Genetics of Bone Biology and Skeletal Disease

__Genetics of Bone Biology and Skeletal Disease, Second Edition,__ is aimed at students of bone biology and genetics and includes general introductory chapters on bone biology and genetics. More specific disease orientated chapters comprehensively summarize the clinical, genetic, molecular, animal model, molecular pathology, diagnostic, counseling, and treatment aspects of each disorder. The book is organized into five sections that each emphasize a particular theme, general background to bone biology, general background to genetics and epigenetics, disorders of bone and joint, parathyroid and related disorders, and vitamin D and renal disorders. The first section is specifically devoted to providing an overview of bone biology and structure, joint and cartilage biology, principles of endocrine regulation of bone, and the role of neuronal regulation and energy homeostasis. The second section reviews the principles and progress of medical genetics and epigenetics related to bone disease, including genome-wide association studies (GWAS), genomic profiling, copy number variation, prospects of gene therapy, pharmacogenomics, genetic testing and counseling, as well as the generation and utilizing of mouse models. The third section details advances in the genetics and molecular biology of bone and joint diseases, both monogenic and polygenic, as well as skeletal dysplasias, and rarer bone disorders. The fourth section highlights the central role of the parathyroids in calcium and skeletal homeostasis by reviewing the molecular genetics of: hyperparathyroidism, hypoparathyrodism, endocrine neoplasias, and disorders of the PTH and calcium-sensing receptors. The fifth section details molecular and cellular advances across associated renal disorders such as vitamin D and rickets. * 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 evaluation of treatments * Demonstrates how the interactions between bone and joint biology, physiology, and genetics have greatly enhanced the understanding of normal bone function as well as the molecular pathogenesis of metabolic bone disorders * Summarizes the clinical, genetic, molecular, animal model, molecular pathology, diagnostic, counseling, and treatment aspects of each disorder Cover GENETICS OF BONE BIOLOGY AND SKELETAL DISEASE Copyright List of Contributors Preface to the Second Edition Preface to the First Edition Section 1: General Background to Genetics Chapter 1 - Introduction to Genetics of Skeletal and Mineral Metabolic Diseases 1 - Introduction 2 - Genetics of skeletal and mineral metabolic diseases 2.1 - Modes of Inheritance 2.2 - Genetic Heterogeneity and Monogenic Skeletal Diseases 2.3 - Identifying Genetic Abnormalities Causing Monogenic Diseases 2.4 - Identifying Genes Causing Polygenic Traits 2.5 - Molecular Insights From the Investigation of Monogenic Disorders and Polygenic Traits 2.6 - Genetic Understanding and Application to Development of Novel Therapeutics 3 - Approach to the patient with genetic skeletal/mineral metabolic disease 3.1 - Clinical Approach 3.2 - Medical History and Physical Examination 3.3 - Family Medical History for Determining Mode of Disease Inheritance 4 - Current genetic tests, their clinical utility, and interpretation 4.1 - Clinical Value of Genetic Testing 4.2 - Pretest Considerations—Which Test? 4.3 - Detection of Chromosomal Abnormalities, Copy Number Variations, and Mutations Causing Disease 4.3.1 - Karyotype 4.3.2 - Fluorescence In Situ Hybridization (FISH) 4.3.3 - Multiplex-Ligation Dependent Probe Amplification (MLPA) 4.3.4 - Whole Genome Arrays 4.3.5 - Microarray-Comparative Genomic Hybridization (aCGH) 4.3.6 - Single Nucleotide Polymorphism Arrays 4.3.7 - Single Gene Testing (Sanger Sequencing) 4.3.8 - Next-Generation Sequencing or Second-Generation Sequencing 4.4 - Challenges of Data Interpretation and Approaches to the Analysis of Variants Identified by NGS Platforms 4.4.1 - Variant Identification 4.4.2 - Variant Interpretation 4.5 - Special