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دانلود کتاب Principles of Bone Biology
دانلود کتاب اصول زیست شناسی استخوان
مشخصات کتاب
Principles of Bone Biology
ویرایش: 4 نویسندگان: John Bilezikian (editor), T. John Martin (editor), Thomas L. Clemens (editor), Clifford J. Rosen (editor) سری: ISBN (شابک) : 0128148411, 9780128148419 ناشر: Academic Press سال نشر: 2019 تعداد صفحات: 1898 زبان: English فرمت فایل : PDF (درصورت درخواست کاربر به PDF، EPUB یا AZW3 تبدیل می شود) حجم فایل: 95 مگابایت
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اصول زیست شناسی استخوان، ویرایش چهارم منبع ضروری برای هر کسی است که در مطالعه استخوان ها دخالت دارد. این جامع ترین، کامل ترین و به روزترین منبع اطلاعات در مورد تمام جنبه های استخوان و زیست شناسی استخوان است. این کتاب که توسط متخصصانی از سراسر جهان گردآوری شده است، برای دانشجویان علاقه مند به این رشته، محققان جوان در سطح فارغ التحصیل و فوق لیسانس که کار تحقیقاتی خود را آغاز می کنند و دانشمندانی که در حال بررسی اختلالات اسکلتی هستند و نیاز به غنی سازی برنامه های تحقیقاتی خود دارند، طراحی شده است.
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توضیحاتی درمورد کتاب به خارجی
Principles of Bone Biology, Fourth Edition remains the essential resource for anyone involved in the study of bones. It is the most comprehensive, complete, up-to-date source of information on all aspects of bones and bone biology. Assembled by experts from around the world, this book is designed for students interested in the field, young investigators at the graduate and post-graduate level beginning their research careers, and scientists investigating skeletal disorders who need to enrich their research programs.
- Includes a repository of knowledge for anyone involved in the study of bone biology
- Provides a one-stop source written by experts in the field
فهرست مطالب
Cover Principles of Bone Biology, Volume 1 Principles of Bone Biology, Volume 2 Copyright Dedication of Fourth Edition to Lawrence G. Raisz List of Contributors Preface to the Fourth Edition VOLUME 1 Part I: Basic principles Section A: Cell biology 1. Molecular and cellular regulation of intramembranous and endochondral bone formation during embryogenesis Introduction Intramembranous ossification The axial skeleton Somitogenesis Sclerotome differentiation The limb skeleton Overview of limb development Proximal-distal axis Anterior-posterior axis Dorsal-ventral axis Mesenchymal condensation and patterning of the skeleton Endochondral bone formation Overview The growth plate Mediators of skeleton formation Systemic mediators Local mediators Growth factor signaling pathways Transforming growth factor β and bone morphogenetic proteins Parathyroid hormone-related protein and Indian hedgehog WNTs and β-catenin Fibroblast growth factors and their receptors C-type natriuretic peptide Notch signaling Transcription factors Epigenetic factors and microRNAs The functional roles of the vasculature in endochondral bone formation References 2. Skeletal stem cells: tissue-specific stem/progenitor cells of cartilage, bone, stroma, and marrow adipocytes Introduction Developmental origins of bone and skeletal stem cells Germ-layer specifications Patterns of bone formation and development of pericytes/skeletal stem cells The skeletal lineage Regulation of SSC/BMSC fate Hormonal regulation Signaling pathways and transcription factors Epigenetic controls MicroRNAs Cell-cell and cell-substrate interactions, cell shape, and mechanical forces Isolation of SSCs/BMSCs Characterization of SSCs/BMSCs Potency Markers Determination of skeletal stem cell self-renewal The role of SSCs/BMSCs in postnatal bone turnover and remodeling Skeletal stem cells in disease Fibrous dysplasia of bone and the McCune-Albright syndrome Inherited forms of bone marrow failure Role of SSCs/BMSCs in acquired inflammation Skeletal stem cells in tissue engineering Cell sources Scaffolds Skeletal stem cells and regenerative medicine Stem cell and non-stem cell functions of skeletal stem cells Summary Acknowledgments References 3. Bone marrow and the hematopoietic stem cell niche Introduction The niche concept: a historical prospective Hematopoietic stem cell microenvironments in the embryo and perinatal period The adult bone marrow niche Mesenchymal stromal/stem cell populations Adipocytes Osteoblastic cells Endothelial cells Hematopoietic cells Megakaryocytes Macrophages Neutrophils T cells Osteoclasts Neuronal regulation of the hematopoietic stem cell niche Hormonal regulation of the hematopoietic stem cell niche Parathyroid hormone Insulin-like growth factor 1 Niche heterogeneity for heterogeneous hematopoietic stem and progenitor cells Conclusions Acknowledgments References 4. The osteoblast lineage: its actions and communication mechanisms Introduction The stages of the osteoblast lineage Mesenchymal precursors Commitment of osteoblast progenitors (preosteoblasts) Mature ``bone-forming'' osteoblasts Bone-lining cells Osteocytes The process of osteoblast lineage differentiation At their various stages of development, cells of the osteoblast lineage signal to one another An example of contact-dependent communication: EphrinB2/EphB4 Communication between different stages of differentiation: IL-6 cytokines Communication at different stages of differentiation: PTHrP/PTHR1 Physical sensing and signaling by osteoblasts and osteocytes How does the osteoblast lineage promote osteoclast formation? Actions of the osteoblast lineage during the bone remodeling sequence Lessons in osteoblast biology from the Wnt signaling pathway From paracrinology to endocrinology in bone: the secretory osteoblast lineage References 5. Osteoclasts Introduction Function of osteoclasts Morphological features of osteoclasts Mechanism of bone resorption DC-STAMP/OC-STAMP Ruffled border formation Role of osteoblastic cells in osteoclastogenesis Coculture system Macrophage colony-stimulating factor Osteoprotegerin and RANKL Osteoclastogenesis supported by RANKL Signal transduction in osteoclastogenesis The M-CSF receptor FMS RANK Tumor necrosis factor receptors ITAM costimulatory signals Calcium signals SIGLEC-15 and FcγR WNT signals Canonical WNT signals Noncanonical WNT signals Induction of osteoclast function Adhesion signals Cytokine signals Characteristics of osteoclast precursors in vivo Conclusion and perspective References 6. The osteocyte Introduction The osteocytic phenotype The osteocyte network Osteocyte formation and death Osteocyte isolation Osteocyte markers Osteocytic cell lines Matrix synthesis The osteocyte cytoskeleton and cell-matrix adhesion Hormone receptors in osteocytes Osteocyte function Blood-calcium/phosphate homeostasis Functional adaptation, Wolff's law Osteocytes as mechanosensory cells Canalicular fluid flow and osteocyte mechanosensing Osteocyte shape and mechanosensing Response of osteocytes to fluid flow in vitro Summary and conclusion Acknowledgments References Further reading 7. Transcriptional control of osteoblast differentiation and function Runx2, a master control gene of osteoblast differentiation in bony vertebrates Runx2 functions during skeletogenesis beyond osteoblast differentiation Regulation of Runx2 accumulation and function Osterix, a Runx2-dependent osteoblast-specific transcription factor required for bone formation ATF4, a transcriptional regulator of osteoblast functions and a mediator of the neural regulation of bone mass Additional transcriptional regulators of osteoblast differentiation and function Transcription factors acting downstream of Wnt signaling in osteoblasts: what do they actually do in differentiated osteobl ... Regulation of osteoblast differentiation by means other than transcription factors References Further reading 8. Wnt signaling and bone cell activity Introduction Wnt genes and proteins Components of the Wnt/β-catenin signaling pathway Lrp5, Lrp6, and frizzled Dishevelled, glycogen synthase kinase-3β, Axin, and β-catenin Transcriptional regulation by β-catenin Wnt signaling and bone cell function Osteoblast differentiation and function Osteoclast function Osteocyte function Interactions between Wnt/β-catenin signaling and other pathways important in bone mass regulation The Wnt signaling pathway as a target for anabolic therapy in bone References Further Reading 9. Vascular and nerve interactions Introduction The vasculature of bone Vascularization of developing bone Vascularization of the mature skeleton Bone cells' control of skeletal vascularization and oxygenation Endothelial and angiocrine signaling in bone The nerve system of bone Innervation of developing bone Innervation of the mature skeleton Somatic nervous system Autonomic nervous system Conclusion References 10. Coupling of bone formation and resorption Introduction:-bone modeling and bone remodeling Development of the concept of coupling Coupled remodeling is asynchronous throughout the skeleton Coupling is unidirectional and sequential: bone formation following bone resorption Coupling as a multicellular process Coupling occurs locally within a basic multicellular unit Coupling and balance: what is the difference? The resorption phase of remodeling and its cessation in the basic multicellular unit Coupling mechanisms originate from several cellular sources Matrix-derived resorption products as coupling factors Coupling factors synthesized and secreted by osteoclasts Membrane-bound coupling factors synthesized by osteoclasts Perspective on candidate osteoclast-derived coupling factors identified to date How other cells