Basic and Applied Bone Biology

Cover......Page 1
BASIC AND APPLIED BONE BIOLOGY......Page 2
Copyright......Page 3
Dedication......Page 4
List of Contributors......Page 5
Biographies......Page 7
Preface (First Edition)......Page 8
Preface (Second Edition)......Page 10
Part I: Basic Bone Biology and Physiology
......Page 11
The Functions of Bone......Page 12
Bone Is Organized as a Multiscale Material......Page 13
Collagen......Page 14
Enzymatically Mediated Collagen Cross-Linking......Page 16
Collagen Orientation......Page 17
Bone Mineral......Page 18
Proteoglycans and Glycosaminoglycans......Page 19
SIBLING Proteins......Page 21
Woven Bone......Page 22
Plexiform Bone......Page 23
Primary Osteons......Page 24
Secondary Bone......Page 25
Cancellous Bone1......Page 26
Skeletal Envelopes......Page 28
Blood Supply......Page 29
Bone Fluid Compartments......Page 31
Tissue Material (Intrinsic) Properties......Page 32
Microdamage Accumulation......Page 34
Suggested Readings......Page 35
2 - Bone Marrow and the Stem Cell Niche......Page 36
Niches in Development......Page 37
Imaging of Niches......Page 38
Mesenchymal Stromal/Stem Cell Populations......Page 39
Endothelial Cells......Page 40
Osteoclasts......Page 41
Niches and Malignancies......Page 42
The Future......Page 43
Suggested Readings......Page 44
Osteoclast Morphology and Function......Page 45
Osteoclast Differentiation and Fusion......Page 49
Regulation of Osteoclast Generation and Survival......Page 52
Osteoblast Morphology and Function......Page 53
Osteoblast Formation and Differentiation......Page 54
Osteoblast Apoptosis......Page 55
Bone Lining Cells......Page 56
Osteocytes......Page 57
Osteocyte Morphology and Functions......Page 58
Preservation of Osteocyte Viability by Mechanical Stimuli......Page 59
Aging and Osteocyte Apoptosis......Page 60
Regulation of Bone Mineralization by Osteocytes......Page 61
Suggested Readings......Page 63
Soluble Ligands......Page 64
Signal Transduction Cascades......Page 65
The RANKL–RANK–OPG System......Page 66
Wnts......Page 68
Noncanonical Wnt Signaling......Page 70
Kremen......Page 71
Insulin-Like Growth Factor......Page 72
Fibroblast Growth Factors......Page 75
Interleukins......Page 77
Tumor Necrosis Factor......Page 79
Bone Morphogenetic Proteins......Page 80
Transforming Growth Factor Beta......Page 81
Regulation of Transforming Growth Factor Beta Bioavailability......Page 82
Prostaglandins......Page 83
Notch......Page 84
Ephrin–Ephrin Receptor......Page 85
Connexins......Page 86
Local Angiogenic Factors That Regulate Bone Cell Activity......Page 87
Cell Surface Attachment Molecules......Page 88
Suggested Readings......Page 90
Endochondral Ossification......Page 92
Bone Modeling......Page 96
Radial Growth......Page 97
Bone Remodeling......Page 98
Events That Signal Remodeling......Page 99
Resorption......Page 100
Reversal......Page 101
Bone Remodeling Cycle Duration......Page 102
Bone Remodeling Balance......Page 103
Mineralization......Page 104
Laboratory Assessment of Modeling and Remodeling......Page 105
Suggested Readings......Page 107
Part II: Assessment of Bone Structure and Function

......Page 108
Conventional Radiography......Page 109
Dual-Energy X-ray Absorptiometry......Page 111
Clinical Diagnostic Computed Tomography......Page 114
Dual Energy or Spectral Imaging Scanning......Page 118
Microcomputed Tomography......Page 119
Quantitative Computed Tomography (Densitometry)......Page 121
Modeling Analysis......Page 122
Magnetic Resonance Imaging......Page 124
Radionuclide Imaging......Page 125
Positron Emission Tomography and Positron Emission Tomography–Computed Tomography......Page 127
Summary......Page 128
Ultrasound......Page 129
