Genetics of Bone Biology and Skeletal Disease

Genetics of Bone Biology and Skeletal Disease

1st Edition - November 2, 2012
There is a Newer Edition Available
  • 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.


    Primary: Academic, medical, and pharmaceutical researchers in bone biology, clinical genetics, rheumatology, endocrinology, osteology; Secondary: 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