contribute to coupling Osteoblast lineage cells-sensing the surface and signaling to one another Macrophages, immune cells, and endothelial cells The reversal phase as a coupling mechanism Conclusion References 11. Modeling and remodeling: the cellular machinery responsible for bone's material and structural strength during growth, ... Summary Bone modeling and remodeling during growth and the attainment of bone's peak material and structural strength Definition of bone modeling and remodeling Bone's material and structural strength Trait variances in adulthood originate before puberty Sex and racial differences in bone structure Bone remodeling by the basic multicellular unit Osteocyte death in signaling bone remodeling The bone remodeling compartment The multidirectional steps of the remodeling cycle Bone remodeling and microstructure during young adulthood, menopause, and advanced age Young adulthood: reversible bone loss and microstructural deterioration Menopause: reversible and irreversible bone loss and microstructural deterioration Advanced age: the predominance of cortical bone loss The net effects of reduced periosteal apposition and endosteal bone loss Sexual dimorphism in trabecular and cortical bone loss The heterogeneous material and structural basis of bone fragility in patients with fractures Bone modeling, remodeling, and drug therapy Antiresorptive therapy reduces the reversible but not the irreversible deficit in mineralized matrix volume Anabolic therapy: restoring the irreversible deficit in mineralized matrix volume and microstructural deterioration by remo ... Combined antiresorptive and anabolic therapy Conclusion References 12. Aging and bone Characteristics of the aged skeleton Human Rodents Bone cell aging Osteoblast progenitors Osteocytes Molecular mechanisms of aging Mitochondrial dysfunction Cellular senescence Loss of autophagy Contribution of bone extrinsic mechanisms to skeletal aging Loss of sex steroids Lipid peroxidation and declining innate immunity Decreased physical activity Future directions References Section B: Biochemistry 13. Type I collagen structure, synthesis, and regulation Introduction The family of fibrillar collagens Structure, biosynthesis, transport, and assembly of type I collagen Structure Regulation of transcription Control of translation Intracellular transport Fibrillogenesis Assembly Consequences of genetic mutations on type I collagen formation Collagen type I degradation and catabolism Collagen type I and bone pathologies Transcriptional regulation of type I collagen genes Proximal promoters of type I collagen genes Transcription factors binding to the pro-α1(I) proximal promoter Factors binding to the pro-COL1A2 proximal promoter Structure and functional organization of upstream segments of type I collagen genes Upstream elements in the pro-Col1a1 gene Upstream elements of the mouse pro-Col1a2 gene Delineating the mode of action of tissue-specific elements Role of the first intronic elements in regulating collagen type I First intron of the pro-COL1A1 gene First intron of the pro-COL1A2 gene Posttranscriptional regulation of type I collagen Critical factors involved in type I collagen gene regulation Growth factors Transforming growth factor β Connective tissue growth factor Fibroblast growth factor Insulin-like growth factor Cytokines Tumor necrosis factor α Interferon γ Other cytokines Interleukin 1 Interleukin 13 Interleukin 4 Interleukin 6 Other interleukins Arachidonic acid derivatives Hormones and vitamins Corticosteroids Thyroid hormones Parathyroid hormone Vitamin D References 14. Collagen cross-linking and bone pathobiology Introduction Advances in collagen cross-link analysis Mature cross-link analysis Divalent cross-link analysis Electrospray mass spectrometry Cross-link formation Bone collagen cross-linking Cross-link structures Divalent cross-links Pyridinium cross-links Pyrrole cross-links Pyridinoline and pyrrolic cross-linked peptides in urine Histidine-containing collagen cross-links and other maturation products Glycosylations and glycations Enzymatic glycosylation Tissue-dependent variations in cross-link glycosylation Potential functions Nonspecific glycations Advanced glycation end products Types of advanced glycation end products Potential consequences Cross-linking lysine-modifying enzymes Lysyl hydroxylases Consequences of lysyl hydroxylase gene mutations Lysyl oxidases Heritable disorders and mouse models Heritable disorders Collagen posttranslational modifications CRTAP, LEPRE1, PPIB TMEM38B PLOD2 and FKBP10 SC65 and P3H3 MBTPS2 Collagen processing Bone morphogenetic protein 1 Collagen chaperone SERPINH1 Bone mineralization IFITM5 SERPINF1 Implications for bone fragility and mineral deposition Future challenges References 15. Secreted noncollagenous proteins of bone Introduction Proteoglycans Aggrecan and versican (PG-100) Decorin (PG-II) and biglycan (PG-I) Other leucine-rich repeat sequence proteins and proteoglycans Hyaluronan Glycoproteins Alkaline phosphatase Sclerostin Periostin Osteonectin (SPARC, culture shock protein, and BM40) Tetranectin RGD-containing glycoproteins Thrombospondins Fibronectin Irisin (FRCP2, fibronectin type III domain-containing protein 5) Vitronectin Fibrillins Bone acidic glycoprotein-75 Small integrin-binding ligands with N-linked glycosylation Osteopontin (spp, BSP-I) Bone sialoprotein (BSP-II) Dentin matrix protein 1 Matrix extracellular phosphoglycoprotein γ-Carboxyglutamic acid-containing proteins Matrix Gla protein Osteocalcin Serum proteins Other proteins Control of gene expression Bone matrix glycoproteins and ectopic calcifications Summary References 16. Bone proteinases Introduction Metalloproteinases Stromelysin Type IV collagenases (gelatinases) Membrane-type matrix metalloproteinases Collagenases Collagenase-3/MMP-13 Plasminogen activators Urokinase-type plasminogen activator Tissue-type plasminogen activator Plasminogen activators in bone Cysteine proteinases Aspartic proteinases Conclusions References 17. Integrins and other cell surface attachment molecules of bone cells Introduction Role of integrins in bone cells Osteoblasts and osteocytes Osteoclasts Chondrocytes Role of cadherins in bone cells Osteoblasts and osteocytes Osteoclasts Chondrocytes Roles of other attachment molecules in bone cells Syndecans Glypicans and perlecan CD44 Immunoglobulin superfamily members Osteoactivin Chondroadherin Conclusion Acknowledgments References 18. Intercellular junctions and cell-cell communication in the skeletal system Introduction Adherens junctions and the cadherin superfamily of cell adhesion molecules Cadherins in commitment and differentiation of chondro-osteogenic cells Cadherins in skeletal development, growth, and maintenance N-cadherin modulation of Wnt/β-catenin signaling in osteoblastogenesis and osteoanabolic responses Connexins and gap-junctional intercellular communication Connexin diseases affecting the skeleton Connexins in the skeleton across the life span Function of connexin43 in bone cells Mechanisms of connexin43 control of bone cell function Conclusions Acknowledgments References Section C: Bone remodeling and mineral homeostasis 19. Histomorphometric analysis of bone remodeling Introduction Tetracycline labeling and the surgical procedure Sample preparation and analysis Routine histomorphometric variables Static parameters Dynamic parameters Normal bone Hyperparathyroidism Osteomalacia Renal osteodystrophy Osteoporosis Clinical indications for bone biopsy Histomorphometric studies of the effects of osteoporosis drugs Anticatabolic agents Calcitonin Hormone therapy Selective estrogen receptor modulators Bisphosphonates Denosumab Osteoanabolic therapies PTH(1-34) and PTH(1-84) Abaloparatide Romosozumab Comparative studies of anabolic and anticatabolic drugs SHOTZ AVA study: differential effects of teriparatide and denosumab on intact parathyroid hormone and bone formation indices Conclusion References 20. Phosphorus homeostasis and related disorders Introduction Regulation of phosphate metabolism Overview Hormonal regulators Parathyroid hormone Fibroblast growth factor 23 The role of osteocytes Nutritional and gastrointestinal considerations Phosphate and bone mineralization Intracellular/extracellular compartmentalization Mechanisms of phosphate transport Intestinal phosphate transport Renal phosphate transport Ubiquitous metabolic phosphate transporters Primary disorders of phosphate homeostasis Fibroblast growth factor 23-mediated hypophosphatemic disorders X-linked hypophosphatemia (OMIM: 307800) Pathophysiology Prevalence Clinical manifestations Therapy Autosomal dominant hypophosphatemic rickets (OMIM: 193100) Autosomal recessive hypophosphatemic rickets Tumor-induced osteomalacia Other FGF23-mediated hypophosphatemic syndromes Fibroblast growth factor 23-independent hypophosphatemic disorders Hereditary hypophosphatemic rickets with hypercalciuria (OMIM: 241530) Epidemiology Cloning and identification of human mutations in NPT2c Pathophysiology Clinical presentation and diagnostic evaluation Laboratory findings and genetic testing Musculoskeletal findings Renal findings Therapy and resources Standard therapy Dent's disease (X-linked recessive hypophosphatemic rickets) (OMIM: 300009) Hypophosphatemia with osteoporosis and nephrolithiasis due to SLC34A1 (OMIM: 612286) and NHERF1 mutations (OMIM: 604990) Autosomal recessive Fanconi syndrome (OMIM: 613388) Fanconi-Bickel syndrome (OMIM: 227810) Intestinal