Circumstances for Genetic Testing 4.5.1 - Detection of Mosaicism 4.5.2 - Prenatal Diagnosis 4.6 - Informed Consent and Ethical Considerations 5 - Conclusions References Chapter 2 - Epigenetics 1 - Introduction 2 - Epigenetic control mechanisms 2.1 - Histone Modifications and Chromatin Remodeling 2.2 - Histone Variants 2.3 - DNA Methylation 2.4 - Noncoding RNAs (ncRNAs) 3 - Transgenerational epigenetic inheritance 4 - Epigenetics and human disease 4.1 - Imprinting Disorders 4.2 - Cancer 4.3 - Other Diseases 4.4 - Epigenetic Therapy 5 - Conclusions References Chapter 3 - Genome-Wide Association Studies 1 - Introduction 2 - Linkage disequilibrium mapping 3 - Study design issues in genome-wide association studies 3.1 - Quality Control 4 - The “missing heritability” question 5 - Rare variant study designs 6 - Conclusions References Chapter 4 - Copy Number Variation 1 - Introduction 1.1 - Potential Mechanisms for Formation of CNVs 2 - CNV detection 3 - CNV and disease 3.1 - Obesity 3.2 - Schizophrenia 3.3 - Autism 3.4 - Cancer 3.5 - Congenital Heart Disease 4 - CNV and osteoporosis 5 - Conclusions Acknowledgments References Chapter 5 - Genomic Profiling in Bone 1 - Introduction 1.1 - Profiling Skeletal Cells and Bone Metabolism 1.2 - Profiling Location and Age Dependent Changes in Skeletal Gene Expression 1.3 - Profiling Biomechanical Effects on Bone 1.4 - Profiling Gene Expression Changes Occurring as a Function of Altered Bone Metabolism 1.4.1 - Profiling Bone in Animal Models With Impaired Bone Metabolism 1.4.2 - Profiling Osteoporosis in Humans 1.5 - Profiling Noncoding RNA Expression in Bone 2 - Conclusions Acknowledgments References Chapter 6 - Functional Genomics 1 - What is functional genomics? 2 - Annotating the genome—an emerging picture 2.1 - Encode and Roadmap: An Overview 2.2 - DNase-seq 2.3 - ChIP-seq and Chromatin Profiling 2.3.1 - SP7/Osterix is Restricted to Bone-Forming Vertebrates Where it Acts as a Dlx Cofactor in Osteoblast Specification 2.3.2 - Distinct Transcriptional Programs Underlie Sox9 Regulation of the Mammalian Chondrocyte 2.3.3 - The Osteoblast-to-Osteocyte Transition: Epigenetic Changes and Response to the Vitamin D3 Hormone 2.3.4 - The Binding of Runx2 During Osteoblastogenesis 2.3.5 - Chromatin Profiling of Parathyroid Glands 3 - From annotated sequences to function 3.1 - In Situ Saturating Mutagenesis With CRISPR/Cas9 3.2 - Multiplexed Reporter Assays (MPRA) to Assess Function of Expression-Modulating Variants 4 - Interrogation of cellular function: genome-wide gain- and loss-of-function screening in mammalian cells 4.1 - RNAi-Based Functional Genomics 4.2 - The Orfeome: A Tool for Gain-of-Function Screening 4.3 - Genetic Screens Using CRISPR/Cas9: The Next Frontier 5 - Outlook 6 - Summary References Chapter 7 - Mouse Models: Approaches to Generate In Vivo Models for Hereditary Disorders of Mineral and Skeletal Homeostasis 1 - Introduction 2 - Methods for generating mouse models 2.1 - Nontargeted Strategies 2.2 - Targeted Knock-Out Strategies 2.3 - Targeted Knock-In Strategies 3 - Genetic bone diseases associated with defective calcium homeostasis 3.1 - Disorders of Parathyroid Development 3.2 - Models for the DiGeorge Syndrome Type 1 Due to TBX1 Mutations 3.3 - Models for Familial Isolated Hypoparathyroidism Due to PTH and GCMB Mutations 3.4 - Disorders of PTH Signaling 3.5 - Blomstrand’s Chondrodysplasia 3.6 - Jansen’s Disease 3.7 - Pseudohypoparathyroidism 3.8 - Disorders of the Calcium-Sensing Receptor (CaSR) 3.9 - FHH and NSHPT Due to Loss-of-Function CaSR Mutations 3.10 - ADHH Due to Gain-of-Function CaSR Mutations 4 - Conclusions References Chapter 8 - Prospects of Gene Therapy for Skeletal Diseases 1 - Introduction 2 - Vectors in skeletal gene therapy 2.1 - Adenovirus 2.2 - Adeno-Associated Virus 2.3 - Retrovirus and Lentivirus 2.4 - Nonviral Vectors 2.5 - Conclusions 3 - Methods of gene delivery 3.1 - In Vivo Delivery 3.2 - Ex Vivo Delivery 4 - The immune response to gene therapy vectors 4.1 - The Innate Immune Response 4.2 - The Adaptive