Translational Endocrinology of Bone

Contributors

Foreword

Chapter 1. Introduction: The Rational of the Work or the Overarching Hypothesis

The Two Faces of Physiology

The Unanticipated Influence of Bone on Whole-Organism Physiology

References

Chapter 2. Basic Principles of Bone Cell Biology

Introduction

The Osteoblast Lineage

Osteoclasts

Bone Remodeling

Coupling of Bone Formation to Resorption in the BMU

Bone as an Endocrine Organ

Acknowledgments

References

Chapter 3. The Central Control of Bone Mass

Introduction

Leptin

Sympathetic Nervous System (SNS)

Serotonin

Neuromedin U

Neuropeptide Y (NPY) and NPY Receptors

Cocaine- and Amphetamine-Regulated Transcripts

Melanocortin and MC4R

The Cannabinoid System

Other Central Hormones and Neuropeptides Regulating Bone Remodeling

References

Chapter 4. Neuropeptide Y and Bone Formation

The Neuropeptide Y System

Neuropeptide Y and Bone Homeostasis

Other NPY Ligands

The NPY Receptors

NPY Interaction with Leptin in the Control of Bone Homeostasis

NPY’S Coordination of Body Weight and Bone Mass

Interactions Between NPY and Sex Hormones in the Control of Bone Homeostasis

Conclusion

References

Chapter 5. Serotonin: The Central Link between Bone Mass and Energy Metabolism

Energy Metabolism and its Regulation

Perturbations in Energy Metabolism and Bone Mass

Discovery of Leptin Regulation of Bone Mass

Gain of Function of Leptin Signaling and Bone Mass

Factors Downstream of Leptin Regulation of Bone Mass

Leptin Acts in the Brain to Regulate Bone Mass

Neurotransmitter Profiling in Leptin-Deficient Mice Brain Points to Serotonin as a Target of Leptin

Serotonin Uses Creb in Arc and Vmh Neurons to Regulate Two Different Functions

Leptin Receptor Deletion on Serotonin Nuclei Results in Increased Appetite

Perspective

Acknowledgment

References

Chapter 6. Gastrointestinal Tract and the Control of Bone Mass

The Relevance of the Gastrointestinal Tract for the Skeleton

Hypochlorhydria, a Major Public Health Problem

Proton Pump Inhibitors and Osteoporosis

How are Proton Pump Inhibitors Affecting the Skeleton?

Gastrectomy and Osteomalacia, an Association not to be Forgotten

Osteopetrorickets, a Rare Disorder Caused by a Combined Acidification Defect of Osteoclasts and Parietal Cells

Animal Models of Impaired Gastric Acidification

Calcium Supplementation in Clinical Practice

Concluding Remarks

References

Chapter 7. Gut-derived Serotonin and Bone Formation

Serotonin: A Tale of Guts and Brain

Regulation of Bone Formation by Gut-Derived Serotonin

Regulation of Serotonin Production in Gut by Lrp5

Regulation of Bone Formation by Serotonin in Humans

Modulation of Tph1 Activity as a Novel Bone Anabolic Therapy

References

Chapter 8. Skeletal Actions of Insulin

Introduction

The Insulin/IGF Family of Ligands and Receptors

Actions of IGF-1 and Insulin in Osteoblasts

Insulin Signaling in the Osteoblasts Regulates Glucose Metabolism

Insulin Signaling Regulates Osteocalcin Production and Bioavailability

From Mouse to Man

Perspectives and Directions for Future Studies

Acknowledgments

References

Chapter 9. Transcriptional Regulation of the Endocrine Function of Bone

Introduction

Foxo1, A Transcriptional Modulator of the Endocrine Function of the Skeleton

Atf4 in Skeletal Regulation of Energy Homeostasis

ΔFosb Reciprocally Affects Bone Mass and Fat Accrual and Favors Insulin Sensitivity