malabsorption of phosphate Hyperphosphatemic syndromes Tumoral calcinosis Normophosphatemic disorders of cellular phosphorus metabolism Summary References 21. Magnesium homeostasis Introduction Magnesium physiology Hereditary disorders of magnesium homeostasis Disturbed Mg2+ reabsorption in the thick ascending limb Disturbed Mg2+ reabsorption in the distal convoluted tubule Acquired hypomagnesemia Cisplatin and carboplatin Aminoglycosides Calcineurin inhibitors Proton pump inhibitors References 22. Metal ion toxicity in the skeleton: lead and aluminum Introduction Research into bone-seeking toxic elements Lead Measurement of lead in bone Lead as an unrecognized risk factor in osteoporosis How does lead cause low bone density? The β-catenin/sclerostin axis: is it the mechanism for lead toxicity in osteoblasts? Mechanism of action of lead: stimulation of sclerostin expression A clinical opportunity Aluminum Summary References 23. Biology of the extracellular calcium-sensing receptor Introduction Structural and biochemical properties of the calcium-sensing receptor Agonists, antagonists, and modulators of the calcium-sensing receptor Cationic agonists of the calcium-sensing receptor Allosteric modulators Synthetic modulators Ligand-biased signaling Calcium-sensing receptor intracellular signaling Calcium-sensing receptor-mediated signaling Calcium-sensing receptor-associated intracellular signaling effectors Calcium-sensing receptor interacting proteins Regulation of calcium-sensing receptor gene expression Roles of calcium-sensing receptor in calciotropic tissues Calcium-sensing receptor in parathyroid glands Calcium-sensing receptor in the kidney Calcium-sensing receptor in bone cells Calcium-sensing receptor in the breast Noncalciotropic roles of the calcium-sensing receptor Calcium-sensing receptor in the pancreas Calcium-sensing receptor in the gastrointestinal system Calcium-sensing receptor in the peripheral vascular system Calcium-sensing receptor in the lung Calcium-sensing receptor in the epidermis References Section D: Endocrine and paracrine regulation of bone 24. Parathyroid hormone molecular biology The parathyroid hormone gene Organization of the parathyroid hormone gene Promoter sequences The parathyroid hormone mRNA Mutations in the parathyroid hormone gene Development of the parathyroid Regulation of parathyroid hormone gene expression 1,25-Dihydroxyvitamin D3 Calcium In vitro studies In vivo studies Phosphate Protein-PTH mRNA interactions determine the posttranscriptional regulation of PTH gene expression by calcium, phosphate, an ... A conserved sequence in the PTH mRNA 3′ UTR binds parathyroid cytosolic proteins and determines mRNA stability The PTH mRNA 3′-UTR-binding proteins that determine PTH mRNA stability AU-rich binding factor K-homology splicing regulator protein The peptidyl-prolyl isomerase Pin1 determines parathyroid hormone mRNA stability and levels in secondary hyperparathyroidism Dynein light-chain Mr 8000 binds the PTH mRNA 3′ untranslated region and mediates its association with microtubules MicroRNA in the parathyroid Parathyroid-specific deletion of Dicer-dependent microRNA Let-7 and miRNA-148 regulate parathyroid hormone levels in secondary hyperparathyroidism Sex steroids Fibroblast growth factor 23 Fibroblast growth factor 23 decreases parathyroid hormone expression Resistance of the parathyroid to FGF23 in chronic kidney disease Parathyroid cell proliferation and mammalian target of rapamycin Phosphorylation of ribosomal protein S6 mediates mammalian target of rapamycin-induced parathyroid cell proliferation in se ... Summary Acknowledgments References 25. Paracrine parathyroid hormone-related protein in bone: physiology and pharmacology Introduction: discovery of parathyroid hormone-related protein Primary structure, active domains, processing, and secretion Interaction with parathyroid hormone receptor 1 PTHrP tissue distribution and function as a cytokine: the vascular tissue example Nuclear import of parathyroid hormone-related protein Nuclear actions: intracrine and autocrine C-terminal PTHrP and osteostatin PTHrP in fetus: early development and endochondral ossification PTHrP in bone after endochondral ossification Parathyroid hormone-related protein and osteosarcoma Distinct roles of PTH and PTHrP in fetal and postnatal bone PTH and PTHrP in adult bone: PTHrP in physiology and PTH in pharmacology PTHrP analogs in pharmacology: could this change the approach to skeletal anabolic therapy? Conclusion Acknowledgments References 26. Cardiovascular actions of parathyroid hormone/parathyroid hormone-related protein signaling Introduction PTH/PTHrP in cardiovascular development PTH receptor signaling in arterial biology: vascular smooth muscle cell and endothelial responses to PTH and PTHrP PTH2R signaling in vascular pharmacology Parathyroid hormone, hyperparathyroidism, and calcific aortic valve disease Impaired vascular PTH1R signaling and cardiovascular disease: the impact of hyperparathyroidism on cardiovascular mortality ... Chronic kidney disease-mineral and bone disorder: the metabolic ``perfect storm'' of cardiovascular risk PTH/PTHrP signaling and the bone-vascular axis PTH1R activation and the renin-angiotensin-aldosterone axis: a feed-forward vicious cycle Summary, conclusions, and future directions Acknowledgments References 27. Parathyroid hormone and parathyroid hormone-related protein actions on bone and kidney Introduction Receptors and second-messenger systems for parathyroid hormone and parathyroid hormone-related protein Expression and actions of parathyroid hormone receptor in bone Effects of parathyroid hormone and parathyroid hormone-related protein on bone cells Molecular mechanisms of action in osteoblasts Transcription factors Growth factors and cytokines Adaptor proteins Effects on gap junctions Effects on bone matrix proteins and alkaline phosphatase Effects on bone proteases Effects of parathyroid hormone and parathyroid hormone-related protein on bone cell proliferation Effects of parathyroid hormone and parathyroid hormone-related protein on bone cell differentiation Effects of parathyroid hormone and parathyroid hormone-related protein on bone cells Survival Effects of parathyroid hormone and parathyroid hormone-related protein on bone Bone resorption Cellular basis of parathyroid hormone action Effects of parathyroid hormone and parathyroid hormone-related protein on bone Bone formation Parathyroid hormone actions on kidney Calcium and phosphate homeostasis Calcium chemistry Serum calcium Phosphate chemistry Serum phosphate Parathyroid hormone actions on mineral-ion homeostasis Parathyroid hormone receptor expression, signaling, and regulation in the kidney Parathyroid hormone receptor expression Parathyroid hormone receptor signal transduction in kidney tubular cells Regulation of parathyroid hormone receptor signaling in tubular epithelial cells Calcium absorption and excretion Renal calcium absorption Parathyroid hormone regulation of renal calcium absorption Parathyroid hormone effects on proximal tubule calcium transport Parathyroid hormone effects on distal tubule calcium transport Phosphate excretion Mechanisms of proximal tubular phosphate absorption Parathyroid hormone regulation of renal phosphate absorption Parathyroid hormone receptor signal transduction in the regulation of calcium and phosphate excretion Parathyroid hormone signaling of renal calcium transport Parathyroid hormone signaling of renal phosphate transport Sodium and hydrogen excretion Parathyroid hormone regulation of proximal tubular sodium and hydrogen excretion Vitamin D metabolism Other renal effects of parathyroid hormone Renal expression and actions of parathyroid hormone-related protein Acknowledgments References 28. Receptors for parathyroid hormone and parathyroid hormone-related protein Introduction The PTHR1 is a class B G-protein-coupled receptor Parathyroid hormone receptor gene structure and evolution Structure of the PTHR1 gene Evolution of the parathyroid hormone receptor-ligand system Mechanisms of ligand recognition and activation by parathyroid hormone receptors Basic structural properties of the PTHR1 Two-site model of ligand binding to the PTHR1 Mechanism of ligand-induced activation at the PTHR1 Conformational selectivity and temporal bias at the PTHR1 Two high-affinity PTH receptor conformational states, R0 and RG Conformation-based differences in signaling responses to PTH and PTHrP ligands Endosomal signaling and signal termination at the PTHR1 Ligand-directed temporal bias and therapeutic implications LA-PTH, a long-acting PTH/PTHrP analog for hypoparathyroidism Abaloparatide: a PTHrP analog for osteoporosis PTHR1 mutations in disease Jansen's metaphyseal chondrodysplasia Other diseases linked to PTHR1 mutations Nonpeptide mimetic ligands for the PTHR1 Other receptors for parathyroid hormone and related ligands PTHR2 and PTHR3 subtypes Possible receptors for C-terminal PTH and PTHrP Conclusions References 29. Structure and function of the vitamin D-binding proteins Introduction Vitamin D-binding protein Genomic regulation Structure and polymorphisms Biologic function Binding to and transport of vitamin D metabolites Actin scavenging Neutrophil recruitment and migration with complement 5a binding Fatty acid binding Formation of vitamin D-binding protein-macrophage-activating factor and its functions Intracellular trafficking of vitamin D metabolites: role of heat shock protein 70 