Immune Response 4.3 - Strategies to Limit Immune Reactions to Gene Therapy Vectors 5 - Gene therapy for pathologies of the skeletal system 5.1 - Bone 5.1.1 - Bone Healing and Osteogenesis 5.1.2 - Implant Stability and Aseptic Loosening 5.1.3 - Osteoporosis 5.1.4 - Osteogenesis Imperfecta 5.2 - Cartilage 5.2.1 - Osteoarthritis 5.2.2 - Rheumatoid Arthritis 5.3 - Tendon 5.4 - Intervertebral Disc 6 - Conclusions References Chapter 9 - Pharmacogenetics and Pharmacogenomics of Osteoporosis: Personalized Medicine Outlook 1 - Complexity of phenotypes 2 - Genetics of osteoporosis 2.1 - Candidate Genes 2.2 - Genome-Wide Studies 2.3 - Pathways 3 - Gene–gene interaction and “missing heritability” 4 - Pharmacogenetics of therapeutic response 5 - Toward individualized assessment and individualized treatment decisions 6 - Conclusions References Chapter 10 - Genetic Testing and Counseling 1 - Genetic testing 1.1 - Small-Scale Variants 1.2 - Large-Scale Variants 1.3 - Evolving Approaches to DNA-Based Genetic Testing 2 - Genetic testing for skeletal disorders 2.1 - Genetic Tests Available 2.2 - When to Order Genetic Testing 3 - Genetic counseling 3.1 - History 3.2 - The Genetic Counseling Process 3.3 - The Genetic Counseling Session 3.3.1 - Family History 3.3.2 - Genetic Testing 3.3.3 - Communicating the Facts 3.3.4 - Counseling and Support References Section 2: General Background to Bone Biology Chapter 11 - Biology of Bone and Cartilage 1 - Introduction 2 - Osteoclasts 2.1 - Regulation of Osteoclast Formation: The RANKL–RANK–OPG Pathway 2.2 - Transcription Factor Regulation of Osteoclastogenesis 2.3 - Costimulatory Signaling-Mediated Osteoclastogenesis 2.4 - RANKL/RANK Downstream Signaling 2.5 - Regulation of Osteoclast Activation 2.6 - Negative Regulation of Osteoclast Formation and Function 2.7 - Osteoclast Apoptosis 3 - Osteoblasts 3.1 - Transcription Factors and Signal Pathways 3.1.1 - BMP/RUNX2 Signaling 3.1.2 - Wingless (Wnt)-β-Catenin 3.1.3 - Notch 3.2 - Epigenetic Modifications 3.2.1 - DNA Methylation 3.2.2 - Histone Modification 3.2.3 - Micro-RNA 3.3 - Regulation of Osteoblast/Osteoclast Communication 3.3.1 - Ephrins 3.3.2 - Semaphorins 4 - Cartilage 4.1 - Chondrocyte Formation 4.2 - Endochondral Ossification 4.3 - Endochondral Ossification in the Adult Skeleton 4.4 - Formation of Articular Cartilage 4.5 - Cartilage Degeneration 5 - Conclusions References Chapter 12 - Overview of Bone Structure and Strength 1 - Introduction 2 - Bone biomechanics and the determinants of whole-bone strength 2.1 - Structural Versus Material Properties of Bone 2.2 - Mechanical Properties of Bone Tissue Depend on Loading Direction 2.3 - Determinants of Biomechanical Properties of Trabecular and Cortical Bone 3 - Contribution of bone geometry to bone strength 3.1 - Age-Related Changes in Bone Size and Shape 4 - Age-related changes in trabecular and cortical bone microarchitecture 5 - Contribution of bone microarchitecture to bone strength 5.1 - Trabecular Microarchitecture 5.2 - Age-Related Changes in Cortical and Trabecular Bone Material Properties 5.3 - Contribution of Bone Structure to Vertebral Strength 5.4 - Contribution of Bone Structure to Proximal Femoral Strength 6 - Contribution of bone structure to fracture risk in humans 7 - Conclusions References Chapter 13 - Overview of Joint and Cartilage Biology 1 - Introduction 2 - Joint development 2.1 - Joint Development as a Part of Skeletal Development 2.2 - Joint Site Determination 2.3 - What Happens in the Joint Interzone? 