Basic and Applied Bone Biology

Cover
BASIC AND APPLIED BONE BIOLOGY
Copyright
Dedication
List of Contributors
Biographies
Preface (First Edition)
Preface (Second Edition)
Part I: Basic Bone Biology and Physiology
1 - Bone Morphology and Organization
	The Functions of Bone
	Bone Is Organized as a Multiscale Material
	Bone Composition
	The Nanoscale Organization of Bone
		Collagen
			Enzymatically Mediated Collagen Cross-Linking
			Nonenzymatically Mediated Collagen Cross-Linking
			Collagen Orientation
		Bone Mineral
		Noncollagenous Extracellular Matrix Proteins
		Proteoglycans and Glycosaminoglycans
			Glycoproteins
			SIBLING Proteins
			Osteocalcin
			Osteonectin
	The Microstructural Organization of Bone
		Woven Bone
		Primary Bone
			Primary Lamellar Bone
			Plexiform Bone
			Primary Osteons
		Secondary Bone
		Interstitial Bone
	The Macroscopic Organization of Bone
		Cortical Bone
		Cancellous Bone1
		Skeletal Envelopes
	The Blood Supply and Innervation of Bone
		Blood Supply
		Innervation of Bone
	Bone Fluid Compartments
	Bone Mass and Bone Quality
		Rate of Bone Turnover
		Bone Trabecular Architecture
		Tissue Material (Intrinsic) Properties
		Microdamage Accumulation
	Suggested Readings
2 - Bone Marrow and the Stem Cell Niche
	Niches in Development
	Imaging of Niches
	Bone Marrow Niche Cells
		Nonhematopoietic
			Osteoblastic Cells
			Mesenchymal Stromal/Stem Cell Populations
			Adipocytes
			Endothelial Cells
		Hematopoietic
			Megakaryocytes
			Macrophages
			Neutrophils
			Osteoclasts
	Neuronal Regulation of the Hematopoietic Stem Cell Niche
	Hormonal Regulation of the Hematopoietic Stem Cell Niche
	Niches and Malignancies
	Aging and the Bone Marrow Microenvironment
	The Future
	Suggested Readings
3 - Bone Cells
	Osteoclasts
		Osteoclast Morphology and Function
		Osteoclast Differentiation and Fusion
		Osteoclast Apoptosis
		Regulation of Osteoclast Generation and Survival
	Osteoblasts
		Osteoblast Morphology and Function
		Osteoblast Formation and Differentiation
		Osteoblast Apoptosis
		Regulation of Osteoblast Generation and Survival
		Bone Lining Cells
	Osteocytes
		Osteocyte Morphology and Functions
		Osteocytogenesis and Osteocyte Maturation
		Osteocyte Apoptosis: Consequences and Regulation
		Preservation of Osteocyte Viability by Mechanical Stimuli
		Aging and Osteocyte Apoptosis
		Hormonal Regulation of Osteocyte Life Span
		Regulation of Bone Formation by Osteocytes: The Sclerostin Paradigm
		Regulation of Bone Resorption by Osteocytes: RANKL and OPG
		Regulation of Bone Mineralization by Osteocytes
	Suggested Readings
4 - Local Regulation of Bone Cell Function
	Overview of Cytokines and Growth Factors and Their Receptors
		Definition: Cytokines Versus Growth Factors
		Soluble Ligands
		Membrane-Bound Ligands
		Receptor Classification
		Signal Transduction Cascades
	Local Factors That Regulate Osteoclast and Osteoblast Differentiation and Function
	Factors That Regulate Osteoclast Differentiation and Function
		The RANKL–RANK–OPG System
		Macrophage Colony-Stimulating Factor
	Factors That Affect Osteoblast Differentiation and Function
		Wnts
			Canonical Wnt Signaling
			Noncanonical Wnt Signaling
			Inhibitors of Wnt Signaling
		Dickkopf
			Kremen
			Sclerostin
		Secreted Frizzled-Related Proteins
			Wise
		Insulin-Like Growth Factor
		Parathyroid Hormone–Related Peptide
		Fibroblast Growth Factors