and hnRNPC1/C2 The vitamin D receptor Genomic location, protein structure, and regulation Vitamin D receptor mechanism of action: genomic Vitamin D binding sites in the genome Coregulators and epigenetic changes regulating VDR function Negative vitamin D response elements Interaction of VDR with β-catenin signaling Vitamin D receptor mechanism of action: nongenomic Conclusions References 30. Vitamin D gene regulation Vitamin D metabolism Role of 1,25(OH)2D3 in classical target tissues Bone Intestine Kidney Parathyroid glands Nonclassical actions of 1,25(OH)2D3 Transcriptional regulation by 1,25(OH)2D3 The vitamin D receptor General features of VDR action Sites of DNA binding Heterodimer formation with retinoid X receptors The vitamin D receptor functions to recruit coregulatory complexes that mediate gene regulation Applying emerging methodologies to study vitamin D receptor action on a genome-wide scale Overarching principles of VDR interaction at target cell genomes in bone cells Genome-wide coregulatory recruitment to target genes via the vitamin D receptor Identifying underlying early mechanistic outcomes in response to VDR/RXR binding The dynamic impact of cellular differentiation and disease on vitamin D receptor cistromes and transcriptional outcomes New approaches to the study of vitamin D-mediated gene regulation in vitro and in vivo Defining the regulatory sites of action of 1,25(OH)2D3, PTH, and FGF23 in the Cyp27b1 and Cyp24a1 genes in the kidney Future directions References Further Reading 31. Nonskeletal effects of vitamin D: current status and potential paths forward Introduction Vitamin D and immunity Vitamin D and muscle performance, balance, and falls Physiology Clinical studies of muscle performance and balance Vitamin D and falls Vitamin D and cancer Cellular mechanisms Vitamin D metabolism MicroRNA Cell cycle regulation and proliferation Apoptosis Animal studies Colorectal cancer Breast cancer Prostate cancer Skin Clinical studies Colorectal cancer Breast cancer Prostate cancer Skin cancer Vitamin D and cardiovascular disease Issues in existing data and paths forward to resolve the role of vitamin D deficiency in nonskeletal disease Vitamin D status assessment Is 25(OH)D measurement enough? Clinical and preclinical studies Conclusion and paths forward References 32. Cellular actions of parathyroid hormone on bone Introduction The regulation of bone remodeling by parathyroid hormone The generation and Maintenance of basic multicellular units Is governed by parathyroid hormone Parathyroid hormone regulates factors that govern the assembly and maintenance of basic multicellular units Osteoclast differentiation and life span Osteoblast differentiation and the coupling of bone formation to bone resorption The bone anabolic effects of intermittent parathyroid hormone Stimulation of anabolic remodeling and modeling Mechanisms underlying overfill of resorption cavities in response to injections of parathyroid hormone Stimulation of bone modeling by osteoblasts in response to injections of parathyroid hormone Unresolved issues References 33. Calcitonin peptides Introduction Calcitonin-family gene and peptide structure Extraskeletal actions of calcitonin-family peptides Calcitonin Calcitonin gene-related peptide Amylin Receptors for calcitonin-family peptides Peptide access to the bone microenvironment Effects on osteoclasts Calcitonin Calcitonin gene-related peptide Amylin Effects on osteoblasts Calcitonin Calcitonin gene-related peptide Amylin Effects of local and systemic peptide administration into laboratory animals Skeletal effects Effects on calcium metabolism The skeletal effects of calcitonin, calcitonin gene-related peptide, and amylin: lessons from genetically modified mice Calcitonin and calcitonin gene-related peptide Amylin Calcitonin receptor The role of calcitonin and calcitonin receptor in situations of calcium stress Calcitonin, calcitonin gene-related peptide, and amylin-relevance to human bone physiology References 34. Regulation of bone remodeling by central and peripheral nervous signals Introduction Afferent signals regulating bone remodeling via the central nervous system Negative regulation of bone remodeling by leptin Dual action of adiponectin on bone remodeling Central and efferent regulators of bone remodeling Leptin's action on bone remodeling is mediated by brain serotonin signaling and the sympathetic nervous system Counterregulation of sympathetic nervous system control of bone remodeling by the parasympathetic nervous system and adipon ... Other regulators of sympathetic nervous system control of bone remodeling NeuromedinU Endocannabinoid signaling Orexin signaling Regulation of bone resorption by melanocortin receptor 4 and cocaine- and amphetamine-regulated transcript Y receptor signaling Brain-derived neurotrophic factor Interleukin-1 Evidence of central/neuronal regulations of bone mass in human Leptin Adrenergic signaling Brain serotonin and neuromedinU Melanocortin receptor 4 and cocaine- and amphetamine-regulated transcript Neuropeptide Y, brain-derived neurotrophic factor, and cannabinoid receptor 2 Conclusions and perspective References Section E: Other systemic hormones that influence bone metabolism 35. Estrogens and progestins Estrogens and estrogen receptors Estrogen receptor mouse models Estrogens-from a clinical perspective Progestins and progesterone receptors in bone biology Summary and conclusions Conflict of Interest References 36. Physiological actions of parathyroid hormone-related protein in epidermal, mammary, reproductive, and pancreatic tissues Introduction Skin Parathyroid hormone-related protein and its receptor expression Biochemistry of parathyroid hormone-related protein Function of parathyroid hormone-related protein Pathophysiology of parathyroid hormone-related protein Mammary gland Embryonic mammary development Adolescent mammary development Pregnancy and lactation Pathophysiology of parathyroid hormone-related protein in the mammary gland Reproductive tissues Parathyroid hormone-related protein and placental calcium transport Uterus and extraembryonic tissues Placenta and fetal membranes Implantation and early pregnancy Pathophysiology of parathyroid hormone-related protein in the placenta Summary Endocrine pancreas Parathyroid hormone-related protein and its receptors Regulation of parathyroid hormone-related protein and its receptors Biochemistry of parathyroid hormone-related protein Function of parathyroid hormone-related protein Pathophysiology of parathyroid hormone-related protein Conclusions Acknowledgments References 37. The pharmacology of selective estrogen receptor modulators: past and present∗ Introduction Selective estrogen receptor modulator mechanism Selective estrogen receptor modulator chemistry Selective estrogen receptor modulator pharmacology Skeletal system Preclinical studies Clinical studies Reproductive system Uterus Estrogen agonism in the uterus Estrogen antagonism in the uterus Mammary Other Ovarian effects Hormonal effects Vaginal effects Cardiovascular system Cardiovascular safety of selective estrogen receptor modulators Potential cardiovascular benefit of selective estrogen receptor modulators Central nervous system Central nervous system safety of selective estrogen receptor modulators Central nervous system efficacy of selective estrogen receptor modulators General safety profile and other pharmacological considerations Other safety Pharmacokinetics Future directions with selective estrogen receptor modulators Summary References 38. Thyroid hormone and bone Introduction Intracellular mechanism of thyroid hormone action Nuclear actions of thyroid hormones Nongenomic actions of thyroid hormones Thyrotropin as an independent agent of bone metabolism Cellular effects of thyroid hormones on the bone Osteoblasts Osteoclasts Remodeling Chondrocytes In vivo responses of the skeleton to thyroid hormones: animal studies Hypothyroidism Hyperthyroidism Pathophysiological effects of altered thyroid hormone status in humans Hypothyroidism Subclinical hypothyroidism Hyperthyroidism Subclinical hyperthyroidism Overview and future directions References 39. Basic and clinical aspects of glucocorticoid action in bone Introduction The physiological role of glucocorticoids in bone Glucocorticoid signaling and prereceptor metabolism Local glucocorticoid metabolism in bone Novel insights from targeted disruption of glucocorticoid signaling in bone Endogenous glucocorticoids promote osteoblastogenesis Glucocorticoid excess and the skeleton Pathogenesis of glucocorticoid-induced osteoporosis Glucocorticoid excess and its effects on osteoblast differentiation Glucocorticoids prevent osteoblast cell cycle progression Glucocorticoids induce osteoblast apoptosis Glucocorticoid excess and the osteocyte Glucocorticoid excess and the osteoclast Glucocorticoid excess and local glucocorticoid metabolism Indirect mechanisms for glucocorticoid-induced osteoporosis Glucocorticoid excess and systemic fuel metabolism Treatment of glucocorticoid-induced osteoporosis Assessment of the patient with glucocorticoid-induced osteoporosis Management of glucocorticoid-induced osteoporosis Bisphosphonates Denosumab Raloxifene Teriparatide Sex hormone replacement Timing and monitoring of therapy New and emerging therapies Selective glucocorticoid receptor activators Antisclerostin/DKK1 Conclusions and future perspectives Acknowledgments References 40. Diabetes and bone Introduction Effects of