2.4 - Joint Cavitation 2.5 - The Differentiation of the Articular Cartilage and Other Joint Structures 2.6 - Integration of the Joints with the Skeleton and Joint Shape Morphogenesis 3 - Joint anatomy 3.1 - The Articular Cartilage 3.1.1 - Collagens 3.1.2 - Proteoglycans 3.1.3 - Noncollagenous Matrix Proteins 3.1.4 - Organization of the Articular Cartilage 3.1.4.1 - Soft Tissues of the Joint 3.1.4.2 - The Enthesis 4 - Joint homeostasis 5 - Joint disease 5.1 - Rheumatoid Arthritis 5.1.1 - Spondyloarthritis 5.1.2 - Osteoarthritis 6 - Joint repair 6.1 - Tissue Repair by Enhancing the Endogenous Healing Response 6.2 - Joint Resurfacing by Tissue Engineering References Chapter 14 - Osteocyte Biology 1 - Introduction 2 - The fundamental role of osteocytes in skeletal homeostasis 2.1 - The Osteocyte Network 2.2 - Osteocytes as Mechanosensory Cells 2.3 - Osteocytes and the Skeletal Response to PTH 3 - Molecular and functional signature of osteocytes 3.1 - Formation and Maintenance of the Osteocytic Network 3.2 - Regulation of Bone Formation by Osteocytes 3.3 - Regulation of Bone Resorption by Osteocytes and the Role of Osteocyte Apoptosis in Targeted Remodeling 4 - Gene deletion and mutations affecting osteocytes 4.1 - Sclerostin, Sclerosteosis, and van Buchem’s Disease 4.2 - LRP Mutations 4.3 - Mutations Leading to Disturbance of Phosphate Homeostasis 5 - Cross talk of bone with other organs/tissues 5.1 - Cross Talk of Bone With Kidney and Heart 5.2 - Cross Talk of Bone With Muscle 5.3 - Cross Talk of Bone and Hematopoietic Cells 5.4 - Cross Talk of Bone and Fat 6 - The dying and aging osteocyte 7 - Conclusions References Chapter 15 - Skeletal Stem Cells/Bone Marrow Stromal Cells 1 - History and definitions of postnatal stem cells 1.1 - Definitions 1.2 - Identification of Skeletal Stem/Progenitor Cells 1.3 - From SSCs/BMSCs to “Mesenchymal Stem Cells”—A Source for all Mesodermal Derivatives? 1.4 - From Bone Marrow–Derived “MSCs” to Ubiquitous “MSCs”? 1.5 - “MSCs” are Pluripotent? 2 - Origins of skeletal stem cells/bone marrow stromal cells 3 - Practical considerations—preparation and assessment of SSCs/BMSCs 3.1 - Isolation 3.2 - Culture Conditions 3.3 - Characterization of the Biological Nature of SSCs/BMSCs 3.3.1 - Cell Surface Markers 3.3.2 - Colony-Forming Efficiency 3.3.3 - Demonstration of Bona Fide Stem Cell Characteristics 3.3.3.1 - Differentiation Potential—In Vitro 3.3.3.2 - Differentiation Potential—In Vivo 3.3.3.3 - Self-Renewal 4 - The role of SSCs/BMSCs in postnatal bone turnover 5 - The role of SSCs/BMSCs in disease 6 - Regulation of SSC/BMSC fate 6.1 - Hormonal Regulation 6.2 - Signaling Pathways and Transcription Factors 6.3 - Epigenetic Controls 6.4 - MicroRNAs 6.5 - Cell–Cell and Cell–Substrate Interactions, Cell Shape, and Mechanical Forces 6.6 - Iatrogenic Effects 7 - SSCs/BMSCs in tissue engineering and regenerative medicine 7.1 - Regeneration of the Bone/Marrow Organ 7.2 - SSCs/BMSCs in Another Form of Regenerative Medicine 8 - Conclusions Acknowledgments References Chapter 16 - Osteoimmunology 1 - Introduction 2 - The RANKL/RANK system in bone metabolism 2.1 - RANKL is Essential for Osteoclastogenesis 2.2 - The Cellular Source of RANKL in Bone Remodeling 2.3 - The Role of RANKL in the Mammary Gland and Cancer 3 - Immunological role of the RANKL/RANK system 4 - Intracellular signaling for osteoclastogenesis 4.1 - RANKL Signaling for Osteoclast Differentiation 4.2 - NFATc1, the Master Transcription Factor of Osteoclast Differentiation 4.3 - Costimulatory Signal for RANK 4.4 - Negative Regulators of Osteoclastogenic Signaling 4.5 - Cell–Cell Communication Between Osteoclasts and Osteoblasts 5 - Mechanisms underlying bone destruction in arthritis 5.1 - Th17 Cells and Treg Cells in Autoimmune Arthritis 5.2 - Therapeutic Strategies for RA 6 - Bone marrow microenvironment 7 - Conclusions References Chapter 17 - Integrating Endocrine and Paracrine Influences on Bone; Lessons From Parathyroid Hormone and Parathyroid Hormone-Re... 1 - Bone remodeling and modeling 2 - Parathyroid hormone and parathyroid hormone-related protein 3 - PTHrP in bone; production in osteoblasts 4 - PTHrP function in bone; lessons from PTHrP null mice 5 - Anabolic actions of PTH and PTHrP 6 - Endocrine PTH, paracrine PTHrP; relationships in development and postnatal life 7 - Are osteoclasts involved in the anabolic action of PTH? 8 - Growth factors in the local actions of PTH and PTHrP 9 - gp130 cytokines as agents of local control of PTH action 10 - Sclerostin as a local factor promoting PTH action 11 - Other influences of