitamin D, Blood Pressure, and Cardiac Functions: Evidence for a Connection

2.1 Epidemiological Evidence

2.2 Clinical Evidence

3 The ReninAngiotensin System: A Central Regulator of Blood Pressure

3.1 The RAS Cascade and Its Functions

3.2 Renin, the Rate-Limiting Enzyme of the RAS Cascade

3.3 Pharmacological Inhibition of the Renin--Angiotensin System

4 Vitamin D Regulation of the ReninAngiotensin System: Mechanism for the Connection?

4.1 Vitamin D: Negative Endocrine Regulator of the Renin--Angiotensin System

4.2 Mechanism of Renin Suppression

4.3 Vitamin D Analogs as Novel Renin Inhibitors

5 Conclusion

Acknowledgments

References

52 Role of Vitamin D and Vitamin D Analogs for Bone Health and Survival in Chronic Kidney Disease

1 Vitamin D and Metabolic Changes of Chronic Kidney Disease

2 Bone Disease and Vitamin D in Ckd

3 Osteitis Fibrosa Cystica

4 Adynamic Bone Disease

5 Osteomalacia

6 Vitamin D and Survival

7 Potential Mechanisms of a Cardiovascular Survival Benefit

8 Infectious Disease Survival and Vitamin D

9 Summary

References

53 Role of Vitamin D and Ultraviolet Radiation in Chronic Kidney Disease

1 Vitamin D Status in Chronic Kidney Disease

2 Vitamin D Supplementation in Chronic Kidney Disease

3 Vitamin D and Uv Radiation in Chronic Kidney Disease Patients on Haemodialysis (Own Experiences and Data)

4 Uv Trials With Patients on Haemodialysis

4.1 Whole-Body Irradiation

4.2 Partial-Body Irradiation

4.3 Vitamin D Metabolism During UVB Irradiation

4.4 Renal Osteodystrophy, Bone Mineral Density, and Bone Turnover

4.5 Physical Work Capacity and Blood Pressure

4.5.1 E rythropoiesis and UV R adiation in ESKD P atients

4.6 Heart Rate Variability and UV Radiation in ESKD Patients

4.7 UVB Radiation in Clinical Routine of a Dialysis Unit

5 Vitamin D and Uv Exposure in Prevention and Treatment of Chronic Kidney Disease

References

54 Role of Vitamin D in Rheumatoid Arthritis

1 INTRODUCTION

2 Rheumatoid Arthritis Disease Mechanism

2.1 Genetic Involvement

2.2 Rheumatoid Arthritis Immune System Involvement

3 Vitamin D And Rheumatoid Arthritis

3.1 Background

3.1.1 Immune System Effects of Vitamin D and Rheumatoid Arthritis

3.2 Joint Destruction in Rheumatoid Arthritis

3.3 Clinical, Animal, and Epidemiologic Studies of Vitamin D and Rheumatoid Arthritis

REFERENCES

55 Vitamin D, Respiratory Infections, and Obstructive Airway Diseases

1 Introduction

2 Respiratory Infections

3 Obstructive Airway Diseases

3.1 Asthma

3.2 Chronic Obstructive Pulmonary Disease

4 Childhood Wheezing

5 Vitamin D And Respiratory Infection

5.1 Tuberculosis

5.2 Epidemiologic Studies on Respiratory Infections

5.3 Preliminary Evidence from Interventional Trials

6 Vitamin D And Asthma

6.1 Asthma Pathogenesis

6.2 Asthma Control

6.3 Asthma Exacerbation

7 Vitamin D And Copd

7.1 COPD Pathogenesis

7.2 Acute Exacerbations of COPD

8 Potential Mechanisms

8.1 Vitamin D and Innate Immunity

8.2 Vitamin D and Adaptive Immunity

8.3 Vitamin D, Atopy, and Allergies

9 Future Research on Vitamin D, Respiratory Infections, and OAD s

10 Conclusions

Acknowledgments

References

Part VII Clinical Uses of Vitamin D Analogues

56 Treatment of Immunomediated Diseases by Vitamin D Analogs

1 INTRODUCTION

2 ENHANCEMENT OF INNATE IMMUNE RESPONSES BY VDR AGONISTS

3 MODULATION OF ADAPTIVE IMMUNE RESPONSES BY VDR AGONISTS

3.1 Induction of Pro-tolerogenic Properties in Myeloid Dendritic Cells

3.2 Modulation of Effector Lymphocytes

3.3 Enhancement of Regulatory T Cells

4 VITAMIN D DEFICIENCY IN AUTOIMMUNE AND OTHER IMMUNOMEDIATED DISEASES

5 ANTI-INFLAMMATORY AND IMMUNOMODULATORY EFFECTS OF VDR AGONISTS IN AUTOIMMUNE AND IMMUNOMEDIATED DISEASES

5.1 Rheumatoid Arthritis

5.2 Systemic Lupus Erythematosus

5.3 Type 1 Diabetes

5.4 Experimental Allergic Encephalomyelitis

5.5 Inflammatory Bowel Disease

5.6 Immunomediated Prostatic Diseases

6 DEVELOPMENT OF VDR AGONISTS FOR THE TREATMENT OF AUTOIMMUNE AND OTHER IMMUNOMEDIATED DISEASES

REFERENCES

57Clinical Utility of 1,25-Dihydroxyvitamin D3 and Its Analoguesfor the Treatment of Psoriasis

