Dynamics of Bone and Cartilage Metabolism (eBook)

Dynamics of Bone and Cartilage Metabolism 3
Dynamics of Bone and Cartilage Metabolism 5
Contents 7
Contributors 15
Preface to the Second Edition 21
Components of the Organic Extracellular Matrix of Bone and Cartilage 23
Structure, Biosynthesis and Gene Regulation of Collagens in Cartilage and Bone 25
I. INTRODUCTION 25
II. THE COLLAGEN FAMILIES 27
III. BONE COLLAGENS 29
IV. CARTILAGE COLLAGENS 31
V. COLLAGEN BIOSYNTHESIS 36
VI. COLLAGEN GENES AND TRANSCRIPTIONAL REGULATION 39
VII. FACTORS REGULATING COLLAGEN BIOSYNTHESIS 43
VIII. CONCLUSIONS 47
Fibrillogenesis and Maturation of Collagens 63
I. INTRODUCTION 63
II. FIBRILLOGENESIS 64
III. CROSS-LINKING 66
IV. CONCLUDING REMARKS 72
Vitamin K Dependent Proteins of Bone and Cartilage 77
I. ABSTRACT 77
II. INTRODUCTION 77
III. OSTEOCALCIN 78
IV. MATRIX Gla PROTEIN 81
V. Gas6 85
VI. VITAMIN K/WARFARIN 86
Noncollagenous Proteins Glycoproteins and Related Proteins
I. INTRODUCTION 93
II. CARTILAGE EXTRACELLULAR MATRIX 94
III. BONE, EXTRACELLULAR MATRIX 99
IV. CONCLUDING REMARKS 101
Proteoglycans and Glycosaminoglycans 107
I. INTRODUCTION 107
II. GLYCOSAMINOGLYCANS 108
III. PROTEOGLYCANS IN CARTILAGE 109
IV. AGGRECAN 110
V. LEUCINE-RICH PROTEOGLYCANS IN CARTILAGE AND BONE 115
VI. PERLECAN IN CARTILAGE 118
Growth Factors 121
I. INTRODUCTION 121
II. INSULIN-LIKE GROWTH FACTORS 121
III. THE TRANSFORMING GROWTH FACTOR-BETA/BONE MORPHOGENETIC PROTEIN SUPERFAMILY 122
IV. FIBROBLAST GROWTH FACTORS 125
V. Wnts 126
VI. ADDITIONAL GROWTH FACTORS 127
VII. SUMMARY 128
Prostaglandins and Proinflammatory Cytokines 137
I. INTRODUCTION 137
II. PROSTAGLANDINS 137
III. THE ROLE THAT CYTOKINES HAVE IN OSTEOCLAST FORMATION AND FUNCTION 139
IV. THE ROLE THAT PROINFLAMMATORY CYTOKINES HAVE IN BONE AND CARTILAGE METABOLISM 140
Integrins and Other Adhesion Molecules 151
I. ABSTRACT 151
II. INTRODUCTION 151
III. MOLECULAR STRUCTURE OF ADHESION MOLECULES 152
IV. ADHESION MOLECULES IN CELLS OF THE OSTEOBLAST LINEAGE 156
V. ADHESION MOLECULES IN OSTEOCLASTS 161
VI. ADHESION MOLECULES IN CHONDROCYTES 164
VII. CONCLUSION 166
Alkaline Phosphatases 175
I. INTRODUCTION 175
II. STRUCTURE AND REGULATION OF THE TNAP GENE 175
III. PROTEIN STRUCTURE 177
IV. FUNCTION OF TNAP 179
V. CLINICAL USE 182
Acid Phosphatases 187
I. ACID PHOSPHATASES 187
II. TARTRATE-RESISTANT ACID PHOSPHATASE (TRACP) 188
III. PROSTATIC ACID PHOSPHATASE (PAP) 195
Matrix Proteinases 203
I. INTRODUCTION 203
II. ASPARTIC PROTEINASES 203