diabetes and insulin on endochondral bone growth Effects of insulin on growth plate cartilage in nondiabetic animal models and in vitro Skeletal growth in T1DM Animal models Children Effects of T1DM on bone T1DM and fracture risk T1DM and bone turnover Animal models of T1DM Clinical data T1DM, bone density, and bone structure Animal models of T1DM Clinical data T1DM and bone strength Animal models of T1DM Clinical data Effects of T2DM and insulin on bone T2DM and fractures T2DM and bone turnover Animal models of T2DM Clinical data T2DM, bone density, and bone structure Hyperinsulinemia, insulin resistance, and bone density Animal models of T2DM Clinical data T2DM and bone strength Animal models Humans Clinical risk factors for fractures in T1DM and T2DM Effect of diabetes treatments on bone Bone repair in T1DM and T2DM Bone and systemic metabolism: a two-way interaction? Metabolic control of glucose and insulin in bone Bone hormones control systemic metabolism What causes diabetic bone disease? The diabetic hormonal milieu Lower circulating insulin-like growth factor 1 Hypercortisolism Calciotropic hormones Low amylin Impaired vascularization of diabetic bones Altered collagenous bone matrix Increased collagen glycosylation Reduced enzymatic collagen cross-linking Increased bone marrow adiposity Inflammation and oxidative stress Loss of incretin effect Sclerostin Treatment of bone fragility in diabetes General conclusions Acknowledgments References 41. Androgen receptor expression and steroid action in bone Introduction Loss-of-function evidence from rare human variants Gain-of-function evidence from human trials Can we reliably measure androgen gain of function in bone health using end points such as bone mineral density? Gender-specific differences in bone geometry and architecture Gain-of-function studies with testosterone treatment and change in bone architecture Loss of function using genetically modified mice Role of estrogen receptor alpha in bone using genetically modified mice is equivocal Gain-of-function studies using selective androgen receptor modulators in sexually mature animal models The muscle-bone interface and its potential impact on bone strength Future prospects for androgens and male skeletal health References Section F: Local regulators 42. Growth hormone, insulin-like growth factors, and IGF binding proteins Introduction Physiology of the GH/IGF/IGFBP system Growth hormone releasing hormone Growth hormone releasing hormone receptor Somatostatin Growth hormone Mechanism of growth hormone secretion Effects of gonadal status on the GH-IGF-I axis Effects of the GH/IGF-I/IGFBP system on the aging skeleton The IGF regulatory system and its relationship to the skeleton IGF-I, IGF-II, IGFBPs, and IGF receptors Insulin-like growth factor binding proteins Insulin-like growth factor binding protein proteases Growth hormone/IGF actions on the intact skeleton GH-IGF-I systemic effects on body size and longitudinal growth Growth hormone and IGF-I effects on modeling and remodeling Insulin-like growth factors, other transcription factors, and osteoblasts Insulin-like growth factors and osteoclasts Insulin-like growth factors and osteocytes Energy utilization by skeletal cells and the role of IGF-I Pathogenic role of GH/IGF/IGFBPs in osteoporosis Effects of growth hormone deficiency on bone metabolism Effects of growth hormone excess on bone mass and bone turnover Changes in the GH-IGF-I axis in patients with osteoporosis GH and IGF-I as treatments for skeletal disorders Growth hormone treatment for skeletal disorders Growth hormone treatment for children with insufficient GH secretion Growth hormone administration for healthy adults Growth hormone treatment for adult-onset GH deficiency Growth hormone administration to elderly men and women Growth hormone treatment for osteoporotic patients Insulin-like growth factor I for the treatment of osteoporosis Overview Murine studies Human studies of insulin-like growth factor I and bone mineral density Limitations to the clinical use of recombinant human insulin-like growth factor I Summary Acknowledgments References Further reading VOLUME 2 43. The periodontium Introduction Periodontal stem/progenitor cells Other candidate periodontal stem/progenitor cells Hedgehog signaling in bone and periodontium Parathyroid hormone/parathyroid hormone-related protein role in long bones and periodontium Wnt signaling in the periodontium and the role of the sost gene Bmp2 gene function in the periodontium Key regulators of mineral metabolism and the periodontium Periodontal stem/progenitor regeneration and methods to control inflammation in periodontal disease Role and mechanism of the junctional epithelium in periodontium function Conclusion References 44. Notch and its ligands Introduction Notch receptors Structure Function Regulatory mechanisms Notch cognate ligands Structure and function Regulatory mechanisms of notch ligands Mechanisms of Notch activation Generation of the Notch intracellular domain Formation of an active transcriptional complex Notch target genes Notch receptors and ligands in chondrocytes Role of Notch signaling in endochondral bone formation Mechanisms of notch action in endochondral bone formation Notch receptors and ligands in osteoblasts Role of notch signaling in osteoblasts Mechanisms of notch action in osteoblasts Notch receptors and ligands in osteocytes Role of Notch signaling in osteocytes Mechanisms of Notch action in osteocytes Notch receptors and ligands in osteoclasts Fracture repair and Notch signaling Congenital skeletal diseases caused by Notch loss of function Alagille syndrome Spondylocostal and spondylothoracic dysostosis Adams Oliver syndrome Congenital skeletal diseases caused by Notch gain of function Hajdu Cheney syndrome Lateral meningocele syndrome Brachydactyly Notch and skeletal malignancies Osteosarcoma Multiple myeloma Metastatic carcinoma of the breast and prostate Conclusions Abbreviations References 45. Fibroblast growth factor (FGF) and FGF receptor families in bone Fibroblast growth factor production and regulation in bone Fibroblast growth factor receptor expression in bone Fibroblast growth factor and FGF receptor signaling Fibroblast growth factor and FGF receptor signaling in chondrogenesis Initiation of chondrogenesis Regulation of fibroblast growth factor receptor 3 expression Fibroblast growth factor receptor 3 signaling in growth plate chondrocytes Fibroblast growth factor receptor 1 signaling in hypertrophic chondrocytes Fibroblast growth factor receptors and chondrodysplasia syndromes Mutations in fibroblast growth factor receptor 3 and fibroblast growth factor 9 Skeletal overgrowth and CATSHL syndrome Fibroblast growth factor and FGF receptor signaling in bone formation and repair Fibroblast growth factor and FGF receptor signaling in osteoblasts Fibroblast growth factor regulation of bone formation Fibroblast growth factor and FGF receptor signaling in bone repair Fibroblast growth factor and FGF receptor signaling in bone resorption Fibroblast growth factor receptors and craniosynostosis Skeletal phenotype Fibroblast growth factor receptor signaling in craniosynostosis Potential therapeutic approaches Conclusion Acknowledgments References Further reading 46. Vascular endothelial growth factor and bone-vascular interactions Introduction Bone development and the skeletal vascular system Vascular endothelial growth factor, a crucial angiogenic factor Vascular endothelial growth factor and endochondral ossification Vascular endothelial growth factor during intramembranous bone formation Nonendothelial effects of vascular endothelial growth factor Vascular endothelial growth factor homologues Regulation of vascular endothelial growth factor expression by oxygen levels Therapeutic potential of vascular endothelial growth factor for bone repair Acknowledgments References 47. Transforming growth factor-β and skeletal homeostasis1 Transforming growth factor-βs as the molecular sensor in the extracellular matrix Latent transforming growth factor-βs in the extracellular matrix Activation of transforming growth factor-βs Proteolytic activation Activation by thrombospondin-1 Activation by integrins Activation by osteoclasts Activation by reactive oxygen species Transforming growth factor-β signaling Canonical signaling pathways (smad-mediated signaling) Smad-independent signaling pathways Transforming growth factor-β signaling and cell reprogramming Transforming growth factor-β signaling in mesenchymal stem cells Transforming growth factor-β signaling and bone remodeling Transforming growth factor-β as the coupler of bone resorption and formation Parathyroid hormone as an endocrine regulator of skeletal transforming growth factor-β signaling Musculoskeletal pathologies associated with aberrant transforming growth factor-β signaling Osteoarthritis associated with aberrant activation of transforming growth factor-β signaling in the subchondral bone Musculoskeletal disorders associated with genetic mutations in transforming growth factor-β signaling components Skeletal metastases of cancer associated with bone matrix-derived transforming growth factor-β Transforming growth factor-β modulation as a promising approach to the management of osteoarthritis Summary References 48. Bone morphogenetic proteins Introduction Canonical bone morphogenetic protein signaling Diversity of the ligand and receptor environment Multiple receptors on bone cells Combinatorial signals