Genetics of Bone Biology and Skeletal Disease

Preface

List of Contributors

Part I: General Background to Bone Biology

Chapter 1. Biology of Bone and Cartilage

I. Introduction

II. Osteoclasts

III. Osteoblasts

IV. Cartilage

References

Chapter 2. Overview of Bone Structure and Strength

I. Introduction

II. Bone Biomechanics and the Determinants of Whole Bone Strength

III. Contribution of Bone Geometry to Bone Strength

IV. Age-Related Changes in Trabecular and Cortical Bone Microarchitecture

V. Contribution of Bone Microarchitecture to Bone Strength

VI. Contribution of Bone Structure to Fracture Risk in Humans

VII. Summary

References

Chapter 3. Overview of Joint and Cartilage Biology

I. Introduction

II. Joint Development

III. Joint Anatomy

IV. Joint Homeostasis

V. Joint Disease

VI. Joint Repair

References

Chapter 4. Integrating Endocrine and Paracrine Influences on Bone: Lessons from Parathyroid Hormone and Parathyroid Hormone-related Protein

I. Bone Remodeling and Modeling

II. Parathyroid Hormone (PTH) and Parathyroid Hormone-Related Protein (PTHrP)

III. PTHrP in Bone: Production in Osteoblasts

IV. PTHrP Function in Bone: Lessons from PTHrP Null Mice

V. Anabolic Actions of PTH and PTHrP

VI. Endocrine PTH, Paracrine PTHrP: Relationships in Development and Postnatal Life

VII. Growth Factors in the Local Actions of PTH and PTHrP

VIII. Are Osteoclasts Involved in the Anabolic Action of PTH?

IX. GP130 Cytokines as Agents of Local Control of PTH Action

X. Sclerostin as a Local Factor promoting PTH Action

XI. Other Influences of PTH/PTHrP on Bone Through the Bone Marrow Microenvironment

XII. The PTH–PTHrP Relationship in Vasculature and Bone

XIII. Conclusion

References

Chapter 5. Energy Homeostasis and Neuronal Regulation of Bone Remodeling

I. Introduction: Energy Metabolism and Bone

II. Coordinated Neuronal Control of Bone and Energy Metabolism

III. Bone as an Endocrine Organ

IV. Conclusions

References

Chapter 6. Neuropeptide Y and Bone Regulation

I. Neural Control of Bone

II. The NPY System

III. NPY and Bone

IV. The Y1 Receptor

V. The Y2 Receptor

VI. The Y4 Receptor

VII. Possible Involvement of Other NPY Ligands

VIII. NPY Interaction With Leptin

IX. Conclusion

References

Part II: General Background to Genetics

Chapter 7. Genome-wide Association Studies

I. Introduction

II. Linkage Disequilibrium Mapping

III. Study Design Issues in Genome-Wide Association Studies

IV. The “Missing Heritability” Question

V. Rare Variant Study Designs

VI. Conclusion

References

Chapter 8. Genomic Profiling in Bone

I. Introduction

II. Profiling Skeletal Cells and Bone Formation

III. Profiling the Growth Plate During Endochondral Ossification

IV. Profiling Biomechanical Effects on Bone

V. Profiling Bone Repair (Endochondral vs Intramembrenous)

VI. Genomic Expression Profiles in Osteoporosis

VII. Concluding Remarks

Acknowledgments

References

Chapter 9. Copy Number Variation

I. Introduction

II. CNV Detection

III. CNV and Disease

IV. CNV and Osteoporosis

V. Summary

Acknowledgments

References

Chapter 10. Prospects of Gene Therapy

I. Introduction

II. Vectors in Skeletal Gene Therapy

III. Cell Types

IV. Diseases

V. Conclusion

References

Chapter 11. Pharmacogenetics and Pharmacogenomics of Osteoporosis: Personalized Medicine Outlook

I. Introduction

II. Complexity of Phenotypes

III. Genetics of Osteoporosis

IV. Pharmacogenetics of Therapeutic Response

V. Toward Individualized Prognosis and Individualized Treatment Decision

VI. Conclusion

References

Chapter 12. Genetic Testing and Counseling

I. Genetic Testing

II. Genetic Testing for Skeletal Disorders

III. Genetic Counseling

References

Chapter 13. Mouse Models: Approaches to Generating in vivo Models for Hereditary Disorders of Mineral and Skeletal Homeostasis

I. Introduction

II. Methods for Generating Mouse Models

III. Genetic Bone Diseases Associated with Defective Calcium Homeostasis

IV. Conclusions

References

Chapter 14. Fetal Control of Calcium and Phosphate Homeostasis – Lessons from Mouse Models