III. CYSTEINE PROTEINASES 204
IV. SERINE PROTEINASES 206
V. METALLOPROTEINASES 208
Structure and Metabolism of the Extracellular Matrix of Bone and Cartilage 221
Mineralization, Structure and Function of Bone 223
I. ABSTRACT 223
II. THE STRUCTURE AND FUNCTION OF BONE 223
III. BONE MINERALIZATION 226
IV. BONE MODELING AND REMODELING 231
Bone Structure and Strength 235
I. INTRODUCTION 235
II. GRAVITY AND THE NEED FOR STIFFNESS, FLEXIBILITY, LIGHTNESS AND SPEED 235
III. THE MATERIAL COMPOSITION AND STRUCTURAL DESIGN OF BONE 236
IV. BONE MODELING AND REMODELING - THE MECHANISM OF BONE'S CONSTRUCTION DURING GROWTH AND DECAY WITH ADVANCING AGE 238
V. STRENGTH MAINTENANCE 239
VI. CONCLUSION 241
The Cells of Bone 243
I. ABSTRACT 243
II. INTRODUCTION 243
III. DEVELOPMENTAL SIGNALS FOR CARTILAGE AND BONE TISSUE FORMATION 244
IV. OSTEOGENIC LINEAGE CELLS 249
V. THE OSTEOCLAST: A FUNCTIONALLY UNIQUE CELL FOR PHYSIOLOGICALLY REGULATED RESORPTION OF BONE MINERAL 258
VI. PERSPECTIVES 264
Signaling in Bone 281
I. ABSTRACT 281
II. INTRODUCTION 281
III. THE CONTROL OF OSTEOCLASTS 282
IV. SIGNALING IN THE CONTROL OF OSTEOCLAST ACTIVITY 283
V. SIGNALS FROM THE OSTEOBLAST LINEAGE THAT CONTROL OSTEOCLAST FORMATION 283
VI. HORMONE AND CYTOKINE INFLUENCES ON THE CONTACT DEPENDENT REGULATION OF OSTEOCLASTS 283
VII. DISCOVERY OF THE PHYSIOLOGICAL SIGNALING MECHANISMS IN OSTEOCLAST CONTROL 284
VIII. RANK SIGNALING 285
IX. COUPLING OF BONE FORMATION TO RESORPTION - RELEASE OF GROWTH FACTORS FROM BONE MATRIX 286
X. COUPLING OF BONE FORMATION TO RESORPTION - AUTOCRINE/PARACRINE REGULATION BY DIFFERENTIATING OSTEOBLASTS 288
XI. COUPLING OF BONE FORMATION TO RESORPTION - ARE OSTEOCLASTS A SOURCE OF COUPLING ACTIVITY? 288
Parathyroid Hormone: Structure, Function and Dynamic Actions 295
I. INTRODUCTION 295
II. STRUCTURE OF THE PTH GENE 295
III. CHROMOSOME LOCATION 296
IV. CONTROL OF GENE EXPRESSION 297
V. BIOSYNTHESIS OF PARATHYROID HORMONE 300
VI. METABOLISM OF PARATHYROID HORMONE 300
VII. RECEPTOR INTERACTIONS OF PARATHYROID HORMONE AND PARATHYROID HORMONE-RELATED PROTEIN 301
VIII. STRUCTURE OF THE PTH/PTHrP (PTH1R) RECEPTOR 301
IX. ACTIVATION OF THE CYCLIC ADENOSINE MONOPHOSPHATE SECOND-MESSENGER SYSTEM BY PARATHYROID HORMONE 303
X. IDENTIFICATION OF A SECOND PTH RECEPTOR 304
XI. PHYSIOLOGICAL ACTIONS OF PTH 304
XII. CELL-TO-CELL COMMUNICATION: OSTEOBLASTS AND OSTEOCLASTS 306
XIII. PREFERENTIAL ACTIONS OF PTH AT SELECTED SKELETAL SITES 307
Interaction of Parathyroid Hormone- related Peptide with the Skeleton 315