PTH/PTHrP on bone through the bone marrow microenvironment 12 - The PTH–PTHrP relationship in vasculature and bone 13 - Conclusions References Chapter 18 - Genetics of Bone Fat and Energy Regulation 1 - Introduction 2 - The complex relationship of adipose tissue to bone mass 3 - A common origin for fat and bone cells 4 - Bioenergetics of cells in the bone marrow niche in relation to energy needs and whole body metabolism 5 - Control of skeletal and adipose tissue remodeling 5.1 - Adipokine Regulation of Bone Remodeling 5.2 - Sympathetic Nervous System Control Over Fat and Bone Remodeling 6 - Anorexia nervosa: energy, bone, and adipose deficiencies 7 - Genetics of fat and bone in animal models 7.1 - Shared Genetic Determinants of Bone and Fat in Animal Models 8 - Genetics of fat and bone in humans 8.1 - Shared Genetic Determinants of Fat and Bone in Humans Acknowledgments References Chapter 19 - The Cross Talk Between the Central Nervous System, Bone, and Energy Metabolism 1 - Introduction 2 - Specific features of bone and whole-organism physiology 2.1 - Coordinated Control of Bone Mass and Energy Metabolism: Regulation of Bone Mass by Adipocytes 2.2 - Coordinated Regulation of Bone Mass and Energy Metabolism: The Central Mode of Action of Leptin 3 - Expanding bone biology without premeditation 4 - The anticipated functions of osteocalcin 4.1 - The Other Side of Osteocalcin 5 - Questions raised by the functions of osteocalcin References Further Reading Chapter 20 - Fetal Control of Calcium and Phosphate Homeostasis 1 - Introduction 2 - Overview of fetal and neonatal mineral metabolism 2.1 - Animal Data 2.2 - Human Data 3 - Overview of placental mineral transport 3.1 - Animal Data 3.2 - Human Data 4 - Overview of endochondral bone development 4.1 - Animal and Human Data 5 - Role of PTHrP 5.1 - Animal Data 5.1.1 - Regulation of Serum Minerals 5.1.2 - Regulation of Placental Mineral Transfer 5.1.3 - Regulation of Endochondral Bone Formation 5.2 - Human Data 6 - Role of PTH 6.1 - Animal Data 6.1.1 - Regulation of Serum Minerals 6.1.2 - Regulation of Placental Mineral Transfer 6.1.3 - Regulation of Endochondral Bone Formation 6.2 - Human Data 7 - Role of PTHrP and PTH in combination 7.1 - Animal Data 7.1.1 - Regulation of Serum Minerals 7.1.2 - Regulation of Placental Calcium Transfer 7.1.3 - Regulation of Endochondral Bone Formation 7.2 - Human Data 8 - Role of estradiol 8.1 - Animal and Human Data 9 - Role of calcitonin 9.1 - Animal and Human Data 10 - Role of vitamin D and calcitriol 10.1 - Animal Data 10.1.1 - Regulation of Serum Minerals 10.1.2 - Regulation of Placental Mineral Transport 10.1.3 - Regulation of Endochondral Bone Development 10.2 - Human Data 10.2.1 - Observational Studies and Case Reports 10.2.2 - Intervention Studies 10.2.3 - Associational Studies 11 - Role of FGF23 11.1 - Animal Data 11.2 - Human Data 12 - Conclusions References Chapter 21 - Control of Mineral and Skeletal Homeostasis During Pregnancy and Lactation 1 - Introduction 2 - Skeletal and mineral physiology during pregnancy 2.1 - Mineral Ions and Calciotropic Hormones (Fig. 21.2) 2.2 - Intestinal Absorption of Calcium 2.3 - Renal Handling of Calcium 2.4 - Skeletal Calcium Metabolism 3 - Disorders of bone and mineral metabolism during pregnancy 3.1 - Osteoporosis in Pregnancy 3.2 - Primary Hyperparathyroidism 3.3 - Familial Hypocalciuric Hypercalcemia 3.4 - Hypoparathyroidism 3.5 - Pseudohypoparathyroidism 3.6 - Pseudohyperparathyroidism 3.7 - Vitamin D Deficiency and Genetic Vitamin D Resistance Syndromes 3.8 - Calcitonin Deficiency 3.9 - Low Calcium Intake 3.10 - Hypercalcemia of Malignancy 3.11 - FGF23-Related Disorders 4 - Skeletal and mineral physiology during lactation 4.1 - Mineral Ions and Calciotropic Hormones (Fig. 21.3) 4.2 - Calcium Pumping and Secretion in Mammary Tissue 4.3 - Intestinal Absorption of Calcium 4.4 - Renal Handling of Calcium 4.5 - Skeletal Calcium Metabolism 4.6 - Brain–Breast–Bone Circuit 5 - Disorders of bone and mineral metabolism during lactation 5.1 - Osteoporosis of