Bone Is a Hierarchical Structure......Page 130
Stress and Strain in Axial Loading......Page 131
Axial Loading in Tension and Compression......Page 134
Torsion......Page 135
Bending......Page 136
Bone Mass: Cancellous Bone......Page 138
Cortical Bone Size (Mass) and Architecture......Page 139
Bone Tissue Material Properties......Page 140
The Bone Extracellular Matrix: Type I Collagen......Page 141
The Bone Extracellular Matrix: Inorganic Hydroxyapatite......Page 142
Methods of Testing the Mechanical Properties of Bone Tissue......Page 143
Other Measures of Bone “Strength”......Page 144
Suggested Readings......Page 145
Specimen Collection......Page 146
In Vivo Labeling......Page 147
Specimen Processing......Page 148
Histomorphometric Analysis......Page 150
Bone Architecture and Geometry......Page 151
Tissue Types......Page 152
Cell Number and Activity......Page 153
Dynamic Histomorphometry......Page 154
Osteocytes......Page 156
Assumptions and Technical Aspects......Page 157
Osteoporosis......Page 158
Secondary Hyperparathyroidism......Page 159
Antiresorptive Therapy......Page 160
Anabolic Therapy......Page 162
Suggested Readings......Page 163
Linkage Analysis......Page 164
Genome-Wide Association Studies......Page 165
Whole Exome and Whole Genome Analysis......Page 167
Omics Analysis of Bone Phenotypes......Page 168
Animals Derived From Homologous Recombination in ES Cells......Page 169
Superovulation......Page 170
DNA Preparation for Microinjection......Page 171
Transfer of Injected Embryos to Recipient Females......Page 172
Microinjection of Genetically Modified Embryonic Stem Cells......Page 175
Generation of ES cell Lines......Page 176
Collection of Blastocysts......Page 177
Transfer of Injected Blastocysts to Recipient Females......Page 178
Identification of Chimeric Animals......Page 179
Designer DNA Nucleases: The CRISPR Revolution......Page 180
Transgenic Animals and Bone Biology......Page 184
Bone Cell–Specific Promoters......Page 185
Conditional Models Using Cre-LoxP Technology......Page 186
Bridging Human Disorders and Mouse Models of Bone Diseases......Page 187
Secondary Challenges and Genetic Background Impacts on Skeletal Phenotypes......Page 188
Suggested Readings......Page 189
Part III: Skeletal Adaptation
......Page 191
Development and Maturation......Page 192
Infancy and Childhood Skeletal Growth......Page 193
Puberty and Adolescence......Page 195
Race and Ethnic Differences......Page 196
Endocrine Regulators......Page 197
Genetic Regulation......Page 198
Timing of Growth Rates......Page 199
Fracture Risk in Children......Page 200
Pregnancy......Page 201
Skeletal Expansion and Age......Page 202
Skeletal Mass and Age......Page 203
Other reading......Page 205
Wolff’s Law—A Historical Perspective......Page 206
Strain Magnitude......Page 207
Strain Frequency......Page 208
Intrinsic Loading Models......Page 209
Invasive (Surgical) Models......Page 210
Noninvasive Models......Page 211
Bone Responds Only Above (or Below) a Threshold of Strain or Strain Rate......Page 212
Rate-Related Phenomena are Critical to Response......Page 213
The Mechanostat......Page 214
Modeling and Remodeling are Antagonistic Processes......Page 215
Bone Formation on the Different Envelopes is Controlled by Local Conditions......Page 216
A Test of Wolff’s Law......Page 217
Mechanotransduction on a Smaller Scale: Cell Types and Their Environment......Page 219
Fluid Flow in Bone Tissue Has Manifold Cellular Effects......Page 220
Cellular Deformation and Stimulation......Page 221
Ion Channels......Page 223
Cell Adhesion and the Cytoskeleton......Page 224
G Protein Signaling......Page 225
Coordinating the Biochemical Response to Mechanical Stimulation......Page 226