I. ABSTRACT 315
II. INTRODUCTION 315
III. MOLECULAR BIOLOGY AND MECHANISM OF ACTION 316
IV. THE SKELETAL ACTIONS OF PTHrP 320
V. SUMMARY 323
The Vitamin D Hormone and its Nuclear Receptor: Mechanisms Involved in Bone Biology 329
I. INTRODUCTION 329
II. METABOLISM OF VITAMIN D 330
III. NUCLEAR VITAMIN D RECEPTOR 331
IV. VITAMIN D AND BONE CELLS 334
V. PATHOLOGY AND THERAPY RELATED TO VITAMIN D AVAILABILITY, METABOLISM, AND FUNCTION 336
VI. CONCLUSIONS 341
Sex Steroid Effects on Bone Metabolism 349
I. ABSTRACT 349
II. INTRODUCTION 349
III. MOLECULAR STRUCTURES, SYNTHESIS, MECHANISM OF ACTION OF MAJOR SEX STEROIDS, AND TRANSCRIPTIONAL COREGULATOR FUNCTION 350
IV. EFFECTS OF SEX STEROIDS ON BONE CELLS AND BONE TURNOVER 353
V. EFFECTS OF ESTROGENS AND ANDROGENS ON BONE METABOLISM IN MEN VERSUS WOMEN 357
VI. EFFECTS OF SEX STEROIDS ON EXTRASKELETAL CALCIUM HOMEOSTASIS 358
VII. SUMMARY 359
Physiology of Calcium and Phosphate Homeostases 367
I. ABSTRACT 367
II. INTRODUCTION 367
III. BODY DISTRIBUTION OF CALCIUM 368
IV. DETERMINANTS OF EXTRACELLULAR CALCIUM CONCENTRATION 368
V. RELATIVE IMPORTANCE OF THE VARIOUS CALCIUM FLUXESIN CONTROLLING EXTRACELLULAR CALCIUM HOMEOSTASIS 371
VI. HOMEOSTATIC RESPONSES TO HYPOCALCEMIA 371
VII. CALCIUM AND BONE GROWTH 374
VIII. BODY DISTRIBUTION OF PHOSPHORUS 375
IX. DETERMINANTS OF EXTRACELLULAR PHOSPHATE CONCENTRATION 375
X. HOMEOSTATIC RESPONSES TO CHANGES IN PHOSPHATE SUPPLY OR DEMAND 378
XI. CONCLUSIONS 379
The Central Control of Bone Remodeling 383
I. INTRODUCTION 383
II. ACTIONS OF LEPTIN 384
III. SYMPATHETIC NERVOUS SYSTEM 387
IV. NEUROPEPTIDE Y AND THE Y RECEPTORS 391
V. INTERACTION BETWEEN LEPTIN AND Y2-REGULATED BONE ANTIOSTEOGENIC PATHWAYS 393
VI. CONCLUDING REMARKS 395
New Concepts in Bone Remodeling 399
I. INTRODUCTION 399
II. AN OVERVIEW OF THE REMODELING CYCLE 399
III. FUNCTIONS OF BONE REMODELING 402
IV. THE ROLE OF APOPTOSIS IN REGULATING BONE BALANCE 403
V. POSSIBLE MECHANISMS WHEREBY A REDUCTION IN ACTIVATION FREQUENCY MAY PROTECT AGAINST FRACTURE 405
Products of Bone Collagen Metabolism 413
I. INTRODUCTION 413
II. PRODUCTS OF BONE COLLAGEN SYNTHESIS, THE PROCOLLAGEN PROPEPTIDES 414
III. DEGRADATION PRODUCTS OF TYPE I COLLAGEN 419
IV. CLOSING REMARKS 424
Supramolecular Structure of Cartilage Matrix 429
I. SUMMARY 429
II. INTRODUCTION 429
III. LIGHT AND ELECTRON MICROGRAPHY 430
IV. BIOCHEMISTRY OF CARTILAGE 431
V. STUDIES OF FIBRIL STRUCTURES BY X-RAY DIFFRACTION 433
VI. STRUCTURE OF FIBRIL FRAGMENTS OBTAINED BY MECHANICAL DISRUPTION OF TISSUE 433