I. Introduction

II. Overview of Fetal and Neonatal Mineral Metabolism

III. Overview of Placental Mineral Transport

IV. Overview of Endochondral Bone Development

V. Role of PTHrP

VI. Role of PTH

VII. Role of PTHrP and PTH in Combination

VIII. Role of Estradiol

IX. Role of Calcitonin

X. Role of Vitamin D and Calcitriol

XI. Conclusions

References

Chapter 15. Control of Skeletal Homeostasis During Pregnancy and Lactation – Lessons from Physiological Models

I. Introduction

II. Skeletal and Mineral Physiology During Pregnancy

III. Disorders of Bone and Mineral Metabolism During Pregnancy

IV. Skeletal and Mineral Physiology During Lactation

V. Disorders of Bone and Mineral Osteoporosis of Lactation

VI. Conclusions

References

Part III: Disorders of Bone and Joint

Chapter 16. Osteoporosis Genes Identified by Genome-wide Association Studies

I. Introduction

II. Genome-Wide Association Studies of Osteoporosis

III. Genes Identified by Genome-Wide Association Studies on Bone Mineral Density

IV. GWAS in Other Ethnic Groups and for Other Osteoporosis Phenotypes

V. Conclusions and Perspective

References

Chapter 17. Osteogenesis Imperfecta

I. Introduction

II. Clinical Description

III. Genetic description

IV. Molecular Genetics

V. Animal models

VI. Diagnostic Aspects

VII. Treatment

VIII. Conclusions

References

Chapter 18. Osteoarthritis – Genetic Studies of Monogenic and Complex Forms

I. Brief Clinical Description

II. Genetics Description

III. Molecular Genetics

IV. Functional and Molecular Pathology

V. Diagnostic Aspects

VI. Treatment

VII. Conclusions

References

Chapter 19. Genetics of Paget’s Disease of Bone

I. Clinical Features

II. Genetic Architecture of Paget’s Disease

III. Environmental Factors

IV. Molecular Genetics

V. Animal Models

VI. Molecular Pathology

VII. Molecular Diagnosis

VIII. Conclusions

References

Chapter 20. Mendelian Disorders of RANKL/OPG/RANK Signaling

I. Introduction

II. The Disorders that Feature RANKL/OPG/RANK Activation

III. The Disorders that Feature RANKL/OPG/RANK Deactivation

IV. Summary

Acknowledgments

References

Chapter 21. Skeletal Dysplasias

I. Introduction

II. Classification of Skeletal Dysplasias

III. Diagnosis

IV. Multiple Epiphyseal Dysplasias

V. Metaphyseal Dysplasias

VI. Conclusion

References

Chapter 22. Hypophosphatasia

I. Introduction

II. Biochemistry and Molecular Biology of Alkaline Phosphatase

III. Physiology of Skeletal Formation and Alkaline Phosphatase Function

IV. Hypophosphatasia

V. Physiological Role of Alkaline Phosphatase Explored in Hypophosphatasia

VI. Concluions

Acknowledgment

References

Chapter 23. Sclerosing Bone Disorders

I. Introduction

II. Clinical Aspects of the Sclerosing Bone Disorders

III. Molecular Genetics and Pathogenic Mechanisms

IV. Diagnostics, Treatment and Genetic Counseling

References

Chapter 24. Fibrodysplasia (Myositis) Ossificans Progressiva

I. Introduction

II. Clinical Description – Fibrodysplasia Ossificans Progressiva (FOP)

III. Genetics and Molecular Genetics of FOP

IV. Animal Models

V. Functional and Molecular Pathology

VI. Diagnostic Aspects

VII. Counseling and Treatment

VIII. Summary

Acknowledgments

References

Part IV: Parathyroid and Related Disorders

Chapter 25. Hyperparathyroidism

I. Introduction

II. Familial Hyperparathyroidism

III. Sporadic Hyperparathyroidism

IV. Ectopic PTH Production

References

Chapter 26. Hypoparathyroidism

I. Introduction

II. Clinical and Diagnostic Aspects

III. Treatment

IV. Complex Syndromes Associated with Hypoparathyroidism

V. Calcium-Sensing Receptor Abnormalities

VI. Isolated Hypoparathyroidism

VII. Conclusions

Acknowledgments

References

Chapter 27. Gsα, Pseudohypoparathyroidism, Fibrous Dysplasia, and McCune–Albright Syndrome