	Local Factors That Affect Both Osteoclasts and Osteoblasts
		Interleukins
		Tumor Necrosis Factor
		Bone Morphogenetic Proteins
		Transforming Growth Factor Beta
			Regulation of Transforming Growth Factor Beta Bioavailability
		Prostaglandins
	Regulation of Bone Cell Differentiation and Function Through Cell–Cell Contact
		Notch
		Ephrin–Ephrin Receptor
		Connexins
	Local Angiogenic Factors That Regulate Bone Cell Activity
	Cell Surface Attachment Molecules
	Suggested Readings
5 - Bone Growth, Modeling, and Remodeling
	Skeletal Development
		Intramembranous Ossification
		Endochondral Ossification
	Bone Modeling
		Events That Signal Modeling
		Cellular Processes
		Modeling During the Life Cycle
		Longitudinal Growth
		Radial Growth
		Bone Drift
	Bone Remodeling
		Events That Signal Remodeling
		Remodeling Cycle
			Activation
			Resorption
			Reversal
			Formation
			Quiescence (Resting)
			Bone Remodeling Cycle Duration
		Bone Remodeling Rate
		Bone Remodeling Balance
	Bone Repair
	Effects of Modeling and Remodeling on Bone Structure and Material Properties
		Bone Structure Effects of Modeling and Remodeling
		Bone Material Property Effects of Remodeling
			Mineralization
			Collagen Cross-Links
			Microdamage
	Laboratory Assessment of Modeling and Remodeling
	Suggested Readings
Part II: Assessment of Bone Structure and Function
6 - Skeletal Imaging
	X-ray
		Conventional Radiography
		Dual-Energy X-ray Absorptiometry
	Computed Tomography
		Clinical Diagnostic Computed Tomography
		Dual Energy or Spectral Imaging Scanning
	High-Resolution Peripheral Quantitative Computed Tomography
		Microcomputed Tomography
		Quantitative Computed Tomography (Densitometry)
		Modeling Analysis
	Magnetic Resonance Imaging
		Ultrashort Echo-Time (TE) Sequences
	Radionuclide Imaging
		Positron Emission Tomography and Positron Emission Tomography–Computed Tomography
	Ultrasound
	Summary
	Suggested Readings
		Computed Tomography
		Dual Energy X-ray Absorptiometry
		Magnetic Resonance Imaging
		Finite Element Analysis
		Radionuclide Imaging
		Ultrasound
7 - Skeletal Hard Tissue Biomechanics
	Introduction to Basic Bone Structure and Function
		Main Functions of Bone in the Body
		Bone Is a Hierarchical Structure
	Fundamentals of Solid Mechanics
		The Force–Displacement Curve
		Stress and Strain in Axial Loading
		Modulus of Elasticity and Poisson’s Ratio
	Methods of testing mechanical properties of whole bone
		Axial Loading in Tension and Compression
		Torsion
		Bending
	Factors Contributing to Whole Bone Mechanical Properties
		Bone Mass: Cancellous Bone
		Cancellous Architecture and Anisotropy
		Cortical Bone Size (Mass) and Architecture
		Bone Tissue Material Properties
		The Bone Extracellular Matrix: Type I Collagen
		The Bone Extracellular Matrix: Inorganic Hydroxyapatite
	Methods of Testing the Mechanical Properties of Bone Tissue
		Other Measures of Bone “Strength”
	Suggested Readings
8 - Techniques in Histomorphometry
	Histologic Specimens
		Specimen Collection
		In Vivo Labeling
		Specimen Processing
	Histomorphometric Analysis
		Static versus Dynamic Measurements
		Primary Versus Derived Variables
		Referents
		Bone Architecture and Geometry
		Tissue Types
		Cell Number and Activity
		Dynamic Histomorphometry
		Osteocytes
		Microdamage
		Marrow
	Assumptions and Technical Aspects
	Histologic Features of Disease and Treatment
		Osteoporosis
		Osteomalacia
		Hyperparathyroidism