VII. STUDIES OF COLLAGEN CROSSLINKING IN CARTILAGE FIBRILS 434
VIII. RECONSTITUTION OF AGGREGATES FROM SOLUBLE COLLAGENS AND OTHER MACROMOLECULES 434
IX. STUDIES OF TRANSGENIC MICE AND OF HUMAN GENETIC MATRIX DISEASES 436
X. CORRELATING STRUCTURE WITH THE BIOMECHANICAL ROLE OF ARTICULAR CARTILAGE 437
XI. MODELS OF CARTILAGE FIBRIL STRUCTURE 438
XII. FUTURE PERSPECTIVES 439
Products of Cartilage Metabolism 443
I. INTRODUCTION 443
II. THE CHONDROCYTE AND ITS EXTRACELLULAR MATRIX 444
III. PRODUCTS OF COLLAGEN METABOLISM 446
IV. PRODUCTS OF AGGRECAN METABOLISM 451
V. PRODUCTS OF THE METABOLISM OF OTHER PROTEOGLYCANS 456
VI. PRODUCTS OF THE METABOLISM OF LINK PROTEIN AND HYALURONAN 457
VII. OTHER PRODUCTS OF CHONDROCYTE METABOLISM 459
VIII. CONCLUDING STATEMENT 460
Fluid Dynamics of the Joint Space and Trafficking of Matrix Products 473
I. INTRODUCTION 473
II. INTERPRETATION OF MARKER DATA AND STRATEGIES FOR DEALING WITH THEM 473
III. CONCLUSION 478
Transgenic Models of Bone Disease 479
I. INTRODUCTION 479
II. GENERATION OF MOUSE MODELS 479
III. TRANSGENIC MODELS IN BONE BIOLOGY 482
IV. PERSPECTIVES AND FUTURE DIRECTIONS 487
Markers of Bone and Cartilage Metabolism 491
The Role of Genetic Variation in Osteoporosis 493
I. ABSTRACT 493
II. OSTEOPOROSIS HAS GENETIC INFLUENCES 493
III. GENOME-WIDE APPROACHES TO FIND THE GENES 495
IV. ASSOCIATION ANALYSIS OF CANDIDATE GENE POLYMORPHISMS 498
V. HAPLOTYPES 500
VI. META-ANALYSES 502
VII. OSTEOPOROSIS CANDIDATE GENES: COLLAGEN TYPE Ia1 AND THE VITAMIN D RECEPTOR 504
VIII. SUMMARY 505
Measurement of Calcium, Phosphate and Magnesium 509
I. MEASUREMENT OF CALCIUM 509
II. MEASUREMENT OF PHOSPHATE 517
III. MEASUREMENT OF MAGNESIUM 521
Measurement of Parathyroid Hormone 529
I. ABSTRACT 529
II. BACKGROUND 529
III. DIFFERENT IMMUNOMETRIC ASSAYS FOR THE DETECTION OF PTH 531
IV. PRIMARY HYPERPARATHYROIDISM 532
V. HYPERPARATHYROIDISM IN RENAL OSTEODYSTROPHY 532
VI. PSEUDOHYPOPARATHYROIDISM ( PHP) 532
VII. CONCLUSION 533
New Horizons for Assessment of Vitamin D Status in Man 535
I. MEASUREMENT OF VITAMIN D3 ( CHOLECALCIFEROL) AND VITAMIN D2 ( ERGOCALCIFEROL) 535
II. MEASUREMENT OF 25- HYDROXYVITAMIN D 535
III. MEASUREMENT OF 1,25-DIHYDROXYVITAMIN D 546
Measurement of Biochemical Markers of Bone Formation 551
I. ABSTRACT 551
II. INTRODUCTION 551
III. PROPEPTIDES OF TYPE I PROCOLLAGEN 552
IV. TOTAL ALKALINE PHOSPHATASE 555
V. BONE ALKALINE PHOSPHATASE 555
VI. OSTEOCALCIN 557
VII. DISCUSSION 559