I. Introduction

II. Pseudohypoparathyroidism/Albright Hereditary Osteodystrophy

III. Fibrous Dysplasia/McCune–Albright Syndrome

References

Chapter 28. Genetic Disorders Affecting PTH/PTHrP Receptor Function

I. Introduction

II. The PTH/PTHrP Receptor System

III. Human Disorders Caused by Mutations in the PTH-PTHrP Signaling Pathway

IV. Mutations in Genes Downstream of the PTH/PTHrP Receptor

V. Conclusions

References

Chapter 29. Genetically Determined Disorders of the Calcium-Sensing Receptor

I. Introduction

II. Clinical and Genetic Features of Familial Hypocalciuric Hypercalcemia (FHH) [OMIM - #14598]

III. Clinical and Genetic Features of Neonatal Severe Primary Hyperparathyroidism (NSHPT) [OMIM 239200]

IV. Clinical and Genetic Features of Autosomal Dominant Hypoparathyroidism Caused by Activating CaSR Mutations (ADH) [OMIM - #601298]

V. Clinical and Genetic Features of Bartter’s Syndrome Subtype V Arising from Activating Mutations of the CaSR: [OMIM - #601199.0035]

References

Chapter 30. Multiple Endocrine Neoplasia Type 1

I. Introduction

II. Clinical Findings and Treatment

III. Parathyroid Tumors

IV. Pancreatic Tumors

V. Pituitary Tumors

VI. Associated Tumors

VII. Genetics

VIII. MEN1 Mutations in Sporadic Non-MEN1 Endocrine Tumors

IX. MEN1 Mutations in Hereditary Endocrine Disorders

X. Function of MEN1 Protein (Menin)

XI. Mouse Models for MEN1

XII. CDNKIB Mutations in MEN1

XIII. Genetic Testing and Screening in MEN1

XIV. Detection of MEN1 Tumors

XV. Conclusions

Acknowledgments

References

Chapter 31. Multiple Endocrine Neoplasia Type 2 and Bone

I. Mutations

II. Tumors

III. Relevance of MEN2 to Bone Biology

IV. Hormonal Secretion from MEN2 Tumors

V. Metastasis

VI. Skeletal Side Effects of Tyrosine Kinase Inhibition

VII. Conclusions

References

Part V: Vitamin D and Renal Disorders

Chapter 32. Heritable Renal Phosphate Wasting Disorders

I. Introduction

II. Phosphate Homeostasis

III. Phosphate Regulation of Vitamin D Metabolism

IV. The Heritable Renal Phosphate Wasting Disorders

V. Autosomal Dominant Hypophosphatemic Rickets (ADHR)

VI. X-Linked Hypophosphatemic Rickets (XLH)

VII. Autosomal Recessive Hypophosphatemic Rickets (ARHR)

VIII. Conclusions

References

Chapter 33. Genetic Disorders of Vitamin D Synthesis and Action

I. Introduction

II. Biosynthesis of 1,25-Dihydroxyvitamin D

III. 1α-Hydroxylase Deficiency

IV. Hereditary Vitamin D Resistant Rickets (HVDRR)

V. Conclusions

References

Chapter 34. Renal Fanconi Syndrome, Dent’s Disease and Bartter’s Syndrome

I. Renal Fanconi Syndrome

II. Dent’s Disease

III. Bartter’s Syndrome

IV. Conclusion

References

Chapter 35. Inherited Magnesium Disorders

I. Introduction

II. Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis (FHHNC)

III. Primary Hypomagnesemia and Secondary Hypocalcemia (HSH)

IV. Isolated Autosomal Recessive Hypomagnesemia (IRH)

V. Autosomal Dominant Renal Hypomagnesemia with Hypocalciuria

VI. Gitelman Syndrome

VII. Hypomagnesemia in Bartter Syndrome

VIII. Autosomal Dominant Hypoparathyroidism

IX. Seizures, Sensorineural Deafness, Ataxia, Mental Retardation and Electrolyte Imbalance (SeSAME Syndrome)/Epilepsy, Ataxia, Sensorineural Deafness and Tubulopathy (EAST Syndrome)

X. KCNA1/Kv1.1 Mutation and its Association with Isolated Hypomagnesemia

XI. Hypomagnesemia with Mitochondrial Inheritance

XII. CNNM2 Mutations in Dominant Hypomagnesemia

XIII. Treatment and Counseling

References

Chapter 36. Genetic Hypercalciuria: A Major Risk Factor in Kidney Stones

I. Introduction

II. Clinical Description and Definition

References

Index