			Primary Hyperparathyroidism
			Secondary Hyperparathyroidism
		Paget’s Disease of Bone (Osteitis Deformans)
		Antiresorptive Therapy
		Anabolic Therapy
	Suggested Readings
9 - Skeletal Genetics: From Gene Identification to Murine Models of Disease
	Genetic Analysis of Bone Phenotypes
		Linkage Analysis
		Genome-Wide Association Studies
		Whole Exome and Whole Genome Analysis
		Functional Analysis
		Omics Analysis of Bone Phenotypes
	Transgenic Technology and the Creation of Novel Research Models
		Production of Transgenic Rodents
			Animals that Arise From Pronuclear Injection
			Animals Derived From Homologous Recombination in ES Cells
		Pronuclear Microinjection
		Isolation of Embryos for Microinjection
			Superovulation
			Collection of Single-cell Embryos
			DNA Preparation for Microinjection
		Pronuclear Microinjection of Embryos Microinjection
		Transfer of Injected Embryos to Recipient Females
		Analysis of Potential Transgenic Founders
		Microinjection of Genetically Modified Embryonic Stem Cells
			Generation of ES cell Lines
			Homologous Recombination
			Collection of Blastocysts
			Injection of ES cells Into Blastocysts
			Transfer of Injected Blastocysts to Recipient Females
			Identification of Chimeric Animals
		Designer DNA Nucleases: The CRISPR Revolution
	Transgenic Animals and Bone Biology
		Bone Cell–Specific Promoters
		Conditional Models Using Cre-LoxP Technology
		Bridging Human Disorders and Mouse Models of Bone Diseases
		Secondary Challenges and Genetic Background Impacts on Skeletal Phenotypes
	Summary
	Suggested Readings
Part III: Skeletal Adaptation
10 - Skeletal Changes Across the Life Span
	Prenatal Growth
		Development and Maturation
		Calcification and Mineral Homeostasis
	Postnatal Growth
		Newborn Mineral Homeostasis
		Infancy and Childhood Skeletal Growth
		Puberty and Adolescence
		Race and Ethnic Differences
		Endocrine Regulators
		Genetic Regulation
		Timing of Growth Rates
		Development of Peak Bone Mass
		Fracture Risk in Children
	Skeletal Changes With Reproduction
		Pregnancy
		Lactation
	Skeletal Changes With Aging
		Skeletal Expansion and Age
		Skeletal Mass and Age
	Suggested Readings
		Peak Bone Mass
		Fetal Programming
		Other reading
11 - Mechanical Adaptation
	Wolff’s Law—A Historical Perspective
	Components of Strain That May Be Osteogenic
		Strain Magnitude
		Strain Distribution
		Strain Duration
		Strain Rate
		Strain Frequency
		Polarity
		Strain Energy
	Animal Models of Skeletal Mechanotransduction
		Intrinsic Loading Models
		Extrinsic Loading Models
			Invasive (Surgical) Models
			Noninvasive Models
	Rules for Bone Adaptation
		Bone Responds Only Above (or Below) a Threshold of Strain or Strain Rate
		Bone Responds Only to Dynamic Loads
		The Loading Period Can Be Short
		Rate-Related Phenomena are Critical to Response
		Strain Rate is a Function of Strain Magnitude and Loading Frequency
	The Mechanostat
		Bone Adaptation is Error Driven
		Set Points Define Four Different Mechanical Usage Windows
		Modeling and Remodeling are Antagonistic Processes
		Bone Formation on the Different Envelopes is Controlled by Local Conditions
	Cell Sensitivity and Refractory Periods
	A Test of Wolff’s Law
	Mechanotransduction on a Smaller Scale: Cell Types and Their Environment
	Fluid Flow in Bone Tissue Has Manifold Cellular Effects
	Cellular Deformation and Stimulation
	What Is the Mechanoreceptor?