Measurement of Biochemical Markers of Bone Resorption 563
I. INTRODUCTION 563
II. COLLAGEN RELATED MARKERS 565
III. NON-COLLAGENOUS PROTEINS OF THE BONE MATRIX 575
IV. OSTECLAST ENZYMES 577
Variability in the Measurement of Biochemical Markers of Bone Turnover 587
I. INTRODUCTION 587
II. SOURCES OF PRE-ANALYTICAL VARIABILITY IN THE MEASUREMENT OF BIOCHEMICAL MARKERS OF BONE TURNOVER 588
III. STATISTICAL CONSIDERATION OF VARIABILITY 593
IV. SUMMARY 599
Validation of Biochemical Markers of Bone Turnover 605
I. INTRODUCTION 605
II. VALIDATION OF BIOCHEMICAL MARKERS BY CALCIUM KINETICS 606
III. VALIDATION OF BIOCHEMICAL MARKERS BY BONE HISTOMORPHOMETRY 610
IV. CONCLUSIONS 614
Genetic Markers of Joint Disease 617
I. INTRODUCTION 617
II. ANKYLOSING SPONDYLITIS 617
III. REACTIVE ARTHRITIS 619
IV. RHEUMATOID ARTHRITIS 620
V. JUVENILE RHEUMATOID ARTHRITIS 627
VI. CONCLUSION 628
Laboratory Assessment of Postmenopausal Osteoporosis 633
I. INTRODUCTION 633
II. POSTMENOPAUSAL BONE LOSS 634
III. MANAGEMENT OF POSTMENOPAUSAL OSTEOPOROSIS 638
IV. CONCLUSION 646
Monitoring Anabolic Treatment 651
I. INTRODUCTION 651
II. CELLULAR AND REGULATORY MECHANISMS OF THE ANABOLIC ACTIONS OF PARATHYROID HORMONE 652
III. PHARMACOKINETICS OF TERIPARATIDE IN HUMAN SUBJECTS 653
IV. ACTIONS OF PARATHYROID HORMONE TO IMPROVE BONE QUALITY 654
V. CONCLUSIONS 664
Monitoring of Antiresorptive Therapy 671
I. INTRODUCTION 671
II. EFFECTS OF PRETREATMENT BONE TURNOVER AND MINERAL DENSITY ON THERAPEUTIC OUTCOMES 672
III. THE ROLE OF MARKERS OF BONE TURNOVER IN MONITORING ANTIRESORPTIVE OSTEOPOROSIS THERAPY 673
IV. INTERPRETATION OF CHANGES IN BONE TURNOVER MARKERS 683
Age-related Osteoporosis and Skeletal Markers of Bone Turnover 693
I. INTRODUCTION 693
II. EPIDEMIOLOGY AND PATHOGENESIS OF AGE-RELATED OSTEOPOROSIS-RELATIONSHIP TO BONE TURNOVER 694
III. MARKERS OF BONE TURNOVER AND AGE-RELATED OSTEOPOROSIS-CLINICAL IMPLICATIONS 701
IV. SUMMARY 705
Steroid-Induced Osteoporosis 711
I. SUMMARY 711
II. INTRODUCTION 711
III. EPIDEMIOLOGY 711
IV. PATHOGENESIS 712
V. EFFECTS OF GLUCOCORTICOIDS ON HISTOLOGICAL INDICES OF BONE TURNOVER 713
VI. EFFECT OF GLUCOCORTICOIDS ON MARKERS OF BONE TURNOVER 714
VII. EVALUATION OF STEROIDTREATED PATIENTS 716
VIII. TREATMENT AND FOLLOW-UP 716
Transplantation Osteoporosis: Biochemical Correlates of Pathogenesis and Treatment 723
I. INTRODUCTION 723
II. KIDNEY TRANSPLANTATION 724
III. CARDIAC TRANSPLANTATION 727
IV. LIVER TRANSPLANTATION 728
V. LUNG TRANSPLANTATION 728
VI. BONE MARROW TRANSPLANTATION 729
