Genetics of Bone Biology and Skeletal Disease

Genetics of Bone Biology and Skeletal Disease

1st Edition - November 2, 2012

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  • Editors: Rajesh Thakker, Michael Whyte, John Eisman, Takashi Igarashi
  • eBook ISBN: 9780123878304
  • Hardcover ISBN: 9780123878298

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This book identifies and analyzes the genetic basis of bone disorders in humans and demonstrates the utility of mouse models in furthering the knowledge of mechanisms and evaluations of treatments. The book is aimed at all students of bone biology and genetics, and with this in mind, it includes general introductory chapters on genetics and bone biology and more specific disease-orientated chapters, which comprehensively summarize the clinical, genetic, molecular genetic, animal model, functional and molecular pathology, diagnostic, counselling and treatment aspects of each disorder.

Key Features

  • Saves academic, medical, and pharma researchers time in quickly accessing the very latest details on a broad range of genetic bone issues, as opposed to searching through thousands of journal articles
  • Provides a common language for bone biologists and geneticists to discuss the development of bone cells and genetics and their interactions in the development of disease
  • Researchers in all areas bone biology and genetics will gain insight into how clinical observations and practices can feed back into the research cycle and will, therefore, be able to develop more targeted genomic and proteomic assays
  • For those clinical researchers who are also MDs, correct diagnosis (and therefore correct treatment) of bone diseases depends on a strong understanding of the molecular basis for the disease


Academic, medical, and pharmaceutical researchers in bone biology, clinical genetics, rheumatology, endocrinology, osteology; Clinicians who threat metabolic bone diseases and musculoskeletal disorders (endocrinologists, rheumatologists, osteologists) and offer genetic counseling

Table of Contents

  • 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


    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


    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


    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


    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


    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


    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


    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



    Chapter 9. Copy Number Variation

    I. Introduction

    II. CNV Detection

    III. CNV and Disease

    IV. CNV and Osteoporosis

    V. Summary



    Chapter 10. Prospects of Gene Therapy

    I. Introduction

    II. Vectors in Skeletal Gene Therapy

    III. Cell Types

    IV. Diseases

    V. Conclusion


    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


    Chapter 12. Genetic Testing and Counseling

    I. Genetic Testing

    II. Genetic Testing for Skeletal Disorders

    III. Genetic Counseling


    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


    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


    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


    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


    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


    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


    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


    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



    Chapter 21. Skeletal Dysplasias

    I. Introduction

    II. Classification of Skeletal Dysplasias

    III. Diagnosis

    IV. Multiple Epiphyseal Dysplasias

    V. Metaphyseal Dysplasias

    VI. Conclusion


    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



    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


    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



    Part IV: Parathyroid and Related Disorders

    Chapter 25. Hyperparathyroidism

    I. Introduction

    II. Familial Hyperparathyroidism

    III. Sporadic Hyperparathyroidism

    IV. Ectopic PTH Production


    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



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

    I. Introduction

    II. Pseudohypoparathyroidism/Albright Hereditary Osteodystrophy

    III. Fibrous Dysplasia/McCune–Albright Syndrome


    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


    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]


    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



    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


    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


    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


    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


    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


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

    I. Introduction

    II. Clinical Description and Definition



Product details

  • No. of pages: 634
  • Language: English
  • Copyright: © Academic Press 2012
  • Published: November 2, 2012
  • Imprint: Academic Press
  • eBook ISBN: 9780123878304
  • Hardcover ISBN: 9780123878298

About the Editors

Rajesh Thakker

Rajesh Vasantlal Thakker FRS FMedSci FRCPath FRCPE FRCP is May Professor of Medicine in the Nuffield Department of Clinical Medicine at the University of Oxford and a Fellow of Somerville College, Oxford.[13] Thakker is also a Consultant physician at the Churchill Hospital and the John Radcliffe Hospital, Principal Investigator (PI) at the Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM) and was Chairman of the Efficacy and Mechanism Evaluation (EME) Board until Spring 2016.

Affiliations and Expertise

May Professor of Medicine, Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford; Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, UK

Michael Whyte

Affiliations and Expertise

Professor of Medicine, Pediatrics, and Genetics, Washington University, School of Medicine; Medical-Scientific Director, Center for Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children, St. Louis, USA

John Eisman

Affiliations and Expertise

Director of Bone Research Program, Garvan Institute of Medical Research, Professor of Medicine, University of New South Wales, Australia

Takashi Igarashi

Affiliations and Expertise

Department of Pediatrics, Faculty of Medicine, The University of Tokyo, Mejirodai, Japan

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