		Ion Channels
		Cell Adhesion and the Cytoskeleton
		G Protein Signaling
	Coordinating the Biochemical Response to Mechanical Stimulation
	Clinical Implications: Exercise Prescription for Optimizing Skeletal Health
	Skeletal Benefits of Physical Activity and Exercise During Growth
		Infancy
		Childhood and Adolescence
	Skeletal Responses to Physical Activity and Exercise in Adulthood
	Principles of Training and Exercise Recommendations for Optimal Bone Health
		Principle of Specificity
		Principle of Progressive Overload
		Principle of Reversibility
		Principle of Initial Values
		Principle of Diminished Returns
	Summary
	Suggested Readings
12 - Fracture Healing
	Types of Bone Fracture
	Primary and Secondary Repair Mechanisms
	Stages of Fracture Repair
		Inflammatory Response
		Soft Callus Formation (Cartilage Formation)
		Hard Callus Formation (Endochondral Ossification)
		Bone Remodeling
	Assessment of Fracture Healing
		Methods of Evaluation
		Biomechanical Stages of Fracture Healing
	Cellular Events of Fracture Repair
	Molecular Regulation of Chondrogenesis and Osteogenesis During Fracture Repair
	Local Regulation of Fracture Repair
		Prostaglandins
		Bone Morphogenetic Proteins
		Platelet-Derived Growth Factor
		Vascular Endothelial Growth Factor
		Endothelial Progenitor Cells
		Skeletal Muscle Interactions
	Systemic Factors in Fracture Repair
		Aging
		Diabetes Mellitus
		Glucocorticoids
	Effects of Osteoporosis Drugs on Fracture Healing
		Parathyroid Hormone
		Bisphosphonates
		Denosumab
	Effects of Mechanical and Electrical Stimulation on Fracture Repair
		Electromagnetic Therapy
		Low-Intensity Pulsed Ultrasound
	Summary
	Suggested Readings
Part IV: Hormonal and Metabolic Effects on Bone
13 - Calcium and Phosphate: Hormonal Regulation and Metabolism
	Organ System Interplay Regulates Calcium and Phosphorus Metabolism
		Distribution of Calcium and Phosphorus in the Body
		Mineral Accrual and Loss Over the Life Span
	Regulation of Whole Body Calcium Metabolism
		Intestinal Calcium Absorption
		Renal Calcium Reabsorption
		Hormones Controlling Calcium Metabolism
			Vitamin D and Its Metabolites
				25-Hydroxyvitamin D Metabolism
				1,25-Dihydroxyvitamin D Regulation and Metabolism
				Vitamin D Actions
			Parathyroid Hormone and Parathyroid Hormone-Related Peptide
				Control of PTH Production and Release
			Estrogen
			Calcitonin
			Somatotropin/Growth Hormone
			Hormones of Pregnancy and Lactation
	Regulation of Whole Body Phosphate Metabolism
		Intestinal Phosphate Absorption
		Renal Phosphate Reabsorption
			Parathyroid Hormone Effects on Phosphate Reabsorption
			Fibroblast Growth Factor 23 is an Important Hormone in Phosphate Reabsorption and Vitamin D Regulation
				Changes in Dietary Phosphate Intake Alter Fibroblast Growth Factor 23 Concentration
				Influence of Iron on FGF23 Metabolism
	Summary
	Suggested Readings
14 - Nutrition
	Macro- and Micronutrient Roles in Bone Health
	When and How Nutrients Influence Bone Mass
	Perturbing Calcium Metabolism
	Whole Diet Matters
		Diet Versus Fortified Foods Versus Supplements
		Acid–Base Balance, Fruit and Vegetable Intakes, and Bone Health
	Dietary Bioactives and Their Mechanisms
	Effects of Obesity and Weight Loss on Bone
		Obesity, Osteoporosis, and Fracture Risk
		Effects of Weight Loss on Bone
	Correcting Nutrient Deficiency Versus Optimizing Intake