VII. MECHANISMS OF BONE LOSS AFTER TRANSPLANTATION 729
VIII. PREVENTION AND MANAGEMENT OF TRANSPLANTATION OSTEOPOROSIS 731
IX. CONCLUSIONS 733
Secondary Osteoporosis 739
I. INTRODUCTION 739
II. HYPERTHYROIDISM AND OSTEOPOROSIS 739
III. OSTEOPOROSIS SECONDARY TO HYPOGONADISM 746
IV. ANTICONVULSANT DRUGS AND OSTEOPOROSIS 752
Osteomalacia and Rickets 761
I. DEFINITION 761
II. ETIOLOGY 763
III. INCIDENCE AND EPIDEMIOLOGY 764
IV. CALCIOPENIC RICKETS AND OSTEOMALACIA 765
V. PHOSPHOPENIC RICKETS AND OSTEOMALACIA 769
VI. NORMAL MINERAL RICKETS AND OSTEOMALACIA 772
Assessment of Bone and Joint Diseases: Renal Osteodystrophy 777
I. INTRODUCTION 777
II. BIOCHEMICAL ASSESSMENT OF RENAL OSTEODYSTROPHY 779
III. SKELETAL IMAGING IN RENAL OSTEODYSTROPHY 783
IV. SUMMARY 784
Primary Hyperparathyroidism 789
I. INTRODUCTION 789
II. ETIOLOGY 789
III. CLINICAL PRESENTATION 790
IV. BONE MARKERS IN PRIMARY HYPERPARATHYROIDISM 792
V. CYTOKINES IN PRIMARY HYPERPARATHYROIDISM 794
VI. TREATMENT OF PRIMARY HYPERPARATHYROIDISM 794
VII. SUMMARY 797
Paget’s Disease of Bone 801
I. INTRODUCTION 801
II. ETIOLOGY AND PATHOGENESIS 801
III. TREATMENT 806
Metastatic Bone Disease 815
I. ABSTRACT 815
II. INTRODUCTION 816
III. USE OF MARKERS OF BONE TURNOVER FOR THE DIAGNOSIS OF BONE METASTASES 818
IV. USE OF MARKERS OF BONE TURNOVER FOR THE MONITORING OF TUMOR BONE DISEASE 824
V. PREDICTION OF THE DEVELOPMENT OF BONE METASTASES 828
Rare Bone Diseases 833
I. INTRODUCTION 833
II. OSTEOPENIA 834
III. OSTEOSCLEROSIS AND HYPEROSTOSIS 839
IV. ECTOPIC CALCIFICATION 845
V. OTHER DISORDERS 847
Osteogenesis Imperfecta 853
I. INTRODUCTION 853
II. CLASSIFICATION 854
III. DIAGNOSIS 855
IV. DIFFERENTIAL DIAGNOSIS 856
V. PATHOGENESIS 856
VI. BISPHOSPHONATE THERAPY IN OI 857
VII. MEDICAL THERAPIES OTHER THAN BISPHOSPHONATES 860
VIII. POTENTIAL FUTURE THERAPIES 861
IX. CONCLUSIONS 861
Rheumatoid Arthritis and other Inflammatory Joint Pathologies 865
I. ABSTRACT 865
II. INTRODUCTION 865
III. EFFECTS OF JOINT INFLAMMATION ON SKELETAL REMODELING 866
IV. EFFECTS OF JOINT INFLAMMATION ON CARTILAGE REMODELING 874
V. CONCLUSION 880
Osteoarthritis and Degenerative Spine Pathologies 893
I. INTRODUCTION 893
II. CHARACTERISTICS OF OA 894
III. ETIOLOGY 894
IV. TREATMENT OPTIONS 895
V. CURRENT DIAGNOSTIC PROCEDURES 895
VI. BIOCHEMICAL ASPECTS OF OSTEOARTHRITIS 895
VII. MARKERS OF BONE TURNOVER 896
VIII. MARKERS OF CARTILAGE METABOLISM 900
IX. SPINE DEGENERATION AND MARKERS 904
X. SUMMARY 905
XI. CONCLUSIONS 906
Index 911
Color Plate 943