Antagonizing bone morphogenetic protein signaling Pathway cross talk in bone Therapeutics and bone diseases Fracture repair and periosteum Osteoporosis Osteoarthritis and articular cartilage maintenance Conclusions References 49. Extraskeletal effects of RANK ligand The role of RANKL in mammary gland development and tumorigenesis RANKL in the lactating mammary gland RANKL in breast cancer development and metastasis The role of RANKL in other malignancies Functions of RANKL in immune and thermal regulation Immune system development and thermoregulation Inflammation, autoimmunity, and antitumor effects References 50. Local regulators of bone: Interleukin-1, tumor necrosis factor, interferons, the IL-6 family, and additional cytokines Introduction Interleukin-1 Tumor necrosis factor Additional tumor necrosis factor superfamily members Fas-ligand Tumor necrosis factor-related apoptosis-inducing ligand Cluster of differentiation 40 ligand Interferons Interleukin-7 Interleukin-10 Interleukin-12 Interleukin-15 Interleukin-17 Interleukin-23 Interleukin-18 and interleukin-33 Interleukin-4, interleukin-13, and interleukin-32 Macrophage migration inhibitory factor The interleukin-6 cytokine family Interleukin-6 Interleukin-11 Oncostatin M Other leukemia inhibitory factor receptor-binding cytokines Leukemia inhibitory factor Cardiotrophin 1 Cytokines that complex with ciliary neurotrophic factor receptor Ciliary neurotrophic factor Cardiotrophin-like cytokine factor 1 and cytokine receptor-like factor 1 Neuropoietin IL-27Rα-binding cytokines Effects of global, cell-specific, and pathway-specific gp130 modulation Insights from mice and a patient with gp130 signaling mutations Contributions of gp130 in the osteoblast lineage to bone structure and parathyroid hormone anabolic action Contribution of gp130 in osteoclasts to bone physiology The contributions of intracellular negative feedback through suppressor-of-cytokine-signaling proteins References 51. Prostaglandins and bone metabolism Introduction Prostaglandin production Eicosanoids Mobilization of arachidonic acid Two isoforms for prostaglandin G/H synthase (cyclooxygenase) Prostaglandin E2 synthases Prostaglandin E2 receptors Prostaglandin E2: role in bone formation and resorption Production in bone and osteoblastic cultures Prostaglandin E2 and bone formation Prostaglandin E2 receptors and bone formation Prostaglandin E2 and bone resorption Prostaglandin E2 receptors and bone resorption Inducible cyclooxygenase knockout mice Basal skeletal phenotype Inducible cyclooxygenase modulation of the effects of parathyroid hormone Inducible cyclooxygenase knockout mice and parathyroid hormone An inducible cyclooxygenase-dependent inhibitor of the anabolic effects of continuous parathyroid hormone Prostaglandin E2 and bone physiology Mechanical loading of bone Fracture and wound healing Skeletal response to nonsteroidal antiinflammatory drugs Summary Acknowledgments References Part II: Molecular mechanisms of metabolic bone disease 52. The molecular actions of parathyroid hormone/parathyroid hormone-related protein receptor type 1 and their implications Introduction Parathyroid hormone/parathyroid hormone-related protein receptor type 1 and its ligands Gαs/adenylyl cyclase/protein kinase A signaling Gq/11/phospholipase C/protein kinase C signaling Coupling to other G-proteins Gα12/13-phospholipase-transforming protein RhoA pathway Gαi/o pathway Extracellular signal-related 1/2-mitogen-activated protein kinase pathway Sodium/hydrogen exchanger regulatory factors Parathyroid hormone actions in kidney Control of 1,25-(OH)2-vitamin D synthesis by CYP27B1 expression Parathyroid hormone-mediated control of proximal tubule phosphate handling Parathyroid hormone-mediated control of distal tubule calcium reabsorption Skeletal parathyroid hormone actions: Focusing on osteocytes Signaling mechanisms controlling parathyroid hormone-induced nuclear factor kappa-B ligand expression Sclerostin: a parathyroid hormone-suppressed osteocyte-derived osteoblast inhibitor Additional parathyroid hormone/parathyroid hormone-related protein receptor type 1 actions in osteocytes Summary References 53. Multiple endocrine neoplasia type 1 Introduction Primary hyperparathyroidism Gastroenteropancreatic neuroendocrine tumors Gastrinoma Insulinoma Glucagonoma VIPoma Somatostatinoma Nonfunctioning neuroendocrine tumors of the gastroenteropancreatic tract Anterior pituitary tumors Thymic and bronchial neuroendocrine tumors Genetics and molecular biology of multiple endocrine neoplasia type 1 References 54. Parathyroid hormone-related peptide and other mediators of skeletal manifestations of malignancy Introduction Characterization of hypercalcemia in malignancy Molecular and cellular biology of PTH-related protein Purification and cloning of PTH-related protein Characteristics of the gene encoding PTH-related protein Eutopic PTH-related protein overproduction in malignancy Transcriptional and posttranscriptional regulation Transcriptional regulators of PTH-related protein Viral proteins Growth factors and hormone regulation of PTH-related protein production Processing and degradation of PTH-related protein Mechanisms of action of PTH-related protein Interaction of amino-terminal PTH-related protein with cell surface receptors Functions of carboxyl and midregion circulating fragments of PTH-related protein Intracellular mechanism of PTH-related protein action PTH-related protein actions to produce the manifestations of humoral hypercalcemia of malignancy Actions in kidney Actions in bone Effect of PTH-related protein on tumor progression and survival Detection of PTH-related protein produced by tumors Circulating levels of PTH-related protein PTH-related protein in tumor tissue Relationship of PTH-related protein-producing tumors with the bone microenvironment Resistance to antiresorptive agents in malignancy-associated hypercalcemia caused by PTH-related protein Experimental approaches to controlling overproduction or overactivity of PTH-related protein in malignancy-associated hyper ... Treatment of local osteolysis Hypercalcemia caused by other systemic and local factors produced by neoplastic cells Cytokines and humoral hypercalcemia of malignancy Cytokines and local osteolysis 1,25-Dihydroxyvitamin D (1,25(OH)2D) and humoral hypercalcemia of malignancy Parathyroid hormone and humoral hypercalcemia of malignancy References Further Reading 55. Localized osteolysis Introduction Osteotropism Adhesion and invasion into bone metastatic niches Tumor dormancy and awakening Cancer-induced bone disease Breast cancer Prostate cancer Other skeletal malignancies Contribution of the bone microenvironment to bone lesion progression Myeloid cells Macrophages T cells Osteoblasts Osteocytes Bone marrow fibroblasts Adipocytes Sympathetic and parasympathetic nerve system signaling Physical microenvironment Hypoxia and alteration of cancer cell metabolism Conclusion References 56. Genetic regulation of parathyroid gland development Complex syndromes associated with hypoparathyroidism DiGeorge syndrome Clinical features and genetic abnormalities Mouse models developing features of DiGeorge syndrome reveal roles of Hox and Pax genes in parathyroid and thymus development Hypoparathyroidism, deafness, and renal anomalies syndrome Clinical features and role of GATA3 mutations Phenotype of the GATA3 knockout mouse model Role of GATA3 in developmental pathogenesis Kenny-Caffey and Sanjad-Sakati syndromes Additional familial syndromes Mitochondrial disorders associated with hypoparathyroidism Pluriglandular autoimmune hypoparathyroidism Isolated hypoparathyroidism Parathyroid hormone gene abnormalities Parathyroid hormone gene structure and function Autosomal dominant hypoparathyroidism Autosomal recessive hypoparathyroidism Glial cells missing homolog 2 gene abnormalities X-linked recessive hypoparathyroidism Autosomal dominant hypocalcemia Calcium-sensing receptor and Gα11 Autosomal dominant hypocalcemia type 1 Autosomal dominant hypocalcemia type 2 Mouse models for autosomal dominant hypocalcemia types 1 and 2 Conclusions Acknowledgments References 57. Genetic disorders caused by mutations in the parathyroid hormone/parathyroid hormone-related peptide receptor, its ligands, ... Introduction The parathyroid hormone/parathyroid hormone-related peptide receptor system Parathyroid hormone Parathyroid hormone-related peptide The parathyroid hormone/parathyroid hormone-related peptide receptor and its role in endochondral bone formation Human disorders caused by mutations in the parathyroid hormone/parathyroid hormone-related peptide signaling pathway Parathyroid hormone, glial cells missing 2, and GNA11 mutations Parathyroid hormone-like peptide mutations Parathyroid hormone/parathyroid hormone-related peptide receptor mutations Jansen's metaphyseal chondrodysplasia Jansen's disease is caused by activating parathyroid hormone/parathyroid hormone-related peptide receptor mutations Blomstrand's lethal chondrodysplasia Blomstrand's disease is caused by inactivating parathyroid hormone/parathyroid hormone-related peptide receptor mutations Eiken familial skeletal dysplasia Enchondromatosis (Ollier's disease) Delayed tooth eruption due to parathyroid hormone/parathyroid hormone-related peptide receptor mutations Mutations in genes downstream of the parathyroid hormone/parathyroid hormone-related peptide receptor GNAS mutations Protein kinase type 1A regulatory subunit protein mutations