	Challenges for Studying Effects of Nutrient Interventions on Bone Outcomes
	Suggested Readings
15 - Hormonal Effects on Bone Cells
	Direct Versus Indirect Effects of Hormones on Bone Cells
	Parathyroid Hormone
		Actions of PTH on Bone
		PTH Receptors and Downstream Signaling
		Effects of PTH on Osteoblasts and Bone Formation
		Inhibition of Osteoblast Apoptosis by PTH
		Downregulation of Sost/Sclerostin by PTH
		Reactivation of Lining Cells by PTH
		Effects of PTH on Osteoclastogenesis and Bone Resorption
	Sex Steroids
		Sex Steroid Production
		Sex Steroid Receptor Signaling
		Sex Steroids During Growth
		Loss of Sex Steroids in the Adult Skeleton
		Changes in Bone Cells Induced by Estrogen Deficiency
		Effects of Estrogens and Androgens on Osteoclasts
		Effects of Estrogens and Androgens on Osteoblasts and Osteocytes
	Glucocorticoids
		Epidemiology and Progression of Glucocorticoid-Induced Bone Disease
		Glucocorticoids and Bone Cells
		Glucocorticoid Receptors and Downstream Signaling
	Thyroid Hormone
	Growth Hormone
	Insulin
	1,25-Dihydroxyvitamin D3
	Leptin
	Suggested Readings
		PTH
		Sex Steroids
		Glucocorticoids
		Other Hormones
Part V: The Interaction of Bone With Other Organ Systems
16 - Bone and Muscle
	Development and Structure of Muscle
		Embryogenesis and Development
		Muscle Structure
		Regulation of Skeletal Muscle
	The Mechanical Interaction of Muscle and Bone
	Endocrine Cross Talk Between Muscle and Bone
		Myostatin
		Insulin-Like Growth Factor (IGF)-1
		Cytokines
		Brain-Derived Neurotrophic Factor
		Irisin
		Musclin
		Beta-Aminoisobutyric Acid
	Bone’s Endocrine Effects on Muscle
		Sclerostin, Dkk1, and Wnts
		RANKL
		Osteocalcin
		Fibroblast Growth Factor 23
		Prostaglandin E2
		Unknown Factors
	Linked Diseases Between Bone and Muscle
		Pleiotropic Genes for Bone and Muscle and Their Potential Role in Musculoskeletal Disease
		Osteogenesis Imperfecta
		Cachexia
	Effects of Aging on the Musculoskeletal System
		Sarcopenia
	Summary
	Suggested Readings
17 - Bone and the Immune System (Osteoimmunology)
	Innate Immunity
	Adaptive Immunity
	B Cells and Bone Remodeling
	T Cells and Bone Remodeling
	Myeloid Cells and Bone Remodeling
	Infections and Bone Cells
	Endocrine Activation of Immune-Mediated Bone Loss
		Role of Immune Activation in Estrogen Deficiency
		Role of T Cells in Parathyroid Hormone Responses in Bone
	Autoimmune Diseases Can Drive Local or Systemic Bone Loss
		Rheumatoid Arthritis
	Suggested Readings
18 - Bone and the Brain
	Introduction to the Nervous System
	Innervation of Bone
	Neural Connections Between Bone and Brain
	Functional Role of Central and Peripheral Efferent Pathways
		The Sympathetic Nervous System
			Leptin
			Serotonin
			Neuropeptide Y
			Endocannabinoids
			Cocaine- and Amphetamine-Regulated Transcript
			Dopamine
			Neuromedin U
		The Parasympathetic Nervous System
			Acetylcholine
			Pituitary Adenylate Cyclase–Activating Polypeptide and Vasoactive Intestinal Peptide
		Other Central Neurotransmitters That Impact Bone
			Orexin
			Oxytocin
			Pro-opiomelanocortin and Melanocortin System
	Functional Role of Sensory Neurotransmitters in Bone
		Calcitonin Gene–Related Peptide
			Substance P
			VIP and PACAP
			Nucleotides
			Glutamate
	Bone Feedback to the Brain
	Bone Impact of Neurological Disorders
	Conclusion
	Suggested Readings
19 - The Microbiome and Bone
	Introduction to the Microbiome
	Effects of the Microbiome on Bone