Childhood and Adolescence......Page 229
Skeletal Responses to Physical Activity and Exercise in Adulthood......Page 230
Principle of Specificity......Page 231
Principle of Progressive Overload......Page 233
Principle of Diminished Returns......Page 235
Suggested Readings......Page 236
Types of Bone Fracture......Page 237
Inflammatory Response......Page 238
Hard Callus Formation (Endochondral Ossification)......Page 239
Bone Remodeling......Page 241
Methods of Evaluation......Page 242
Cellular Events of Fracture Repair......Page 243
Molecular Regulation of Chondrogenesis and Osteogenesis During Fracture Repair......Page 244
Prostaglandins......Page 246
Platelet-Derived Growth Factor......Page 247
Vascular Endothelial Growth Factor......Page 248
Skeletal Muscle Interactions......Page 249
Aging......Page 250
Glucocorticoids......Page 251
Parathyroid Hormone......Page 252
Denosumab......Page 253
Summary......Page 254
Suggested Readings......Page 255
Part IV: Hormonal and Metabolic Effects on Bone
......Page 256
Distribution of Calcium and Phosphorus in the Body......Page 257
Mineral Accrual and Loss Over the Life Span......Page 259
Regulation of Whole Body Calcium Metabolism......Page 260
Intestinal Calcium Absorption......Page 261
Renal Calcium Reabsorption......Page 264
25-Hydroxyvitamin D Metabolism......Page 266
1,25-Dihydroxyvitamin D Regulation and Metabolism......Page 267
Vitamin D Actions......Page 268
Parathyroid Hormone and Parathyroid Hormone-Related Peptide......Page 269
Control of PTH Production and Release......Page 270
Estrogen......Page 272
Hormones of Pregnancy and Lactation......Page 273
Regulation of Whole Body Phosphate Metabolism......Page 274
Intestinal Phosphate Absorption......Page 276
Fibroblast Growth Factor 23 is an Important Hormone in Phosphate Reabsorption and Vitamin D Regulation......Page 279
Influence of Iron on FGF23 Metabolism......Page 280
Summary......Page 281
Suggested Readings......Page 282
Macro- and Micronutrient Roles in Bone Health......Page 283
When and How Nutrients Influence Bone Mass......Page 288
Perturbing Calcium Metabolism......Page 289
Diet Versus Fortified Foods Versus Supplements......Page 291
Acid–Base Balance, Fruit and Vegetable Intakes, and Bone Health......Page 292
Dietary Bioactives and Their Mechanisms......Page 293
Obesity, Osteoporosis, and Fracture Risk......Page 294
Effects of Weight Loss on Bone......Page 295
Challenges for Studying Effects of Nutrient Interventions on Bone Outcomes......Page 296
Suggested Readings......Page 298
PTH Receptors and Downstream Signaling......Page 299
Downregulation of Sost/Sclerostin by PTH......Page 300
Sex Steroids......Page 301
Sex Steroid Receptor Signaling......Page 302
Sex Steroids During Growth......Page 303
Changes in Bone Cells Induced by Estrogen Deficiency......Page 304
Epidemiology and Progression of Glucocorticoid-Induced Bone Disease......Page 305
Glucocorticoid Receptors and Downstream Signaling......Page 306
Thyroid Hormone......Page 307
Growth Hormone......Page 308
Insulin......Page 310
Leptin......Page 311
Other Hormones......Page 313
Part V: The Interaction of Bone With Other Organ Systems
......Page 314
Embryogenesis and Development......Page 315
Muscle Structure......Page 317
The Mechanical Interaction of Muscle and Bone......Page 319
Endocrine Cross Talk Between Muscle and Bone......Page 320
Myostatin......Page 322
Musclin......Page 323
RANKL......Page 324
Fibroblast Growth Factor 23......Page 325
Osteogenesis Imperfecta......Page 326
Cachexia......Page 327
Sarcopenia......Page 328
Suggested Readings......Page 330
Innate Immunity......Page 331
Adaptive Immunity......Page 332