Phosphodiesterase 4D mutations Phosphodiesterase 3A mutations Histone deacetylase 4-mutations Conclusions References 58. Molecular basis of parathyroid hormone overexpression Introduction Molecular oncology Clonality of parathyroid tumors Genetic derangements in benign parathyroid tumors Cyclin D1/PRAD1 Tumor-suppressor genes: multiple endocrine neoplasia type 1 and cyclin-dependent kinase inhibitors Candidate oncogenes and tumor-suppressor genes Further genetic aspects Calcium-sensing receptor and associated proteins Familial hypocalciuric hypercalcemia Hyperparathyroidism-jaw tumor syndrome Familial isolated hyperparathyroidism Molecular pathogenesis of parathyroid carcinoma Ectopic secretion of parathyroid hormone References 59. Diseases resulting from defects in the G protein Gsα Overview Gsα structure and function The Gsα Gene GNAS Albright hereditary osteodystrophy Clinical presentation Molecular genetics Diagnosis and management Pathogenesis Progressive osseous heteroplasia Clinical features Genetics Pathogenesis Pseudohypoparathyroidism type IB Clinical features Genetics Pathogenesis Fibrous dysplasia of bone and the McCune-Albright syndrome Clinical features Genetics Pathogenesis Diagnosis and management References 60. Renal osteodystrophy and chronic kidney disease-mineral bone disorder Introduction to chronic kidney disease Chronic kidney disease-mineral bone disorder CKD-MBD: biochemical abnormalities CKD-MBD: vascular calcification CKD-MBD: bone abnormalities Historical classification TMV classification system The spectrum of renal osteodystrophy in CKD Pathogenesis of abnormal bone Parathyroid hormone and decreased 1,25(OH)2D3 Abnormalities in the fibroblast growth factor-23-klotho pathway Disordered osteoblast function or differentiation Impaired Wnt signaling Transforming growth factor β family abnormalities Abnormalities of bone collagen Diagnostic tests for abnormal bone in CKD Bone density and the fracture risk assessment tool Bone quality imaging: TBS, QCT, HR-pQCT, and micro-MRI Calciotropic hormones and bone turnover markers Conclusion References 61. Osteogenesis imperfecta Introduction Clinical classification Severe-deforming osteogenesis imperfecta Mild nondeforming osteogenesis imperfecta Molecular classification Primary mutations within type I collagen genes A1 and A2 Mutation of genes that modify the synthesis of type I collagen chains Mutations that control the level of differentiation of osteoblasts Mutation of genes that regulate the maturation of secreted procollagen into collagen fibril Pathophysiology of osteogenesis imperfecta Osteogenesis imperfecta secondary to production of an abnormal collagen molecule Osteogenesis imperfecta due to underproduction of a normal type I collagen molecule Therapeutic options Antiresorptive agents Anti-TGFß and anti-activin agents Anabolic agents Cell and gene-therapy options Use of induced pluripotential stem cells as a diagnostic tool References Further reading 62. Hereditary deficiencies in vitamin D action Introduction Clinical features of rickets and osteomalacia Hereditary vitamin D-dependent rickets Hereditary vitamin D-dependent rickets type A Hereditary vitamin D-dependent rickets type B Hereditary vitamin D-dependent rickets type C Diagnosis and treatment Hereditary defects in the vitamin D receptor-effector system, or hereditary calcitriol-resistant rickets Introduction Clinical and biochemical features General features Ectodermal anomalies Vitamin D metabolism Mode of inheritance Cellular and molecular defects Methods Types of defects Defects in the hormone-binding region (including heterodimerization) Deficient hormone binding Deficient nuclear uptake Defects in the DNA-binding region In vitro posttranscriptional and transcriptional effects of 1,25(OH)2D3 Cellular defects and clinical features Diagnosis Treatment Animal models Concluding remarks References Further reading 63. Fibroblast growth factor 23 Identification of fibroblast growth factor 23 Actions of fibroblast growth factor 23 Regulation of fibroblast growth factor 23 level A receptor for fibroblast growth factor 23 Hypophosphatemic diseases caused by excessive actions of fibroblast growth factor 23 Autosomal dominant hypophosphatemic rickets X-linked hypophosphatemic rickets Autosomal recessive hypophosphatemic rickets Other hypophosphatemic diseases with known genetic causes Acquired fibroblast growth factor 23-related hypophosphatemic disease Treatment of fibroblast growth factor 23-related hypophosphatemic diseases Hyperphosphatemic diseases caused by impaired actions of fibroblast growth factor 23 (Table 63.1) Treatment of hyperphosphatemic familial tumoral calcinosis Fibroblast growth factor 23 and chronic kidney disease-mineral and bone disorder References 64. Tumor-induced osteomalacia Background Phosphaturic mesenchymal tumors Clinical presentation and diagnosis Tumor localization Treatment Surgical treatment Minimally invasive treatment Conventional medical treatment Future directions References 65. Osteopetrosis Introduction Clinical features Radiographic features Genetic features Current therapies Future therapeutic scenarios Conclusions Acknowledgments References 66. Hypophosphatasia: nature's window on alkaline phosphatase function in humans Introduction History and proposed physiological roles of alkaline phosphatase Genomic structure, protein chemistry, and enzymology of alkaline phosphatase Hypophosphatasia History Clinical features Perinatal hypophosphatasia Infantile hypophosphatasia Childhood hypophosphatasia Adult hypophosphatasia Odontohypophosphatasia Pseudohypophosphatasia Benign prenatal hypophosphatasia Laboratory diagnosis Biochemical findings Mineral homeostasis Phosphoethanolamine Pyridoxal 5′-phosphate Inorganic pyrophosphate Radiographic findings Histopathological findings Skeleton Dentition Biochemical and genetic defects Tissue-nonspecific alkaline phosphatase deficiency Inheritance ALPL gene defects ALPL structural defects Prognosis Treatment Supportive Medical Prenatal diagnosis Physiological role of alkaline phosphatase explored in hypophosphatasia Tissue-nonspecific alkaline phosphatase substrates Phosphoethanolamine Pyridoxal 5′-phosphate Inorganic pyrophosphate Circulating tissue-nonspecific alkaline phosphatase Hypophosphatasia fibroblast studies Alpl knockout animals Asfotase alfa treatment for hypophosphatasia Summary and conclusions Acknowledgments References 67. Paget's disease of bone The patient Radiology and nuclear medicine Histopathology Biochemistry Treatment of Paget's disease Evidence for the presence of paramyxoviruses in Paget's disease Cellular and molecular biology of Paget's disease Genetic mutations linked to Paget's disease The etiology of Paget's disease References Further reading 68. Genetic determinants of bone mass and osteoporotic fracture Introduction Genome-wide association studies Follow-up of genome-wide association studies Functional annotations Expression quantitative trait loci in human bone tissue and cells Cell/tissue types targeted by genome-wide association study loci for bone mineral density and osteoporotic fractures Informing genome-wide association studies using biological knowledge and networks Knockout animal models for functional analysis Genome-wide association studies for bone traits in mice Resources and the application of genome-wide association studies for skeletal traits in mice Inbred strains Hybrid mouse diversity panel Collaborative cross and diversity outbred Advantages of genome-wide association studies in mice Identifying less common and rare variants associated with bone-relevant phenotypes via next generation sequencing Future directions References Part III: Pharmacological mechanisms of therapeutics 69. Pharmacologic mechanisms of therapeutics: parathyroid hormone Introduction Physiology of parathyroid hormone Pharmacokinetic mechanism: effects of ligand exposure Molecular mechanisms: ligand selectivity for receptor conformational state Cellular mechanisms: Indirect effect on osteoclasts, and direct effects on osteoblast and osteocytes Use of osteoanabolic agents in osteoporosis Teriparatide Abaloparatide Use of parathyroid hormone in hypoparathyroidism Recombinant human PTH (1-84) References 70. Calcium Introduction Bone as the body's calcium sink and reserve Calcium in bone The calcium requirement What the requirement ensures The physiological adaptations to a low calcium intake Defining the calcium requirement Achieving the calcium requirement: dietary sources Nutritional factors influencing the calcium requirement Toxicity Calcium and osteoporosis treatment Calcium supplementation and bone health Calcium supplementation and cardiovascular risk Summary References Further Reading 71. Drugs acting on the calcium receptor: calcimimetics and calcilytics Introduction Primary hyperparathyroidism Other hypercalcemic disorders Secondary hyperparathyroidism Cinacalcet Calciotropic end points Skeletal end points Cardiovascular end points Evocalcet Etelcalcetide Calcilytics Osteoporosis Repurposing calcilytics for new indications Hypoparathyroidism Pulmonary indications Conclusion References 72. Clinical and translational pharmacology of bisphosphonates Introduction Mechanisms of action Therapeutic Side effects Mathematical pharmacodynamic (PD) models of BPs Pharmacokinetics (PK) Mathematical pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) models of BPs Applications of the clinical and translational pharmacology of