Lactation 5.2 - Primary Hyperparathyroidism 5.3 - Familial Hypocalciuric Hypercalcemia 5.4 - Hypoparathyroidism 5.5 - Pseudohypoparathyroidism 5.6 - Pseudohyperparathyroidism 5.7 - Vitamin D Deficiency and Genetic Vitamin D Resistance Syndromes 5.8 - Calcitonin Deficiency 5.9 - Low Calcium Intake 5.10 - FGF23-Related Disorders 6 - Conclusions References Section 3: Disorders of Bone and Joint Chapter 22 - Osteoporosis Genes Identified by Genome-Wide Association Studies 1 - Introduction 2 - Genome-wide association studies of osteoporosis 3 - Genes identified by genome-wide association studies on bone mineral density 3.1 - 1p31.3 WLS 3.2 - 1p36.12 ZBTB40 and WNT4 3.3 - 2p16.2 SPTBN1 3.4 - 2q14.2 EN1 3.5 - 2q24.3 GALNT3 3.6 - 3p22.1 CTNNB1 3.7 - 4q22.1 IBSP, MEPE, and SPP1 3.8 - 5q14.3 MEF2C 3.9 - 6p22.3 SOX4 3.10 - 6q22.33 RSPO3 3.11 - 6q25.1 ESR1 3.12 - 7p14.1 SFRP4 and STARD3NL 3.13 - 7q21.2 COL1A2 3.14 - 7q21.3 SHFM1 and C7orf76 3.15 - 7q31.31 FAM3C, CPED1, and WNT16 3.16 - 8q24.12 TNFRSF11B (OPG) 3.17 - 9q22.32 PTHC1 3.18 - 11p11.2 LRP4 and ARGHAP1 3.19 - 11p14.1 DCDC5, LIN7C, and LGR4 3.20 - 11p15.1 SOX6 3.21 - 11q13.2 LRP5 3.22 - 12q13.12 DHH 3.23 - 12q13.13 SP7 3.24 - 13q14.11 TNFSF11 (RANKL) 3.25 - 14q32.32 MARK3 3.26 - 16p13.3 CLCN7 and AXIN1 3.27 - 16q24.1 FOXL1 and FOXC2 3.28 - 17q12-22 CRHR1 3.29 - 17q21.31 SOST and HDAC5 3.30 - 18q21.33 TNFRSF11A 3.31 - 20p12 JAG1 4 - GWAS in other ethnic groups and for other osteoporosis phenotypes 5 - Conclusions References Chapter 23 - Osteogenesis Imperfecta 1 - Introduction 2 - Clinical description 3 - Genetic description 4 - Molecular genetics 4.1 - Defects in Collagen Synthesis and Structure (Types I–IV) 4.2 - Bone Mineralization Defects (Types V and VI OI) 4.3 - Defects in Collagen Modification: The Prolyl 3-Hydroxylase Complex (Types VII, VIII, and IX OI) 4.4 - Defects in Collagen Processing and Crosslinking (Types X–XII OI) 4.5 - Defects in Osteoblast Differentiation and Function (Types XIII–XVIII OI) 5 - Animal models 5.1 - Dominant Type I Collagen Murine Models 5.2 - Recessive Murine Models 6 - Diagnostic aspects 7 - Treatment 8 - Conclusions References Chapter 24 - Osteoarthritis: Genetic Studies of Monogenic and Complex Forms 1 - Brief clinical description 1.1 - Diagnosis 1.2 - Mortality of OA 1.3 - Economic burden of OA 1.4 - Risk factors 2 - Genetics description 2.1 - Familial Aggregation and Heritability of OA 3 - Molecular genetics 3.1 - Monogenic Syndromes 3.1.1 - Osteochondritis Dissecans 3.1.2 - Multiple Epiphyseal Dysplasia 3.1.3 - Pseudoachondroplasia 3.1.4 - Spondyloepiphyseal Dysplasia Tarda 3.1.5 - Otospondylomegaepiphyseal Dysplasia 3.1.6 - Stickler Syndrome 3.1.7 - Marshall Syndrome 3.1.8 - Progressive Pseudorheumatoid Displasia 3.1.9 - Dyggve–Melchior–Clausen Syndrome and Smith–McCort Dysplasia 3.1.10 - Spondyloepiphyseal Dysplasia 3.1.11 - Spondyloepimetaphyseal Dysplasias 3.2 - Genetic Association Studies and Genome-Wide Scans 3.2.1 - Candidate Gene Studies 3.2.2 - Genome-Wide Association Studies 4 - Functional and molecular pathology 4.1 - Comparison Between OA Genes and Monogenic Syndromes 4.2 - A Disease of the Whole Joint 4.3 - Molecular Pathways Implicated in OA Genetic Risk 4.3.1 - Functional Validation of GWAS Hits 4.3.2 - Bone Morphogenetic Proteins 4.3.2.1 - GDF5 4.3.3 - Inflammation and Immune Response 4.4 - Wnt Signaling 4.5 - Pain in OA and Its Genetic Contribution 5 - Diagnostic aspects 6 - Treatment 6.1 - Surgical Options 7 - Conclusions References Futher Reading Chapter 25 - Genetics of Paget’s Disease of Bone 1 - Clinical features 2 - Genetic architecture of Paget’s disease 3 - Environmental factors 4 - Molecular genetics 4.1 - CSF1 4.2 - OPTN 4.3 - SQSTM1 4.4 - TNFRSF11A 4.5 - TNFRSF11B 4.6 - VCP 4.7 - HNRNPA2B1 and HNRNPA1 4.8 - DCSTAMP 4.9 - RIN3 4.10 - PML 4.11 - 7q33 Locus 4.12 - Other Susceptibility Genes and Loci 5 - Animal models 5.1 - Models of PDB Mimicking Measles Infection 5.2 - Genetic Models of PDB 5.2.1 - SQSTM1 5.2.2 - VCP 5.2.3 - OPTN 5.3 - Complex Disease Models 6 - Molecular pathology 6.1 - Cellular Abnormalities 6.2 - Cytokines and Growth Factors 6.3 - Intracellular Signaling Pathways 6.4 - Somatic Mutations 7 - Molecular diagnosis 8 - Conclusions References Chapter 26 - Mendelian Disorders of RANKL/OPG/RANK/NF-kB Signaling 1 - Introduction 2 - Disorders from constitutive RANK activation 2.1 - Familial Expansile Osteolysis 2.1.1 - FEO(Ger) 2.1.2 - FEO(NI) 2.1.3 - FEO(Am) 2.1.4 - FEO(Sp) 2.1.5 - Additional Reports of FEO 2.1.6 - FEO Treatment 2.2 - Early-Onset Paget’s Disease of Bone (PDB2) 2.2.1 - PDB2(Jpn) 2.2.2 - PDB2(Chn) 2.3 - Expansile Skeletal Hyperphosphatasia 2.4 - Panostotic Expansile Bone Disease 2.5 - Juvenile Paget’s Disease, Type 2 (JPD2) 2.6 - Other Phenotypes 2.7 - Pathogenesis From Constitutive RANK Activation 2.8 - Phenotype Variation of FEO, PDB2, ESH, PEBD, and JPD2 3 - Disorders of OPG deficiency 3.1 - Juvenile Paget’s Disease 3.2 - Acquired OPG Deficiency 4 - Disorders of the NF-kB complex 5 - Disorders Of RANKL and RANK deactivation 6 - Conclusions Acknowledgments Abbreviations References Chapter 27 - Skeletal Dysplasias 1 - Introduction 2 - Classification of skeletal dysplasias 3 - Diagnosis 4 - Multiple epiphyseal dysplasias 5 - Metaphyseal dysplasias 6 - Conclusions References Chapter 28 - Hypophosphatasia and How Alkaline Phosphatase Promotes Mineralization 1 - Introduction 2 - Molecular biology and biochemistry of alkaline phosphatase 3 - Physiology of skeletal mineralization 4 - Hypophosphatasia 4.1 - History 4.2 - Clinical Features 4.2.1 - Perinatal Hypophosphatasia 4.2.2 - Infantile Hypophosphatasia 4.2.3 - Childhood Hypophosphatasia 4.2.4 - Adult Hypophosphatasia 4.2.5 - Odontohypophosphatasia 4.2.6 - Pseudohypophosphatasia 4.2.7 - Benign Prenatal Hypophosphatasia 4.3 - Laboratory Findings 4.3.1 - Biochemical 4.3.1.1 - ALP Activity 4.3.1.2 - Minerals 4.3.1.3 - Routine Studies 4.3.1.4 - TNSALP Natural Substrates 4.4 - Radiological Findings 4.5 - Histopathological Findings 4.5.1 - Skeleton 4.5.2 - Dentition 4.6 - Biochemical and Genetic Defect 4.6.1 - TNSALP Deficiency 4.6.2 - Genetic Defect in HPP 4.6.3 - Inheritance 4.6.4 - Epigenetic and Nongenetic Effects 4.7 - Treatment 4.7.1 - Prognosis 4.7.2 - Supportive 4.7.3 - Experimental 4.7.4 - Prenatal Diagnosis 4.8 - Mouse Model for Hypophosphatasia 5 - Enzyme replacement therapy for HPP 6 - Physiological role of alkaline phosphatase explored in hypophosphatasia 6.1 - Phosphoethanolamine 6.2 - Pyridoxal 5′-Phosphate 6.3 - Inorganic Pyrophosphate 6.4 - Alkaline Phosphatase in Serum 6.5 - Overview for Tissue-Nonspecific Alkaline Phosphatase Function Acknowledgments Abbreviations References Chapter 29 - Sclerosing Bone Disorders 1 - Introduction 2 - Clinical aspects of the sclerosing bone disorders 3 - Molecular genetics and pathogenic mechanisms 3.1 - Disorders Caused by Bone Resorption Defects 3.1.1 - Osteopetroses 3.1.2 - Pycnodysostosis 3.1.3 - Osteosclerotic Metaphyseal Dysplasia 3.2 - Disorders Caused by Increased Bone Formation 3.2.1 - High–Bone Mass Phenotype, Sclerosteosis, and van Buchem’s Disease 3.2.2 - Osteopathia Striata With Cranial Sclerosis 3.2.3 - Osteopoikilosis and Melorheostosis 3.2.4 - Craniometaphyseal Dysplasia 3.2.5 - Camurati–Engelmann Disease 3.2.6 - Lenz–Majewski Syndrome 3.2.7 - Tricho–Dento–Osseous Syndrome 3.2.8 - Raine Syndrome 4 - Diagnostics, treatment, and genetic counseling References Chapter 30 - Fibrodysplasia (Myositis) Ossificans Progressiva 1 - Introduction 2 - Clinical description: fibrodysplasia ossificans progressiva 2.1 - Heterotopic Endochondral Ossification in FOP 2.2 - Histopathology of FOP Lesions 2.3 - Skeletal Development in FOP 2.4 - Additional Clinical Features of FOP 2.5 - Atypical FOP Phenotypes 3 - Genetics and molecular genetics of FOP 3.1 - ACVR1 (ALK2) R206H Mutations in FOP 3.2 - ACVR1 Mutations in Atypical FOP 3.3 - Phenotypic Variability 3.4 - ACVR1 Mutations in Diffuse Intrinsic Pontine Gliomas (DIPGs) 4 - Animal models 4.1 - In Vivo Models for BMP Signaling 4.1.1 - Drosophila and Mutations in Sax 4.1.2 - Zebrafish Models and the Alk8 Receptor 4.1.3 - BMP Signaling in Genetically-Engineered Mouse Models 4.2 - BMP Induction of Endochondral Ossification in Nongenetic and Genetic Models 4.2.1 - Nongenetic Induction of HO: BMP Implants 4.2.2 - Transgenic Mice Overexpressing BMP: Nse-BMP4 4.2.3 - Constitutively Active Alk2 Mice (Alk2Q207D) 4.2.4 - Acvr1 R206H Knock-In and Conditional Knock-In Mice 4.3 - Nongenetic Injury-Induced Models of Heterotopic Ossification 4.4 - Naturally Occurring Animal Models of Heterotopic Ossification 4.5 - Osteochondromas and Mouse Models 5 - Functional and molecular pathology 5.1 - BMP Signaling and ACVR1/ALK2 5.1.1 - Structural Modeling of Mutant ALK2 Receptors 5.1.2 - BMP Pathway Signaling in FOP Patient Cells 5.1.3 - Effects of ACVR1/ALK2 Mutations on BMP Pathway Signaling 5.1.4 - Activin A Induction of TGFβ/BMP Signaling Pathway 5.2 - Effects of FOP ACVR1/ALK2 Mutation on Lesion Progression 5.2.1 - Immunological Contributions to Heterotopic Ossification Development in FOP 5.2.2 - Role of Activin A in FOP Lesion Pathology 5.2.3 - Role of Hypoxia in Heterotopic Ossification Pathology 5.2.4 - Origin of Progenitor Cells Contributing to HO Formation 5.2.5 - Chondrogenesis and Osteogenesis 6 - Diagnostic aspects 7 - Counseling and treatment 7.1 - Blocking Activity of the Mutant Receptor in FOP 7.2 - Altering the Cellular Microenvironment Supporting Heterotopic Ossification 7.3 - Diverting Progenitor Cells From an Osseous to a Soft Tissue Fate 8 - Conclusions Acknowledgments References Chapter 31 - Thyroid Hormone in Bone and Joint Disorders 1 - Introduction 2 - Thyroid hormone physiology and action 2.1 - Hypothalamic-Pituitary-Thyroid Axis 2.2 - TSH Action 2.3 - Thyroid Hormone Transport 2.4 - Thyroid Hormone Metabolism 2.5 - Nuclear Actions of Thyroid Hormones 2.6 - Nongenomic Actions of Thyroid Hormones 3 - Role of thyroid hormones in skeletal growth and development 3.1 - Skeletal Cell Types 3.2 - Intramembranous and Endochondral Ossification 3.3 - Linear Growth and Bone Modeling 3.4 - Expression of TSH, TSHR, Thyroid Hormone Transporters, Deiodinases, and Thyroid Hormone Receptors in Skeletal Cells 3.5 - Pediatric Consequences of Thyroid Dysfunction 3.6 - Genetic Disorders of Thyroid Signaling 3.6.1 - TSHB 3.6.1.1 - Loss-of-Function Mutations 3.6.2 - TSHR 3.6.2.1 - Loss-of-Function Mutations 3.6.2.2 - Gain-of-Function Mutations 3.6.3 - SBP2 3.6.3.1 - Loss-of-Function Mutations 3.6.4 - THRB 3.6.4.1 - Dominant-Negative Mutations 3.6.5 - THRA 3.6.5.1 - Dominant-Negative Mutations 3.6.5.2 - Mutations Affecting TRα1 3.6.5.3 - Mutations Affecting Both TRα1 and α2 3.7 - TSH Action in the Growth Plate 3.8 - Thyroid Hormone Action in the Growth Plate 4 - Role of thyroid hormones in bone maintenance and mass 4.1 - Bone Remodeling Cycle 4.2 - Clinical Consequences of Thyroid Dysfunction 4.2.1 - Discriminating Thyroid Hormone and TSH Effects on the Skeleton 4.2.2 - Consequences of Variation of Thyroid Status Within the Reference Range 4.2.3 - Consequences of Hypothyroidism 4.2.4 - Consequences of Subclinical Hypothyroidism 4.2.5 - Consequences of Subclinical Hyperthyroidism 4.2.6 - Consequences of Hyperthyroidism 4.3 - Human Population Studies 4.4 - TSH Action in Osteoblasts and Osteoclasts 4.5 - Thyroid Hormone Action in Osteoblasts and Osteoclasts 4.5.1 - Osteoblasts 4.5.2 - Osteoclasts 5 - Genetically modified mice 5.1 - Targeting TSHR Signaling 5.1.1 - Skeletal Development and Growth 5.1.2 - Adult Bone Maintenance 5.2 - Targeting Thyroid Hormone Transport and Metabolism 5.2.1 - Thyroid Hormone Transporters 5.2.2 - Deiodinases 5.3 - Targeting TRα (Fig. 31.4) 5.4 - Targeting TRβ (Fig. 31.4) 5.4.1 - Cellular and Molecular Mechanisms 5.4.2 - Downstream Signaling Responses in Skeletal Cells 6 - Role of thyroid hormones in osteoarthritis 6.1 - Human Population Studies 6.2 - Rodent Models of Osteoarthritis 6.3 - Thyroid Hormone Action in Articular Chondroc 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. 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--