Creb Versus Atf4 in Central Control of Bone Mass: Leptin

Creb in Central Versus Local Control of Bone Formation: Serotonin

Creb in Bone Regulation of Male Reproduction

Perspective

References

Chapter 10. Regulation of Bone Resorption by PPARγ

Introduction

PPARγ Expression Specifies Osteoclast Progenitor

PPARγ Activation Stimulates Osteoclast Differentiation by Inducing C-FOS

PPARγ Activation Stimulates Osteoclast Differentiation by Downregulating β-Catenin

PPARγ Activation Promotes Osteoclastogenesis by Activating PGC1β and ERRα

Other Signaling Pathways that may Intersect with PPARγ During Osteoclastogenesis

TZDS Induce Bone Loss by Activating Bone Resorption and Inhibiting Bone Formation

Systemic PPARγ Activation Enhances Bone Resorption by Both Osteoclast-Autonomous and Non-Autonomous Mechanisms

PPARγ Effects on Bone Resorption are Context Dependent

Conclusion

Acknowledgments

References

Chapter 11. From Gonads to Bone, and Back

Introduction

Sex Steroid Hormones Effects on Bone Physiology

Sex Steroid Hormone Regulation of Bone Growth

Sex Steroid Hormone Regulation of Bone Mass Maintenance

Estrogen and Androgen Mode of Action in Skeleton

Genomic and Non-Genomic Sex Steroid Hormone Signaling in Bone Cells

Osteocalcin, a New Player in the Regulation of Testosterone Production

Osteocalcin Mode of Action in Leydig Cells

Correlative Observation of the Osteocalcin-Dependent Regulation of Testosterone Production in Humans

Disturbances in Osteocalcin or its Receptor Activity are Associated to Prostate Cancer

Conclusion

References

Chapter 12. Regulation of Phosphate Metabolism by FGF23

Introduction

Phosphate Metabolism

FGF Biology

FGF23 and Phosphate Metabolism

FGF23: Emerging Roles in Disease Processes

Summary

Acknowledgments

References

Chapter 13. Clinical Aspects of Fibroblast Growth Factor 23

Introduction

Hypophosphatemic Diseases

Treatment of FGF23-Related Hypophosphatemic Diseases

Tumoral Calcinosis

Chronic Kidney Disease–Mineral and Bone Disorder (CKD–MBD)

FGF23 in Epidemiological Studies

Future Direction

References

Chapter 14. Bone Marrow Fat and Bone Mass

Introduction

Historical Vignette

Molecular and Cellular Aspects of Marrow Adipogenesis

Development of Marrow Fat

The Function of Marrow Fat

Mouse Models to Study Marrow Adipocytes

Marrow Fat in Humans

Future Direction

References

Chapter 15. Osteocalcin, Undercarboxylated Osteocalcin, and Glycemic Control in Human Subjects

Obesity, Diabetes, and Low Serum Osteocalcin: Cross-Sectional Studies in Human Subjects

Osteocalcin and Glycemic Control: Interventional Studies

Interventional Studies Manipulating Vitamin K Levels

What is the Active Form of Osteocalcin in Humans?

Endosteal Surface Area, Remodeling, and Glycemic Control

Osteocalcin and Glycemic Control: Conclusions and Clinical Implications

Acknowledgments

References

Chapter 16. Clinical Implications of Serotonin Regulation of Bone Mass

Introduction

Synthesis and Function of Serotonin in the Nervous System

Studies of Serotonin Influence on Bone in Human Development

Clinical Studies Demonstrating an Effect of Serotonin on Bone in Adults

Bone Density

Fractures

Considerations for Determination of Causality in Epidemiologic Studies

Limitations of Current Studies on SSRIS’ Effect on Bone

Implications for Screening and Population Health

Conclusion

References

Chapter 17. Significance of Organ Crosstalk in Insulin Resistance and Type 2 Diabetes

Introduction

Mechanisms of β-Cell Failure/Loss

Insulin Resistance—Multiorgan Crosstalk of Insulin Target Tissues

Non-Canonical Insulin Target Tissues

Therapy for Type 2 Diabetes Mellitus

Perspective

Acknowledgments

References

Color Plates

Index