		Preclinical Manipulations of the Microbiome
		The Effects of the Microbiome on Bone Mass, Remodeling, and Strength
	Mechanisms Linking the Microbiome to Bone
	Summary
	Suggested Readings
20 - Bone and Kidney
	CKD-MBD—Bone Abnormalities
		Renal Osteodystrophy
		Bone Imaging
		Bone Biomarkers
		Pathogenesis of Abnormal Bone in Patients With CKD
			Abnormal Hormones
			Disordered Osteoblast Function or Differentiation
			Abnormalities of Bone Collagen
	CKD-MBD—Biochemical Abnormalities
	CKD-MBD—Vascular Calcification
	Summary
	Suggested Readings
Part VI: Skeletal Disease and Treatment
21 - Pharmaceutical Treatments of Osteoporosis
	Osteoporosis
		Definition
		Risk Factors
		Diagnosis
		Pathogenesis
	Osteoporosis Therapies
		Calcium and Vitamin D
		Antiremodeling Therapies
			Estrogen
			Selective Estrogen Receptor Modulators
			Calcitonin
			Bisphosphonates
			Denosumab
		Anabolic Therapies
			Teriparatide
			Abaloparatide
			Antisclerostin Antibody
	Treatment Guidelines and Decisions
		Sequential Treatments
			Antiremodeling Agent Followed by an Anabolic
			Anabolic Followed by an Antiremodeling Agent
			Antiremodeling Agent Followed by an Antiremodeling Agent
		Combination (Concurrent) Treatments
			Concurrent Antiremodeling Agent and Anabolic
			Concurrent Antiremodeling Agents
	Conclusion
	Suggested Readings
22 - Bone and Cancer
	Abnormalities of Bone Remodeling Induced by Cancer in Bone
	Mechanisms Responsible for Bone Metastasis
	Intrinsic Properties of Tumor Cells That Enhance Their Bone Metastatic Potential
	Changes in the Phenotype of Cancer Cells Induced by the Bone Microenvironment
	Generation of the Premetastatic Niche in Bone
	Tumor Cell Homing to Bone
	Immune Suppression in Bone Metastasis
	Physical Characteristics of Bone Contribute to Bone Metastasis
	Contributions of Bone Cells to Tumor Cell Dormancy, Reactivation, Chemoresistance, and Tumor Progression in Bone
	Role of Osteoclasts in the Development and Progression of Bone Metastasis
	Role of Osteoblasts in the Development and Growth of Bone Metastasis
	Imaging of Bone Metastases
	Bone Turnover Markers and Other Biomarkers of Cancer in Bone
	Bone-Targeted Therapies for Bone Metastasis
	Summary
	Suggested Readings
23 - Sweet Bones: Diabetes Effects on Bone
	Introduction
	Fractures in Diabetes
		Fracture Risk in Type 1 Diabetes
		Fracture Risk in Type 2 Diabetes
		Fracture Morbidity and Mortality in Diabetes
		Fracture Healing in Diabetes
	Skeletal Changes in Diabetes
		Bone Mineral Density in Type 1 Diabetes
		Bone Mineral Density in Type 2 Diabetes
		Bone Geometry and Architecture in Type 1 Diabetes
		Bone Geometry and Architecture in Type 2 Diabetes
	Mineral Homeostasis and Bone Turnover in Diabetes
	Other Hormonal/Cellular Level Changes in Diabetes
		Osteocalcin
		Adipocytokines
		Oxidative Stress
	Bone Tissue Material Properties
		Bone Collagen Glycation
	Management and Treatment Approaches
		Effects of Diabetes Management on Bone Health
			Insulin
			Metformin
			Sulfonylureas
			Thiazolidinedione
			Incretin-Based Treatments
				GLP-1 Receptor Agonists
				DPP-4 Inhibitors
			Sodium-Glucose Cotransporter 2 Inhibitors
			Amylin Analogs
			Bariatric Surgery
		Bone Health Management in Diabetes
	Conclusions
	Suggested Readings
Index
	A
	B
	C
	D
	E
	F
	G
	H
	I
	J
	K
	L
	M
	N
	O
	P
	Q
	R
	S
	T
	U
	V
	W
	X
	Y
	Z
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