1 THE VITAMIN D SYSTEM IN THE SKIN

2 PSORIASIS: PATHOGENESIS, IMMUNOLOGY, AND HISTOLOGY OF SKIN LESIONS

3 CLINICAL STUDIES OF VITAMIN D AND ANALOGUES IN PSORIASIS AND OTHER SKIN DISEASES

3.1 Treatment of Scalp Psoriasis

3.2 Treatment of Nail Psoriasis

3.3 Treatment of Face and Flexures

3.4 Treatment of Skin Lesions in Children

3.5 Treatment of Psoriatic Lesions in HIV Patients

3.6 Combination of Vitamin D Analogues with Other Therapies

4 TREATMENT OF OTHER SKIN DISORDERS WITH VITAMIN D ANALOGUES

4.1 Vitamin D and Ichthyosis

4.2 Vitamin D and Scleroderma

4.3 Vitamin D and Vitiligo

4.4 Vitamin D and Skin Cancer

4.5 Vitamin D and Other Skin Diseases

5 BIOLOGICAL EFFECTS OF VITAMIN D AND ANALOGUES IN PSORIASIS

6 PERSPECTIVES FOR THE EVALUATION OF NEW VITAMIN D ANALOGUES WITH LESS CALCEMIC ACTIVITY THAT CAN BE USED FOR THE TREATMENT OF HYPERPROLIFERATIVE SKIN DISORDERS

REFERENCES

58Affinity Alkylating Vitamin D Analogs as Molecular Probesand Therapeutic Agents

1 Affinity And Photoaffinity Labeling Reagents as Molecular Probes of Enzymes and Receptors

2 Affinity Alkylating Compounds as Therapeutic Agents

3 Vitamin D and Its Metabolites: Biosynthesis, Properties, and Mechanism of Action

4 Mineral Homeostatic and Cell-Regulatory Properties of 1,25(OH) 2 D

5 Transcriptional Mechanism of 1,25(OH) 2 D

6 Vdr and Its Ligand-Binding Domain (Vdr-Lbd)

7 Affinity Labeling of Vdr from Endogenous Sources

8 Affinity Labeling of Recombinant Vdr and Identification of a Contact Point

9 Vdr-Affinity Alkylating Derivatives of 1,25(OH) 2 D AND 25(OH)D As Potential Therapeutic Agents

10 Pharmacokinetic Property of 1,25(OH) 2 D as it Relates to its Therapeutic Activity

11 1,25(OH) 2 D-3-Be, A Derivative of 1,25(OH) 2 D, with a Potential of Less Catabolic Degradation: Our Hypothesis

12 Kinetic And Stoichiometric Studies With 1,25(OH) 2 D-BE AND VDR

13 Antiproliferative Effects Of 1,25(Oh) 2 D-Be In Various Cancer Cells

14 Molecular Mechanisms Related To The Growth-Inhibitory Effect Of 1,25(OH) 2 D-3-Be

14.1 VDR-Related Mechanisms

14.2 Additional VDR-Related and VDR-Unrelated Mechanisms

15 Therapeutic Potential Of 1,25(OH) 2 D-3-Be And Related Compounds In Cancer

16 Summary

Acknowledgment

References

59Anti-inflammatory Activity of Calcitriol That Contributesto Its Therapeutic and Chemopreventive Effects in Prostate Cancer

1 INTRODUCTION

2 CALCITRIOL AND PROSTATE CANCER

2.1 Anti-proliferative Effects of Calcitriol in PCa Cells

2.2 Tumor Inhibitory Effects of Calcitriol in Animal Models of PCa

3 MECHANISMS OF THE ANTI-PROLIFERATIVE EFFECTS OF CALCITRIOL

3.1 Growth Arrest

3.2 Apoptosis

3.3 Differentiation

3.4 Modulation of Growth Factor Actions

3.5 Inhibition of Invasion, Metastasis, and Angiogenesis

3.6 Novel Molecular Pathways of Calcitriol Actions in PCa Cells

4 ANTI-INFLAMMATORY EFFECTS OF CALCITRIOL IN PROSTATE CANCER

4.1 Regulation of Prostaglandin Metabolism and Signaling

4.1.1 COX-2 and Prostate Cancer

4.1.2 15-PGDH

4.1.3 PG Receptors

4.1.4 Calcitriol Effects on the PG Pathway in Prostate Cells

4.1.5 Combination of Calcitriol and Non-steroidal Anti-inflammatory Drugs (NSAIDs)as a Therapeutic Approach in Prostate Cancer

4.2 Induction of MKP5 and Inhibition of Stress-Activated Kinase Signaling

4.3 Inhibition of NFB Activation and Signaling

5 THE ROLE OF ANTI-INFLAMMATORY EFFECTS OF CALCITRIOL IN PROSTATE CANCER PREVENTION AND TREATMENT

5.1 Inflammation and Prostate Cancer

5.2 Calcitriol and Prostate Cancer Chemoprevention

6 SUMMARY AND CONCLUSIONS

REFERENCES

Subject Index

About the Editor

About the Series Editor