B Cells and Bone Remodeling......Page 335
T Cells and Bone Remodeling......Page 336
Infections and Bone Cells......Page 337
Endocrine Activation of Immune-Mediated Bone Loss......Page 339
Role of Immune Activation in Estrogen Deficiency......Page 340
Role of T Cells in Parathyroid Hormone Responses in Bone......Page 341
Rheumatoid Arthritis......Page 342
Suggested Readings......Page 344
Introduction to the Nervous System......Page 346
Innervation of Bone......Page 347
Neural Connections Between Bone and Brain......Page 350
The Sympathetic Nervous System......Page 353
Leptin......Page 355
Serotonin......Page 357
Neuropeptide Y......Page 358
Dopamine......Page 359
Pituitary Adenylate Cyclase–Activating Polypeptide and Vasoactive Intestinal Peptide......Page 360
Calcitonin Gene–Related Peptide......Page 361
Substance P......Page 362
Bone Feedback to the Brain......Page 363
Suggested Readings......Page 364
Introduction to the Microbiome......Page 365
Preclinical Manipulations of the Microbiome......Page 367
The Effects of the Microbiome on Bone Mass, Remodeling, and Strength......Page 368
Mechanisms Linking the Microbiome to Bone......Page 369
Suggested Readings......Page 370
20 - Bone and Kidney......Page 371
Renal Osteodystrophy......Page 373
Bone Imaging......Page 374
Pathogenesis of Abnormal Bone in Patients With CKD......Page 376
Abnormal Hormones......Page 378
CKD-MBD—Biochemical Abnormalities......Page 379
CKD-MBD—Vascular Calcification......Page 380
Summary......Page 381
Suggested Readings......Page 382
Part VI: Skeletal Disease and Treatment
......Page 383
Definition......Page 384
Risk Factors......Page 386
Pathogenesis......Page 388
Calcium and Vitamin D......Page 389
Estrogen......Page 391
Selective Estrogen Receptor Modulators......Page 392
Bisphosphonates......Page 393
Denosumab......Page 398
Anabolic Therapies......Page 399
Teriparatide......Page 400
Antisclerostin Antibody......Page 401
Treatment Guidelines and Decisions......Page 402
Sequential Treatments......Page 403
Concurrent Antiremodeling Agent and Anabolic......Page 404
Suggested Readings......Page 405
22 - Bone and Cancer......Page 406
Abnormalities of Bone Remodeling Induced by Cancer in Bone......Page 407
Mechanisms Responsible for Bone Metastasis......Page 408
Changes in the Phenotype of Cancer Cells Induced by the Bone Microenvironment......Page 409
Generation of the Premetastatic Niche in Bone......Page 410
Contributions of Bone Cells to Tumor Cell Dormancy, Reactivation, Chemoresistance, and Tumor Progression in Bone......Page 411
Role of Osteoclasts in the Development and Progression of Bone Metastasis......Page 412
Role of Osteoblasts in the Development and Growth of Bone Metastasis......Page 413
Bone Turnover Markers and Other Biomarkers of Cancer in Bone......Page 416
Bone-Targeted Therapies for Bone Metastasis......Page 417
Suggested Readings......Page 418
Introduction......Page 419
Fracture Risk in Type 1 Diabetes......Page 421
Skeletal Changes in Diabetes......Page 424
Bone Geometry and Architecture in Type 1 Diabetes......Page 425
Mineral Homeostasis and Bone Turnover in Diabetes......Page 427
Osteocalcin......Page 428
Bone Tissue Material Properties......Page 429
Insulin......Page 430
GLP-1 Receptor Agonists......Page 431
Sodium-Glucose Cotransporter 2 Inhibitors......Page 432
Amylin Analogs......Page 433
Conclusions......Page 434
Suggested Readings......Page 435
A......Page 436
B......Page 437
C......Page 438
E......Page 440
F......Page 441
H......Page 442
I......Page 443
M......Page 444
N......Page 445
O......Page 446
P......Page 447
Q......Page 448
S......Page 449
T......Page 451
W......Page 452
Z......Page 453
Back Cover......Page 454