BPs Conclusions References 73. Pharmacological mechanisms of therapeutics: receptor activator of nuclear factor-kappa B ligand inhibition History of osteoprotegerin/receptor activator of nuclear factor-kappa B ligand-based drug development Physiologic mechanisms and effects of receptor activator of nuclear factor-kappa B ligand inhibitors in bone Clinical studies demonstrating the effects of denosumab (Table 73.1) Osteoporosis indications Postmenopausal osteoporosis Male osteoporosis Use of denosumab in combination/sequence with other osteoporosis agents Cancer indications Denosumab for cancer treatment-induced bone loss Androgen deprivation in men with prostate cancer Aromatase inhibitors in women with breast cancer Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy Breast cancer Prostate cancer Other solid tumors Multiple myeloma Giant cell tumors Denosumab for the treatment of metastatic bone disease, multiple myeloma, and giant cell tumors Additional denosumab data Glucocorticoid-induced osteoporosis Rheumatoid arthritis Other potential applications Denosumab safety Hypocalcemia Osteonecrosis of the jaw Atypical femoral fractures Denosumab discontinuation: effects on bone turnover, bone mass, and fracture risk Hypersensitivity, serious infections, and musculoskeletal pain Use in women of reproductive age Theoretical impact of receptor activator of nuclear factor-kappa B ligand inhibition on insulin resistance and vascular cal ... Summary References 74. Pharmacologic basis of sclerostin inhibition Introduction Sclerostin biology and biochemistry Human monogenic high bone mass conditions related to sclerostin: sclerosteosis and van Buchem disease Expression of sclerostin protein Structure and functional domains of sclerostin Sclerostin mechanism of action in the skeleton Sclerostin interaction with LRP4/5/6 Sclerostin inhibition of the canonical Wnt signaling pathway Sclerostin effects on mesenchymal stem cells Genetic manipulation of sclerostin expression in mice: SOST knockout and overexpression Antibodies to neutralize sclerostin (Scl-Ab) Pharmacologic inhibition of sclerostin by Scl-Ab: cell-level effects Osteoblast lineage Osteoclast lineage Pharmacologic inhibition of sclerostin by Scl-Ab in vivo Effects of Scl-Ab in animal models of postmenopausal osteoporosis Action of Scl-Ab on modeling- and remodeling-based bone formation Effects of Scl-Ab on bone mass and structure Effects of Scl-Ab on bone strength and quality Probing Scl-Ab treatment regimens in preclinical models of osteoporosis Effects of Scl-Ab in other animal models of low bone mass Pharmacologic inhibition of sclerostin by Scl-Ab in humans Summary Abbreviations Acknowledgments References 75. Vitamin D and its analogs Introduction Pharmacologically important vitamin D compounds Vitamin D and its natural metabolites Vitamin D prodrugs Calcitriol analogs Miscellaneous vitamin D analogs and associated drugs Clinical applications of vitamin D compounds Secondary hyperparathyroidism Hyperproliferative conditions: psoriasis and cancer Criteria that influence pharmacological effects of vitamin D compounds Activating enzymes Vitamin D-binding protein Vitamin D receptor/retinoid X receptor/vitamin D response element interactions Target cell catabolic enzymes Hepatic clearance or nonspecific metabolism The potential role of gene targets and the unique features of their regulation as major determinants of analog action Proposed molecular mechanisms of action of vitamin D compounds Future prospects Acknowledgments References 76. Mechanisms of exercise effects on bone quantity and quality Introduction Bone's sensitivity to mechanical signals Bone's mechanical milieu elicited by physical activity Strains in bone Locomotion induces a nonuniform strain environment The influence of muscle on bone's strain environment Regulation of bone morphology by mechanical stimuli Toward identifying the osteogenic parameters of the strain milieu Strain magnitude Differential bone remodeling to distinct components of the strain tensor Strain rate Cycle number Strain distribution Strain gradient Fluid flow Low-magnitude, high-frequency mechanical signals Low-level mechanical signals increase bone quantity and strength Low-level mechanical signals normalize bone formation Vibrations can decrease resorptive activity Genetic variations modulate bone's response to mechanical signals Inhibition of postmenopausal bone loss by low-level vibrations Low-level mechanical signals mitigate bone loss due to cancer Low-level mechanical signals are anabolic to the musculoskeletal system How can bone sense a signal so small? Biochemical modulation of mechanical signals Which cells sense the stimulus? Bone marrow mesenchymal stem cells Osteoblasts Osteoclasts Osteocytes Bone marrow vasculature Mechanoreceptors in bone cells Integrins and integrin-associated proteins Connexins Channels Membrane structure Primary cilium Nuclear connectivity Mechanically activated intracellular signaling MAPK signaling Activation of Wnt/catenin signals Nitric oxide signaling Prostaglandins Summary Acknowledgments References Part IV: Methods in bone research 77. Application of genetically modified animals in bone research Introduction Large-scale phenotyping resources and repositories Overexpression approaches to assess gene function in skeletal tissues Tendon and ligament Chondrocytes Osteoblasts/osteocytes Osteoclasts Transgenic mouse reporters of signaling pathways Gene targeting Advantages and disadvantages of conventional gene deletion Conditional loss-of-function approaches Uncondensed mesenchyme and precartilage condensations Chondrocytes Osteoprogenitors/osteoblasts/osteocytes Osteoclasts Lineage tracing and overexpression tools of the Rosa26 locus Lineage tracing Overexpression using the Rosa26 locus Genomic engineering using CRISPR/Cas9 Conclusions Acknowledgments References 78. Bone turnover markers Introduction Established biochemical markers of bone metabolism Novel biological markers of bone metabolism Periostin Circulating periostin as a potential clinical biomarker Receptor activator of NF-kB ligand and osteoprotegerin Dickkopf-related protein 1 Sphingosine-1-phosphate Sclerostin Fibroblast growth factor 23 and klotho Proteomic signature Metabolomic signature MicroRNAs Variability of biochemical markers of bone turnover Reference ranges Clinical uses of bone markers in osteoporosis Diagnosis of osteoporosis and prognosis of bone loss Prediction of fracture risk Predicting and monitoring treatment efficacy Monitoring side effects of osteoporosis therapies Treatment holiday monitoring Diagnosis and monitoring of treatment in Paget's disease of bone Bone turnover markers for rare bone diseases Fibrous dysplasia Hypophosphatasia Fibrodysplasia ossificans progressiva (FOP) Osteogenesis imperfecta X-linked hypophosphatemia Bone turnover markers in metastatic bone disease Multiple myeloma Metastatic bone disease from solid tumors Bone turnover markers for the development of bone drugs Bisphosphonates Osteoporosis Metastatic bone disease Denosumab Cathepsin K inhibitors Overall antiresorptive treatment Anabolic agents Dual-action drugs such as romosozumab The challenge for new drugs with new mechanisms of action Bone turnover markers to assess skeletal safety of new drugs References 79. Microimaging Introduction In vitro microimaging Hierarchical imaging of bone microarchitecture Biomechanical imaging of bone competence Quantitative image processing Filtration and segmentation Quantitative morphometry Finite element analysis In vivo microimaging In vivo animal microimaging Radiation considerations Reproducibility Dynamic morphometry In vivo human microimaging Clinical computed tomography Peripheral quantitative computed tomography High-resolution peripheral quantitative computed tomography Radiation dose Normative data Fracture prediction Summary References 80. Macroimaging Introduction Radiography Standard DXA DXA technique Fracture prediction using areal bone mineral density Monitoring osteoporosis treatment with DXA Vertebral fracture assessment Computed tomography Standard quantitative computed tomography to assess bone mineral density Components of bone quality Cortical bone High-resolution computed tomography HR-pQCT Opportunistic screening DXA beyond bone mineral density Trabecular bone score Hip geometry, hip structure analysis, and finite element analysis Three-dimensional DXA Magnetic resonance imaging Trabecular structure Cortical water Bone marrow Quantitative muscle imaging Summary References 81. Methods in lineage tracing Introduction Cre recombinase Reporters Experimental design for lineage tracing Effects of tamoxifen on bone Tet expression systems Intersectional strategies to identify cells Lineage tracing during embryonic development Postnatal lineage tracing Osteoblast-to-chondrocyte transition Lineage tracing following injury Lineage tracing in heterotopic ossification Conclusions References 82. Bone histomorphometry in rodents Introduction Methodologies In vivo labeling Sample preparation Fixation Standard methylmethacrylate embedding Low temperature methylmethacrylate embedding Sectioning of plastic-embedded bone specimens Microtome sectioning Micromilled cross sections of cortical bone Cryoembedding and cryosectioning Staining Von Kossa/MacNeal's stain Toluidine blue stain Masson-Goldner stain Cement line stain Histochemical tartrate resistant acid phosphatase staining Staining of micromilled cross sections Cancellous bone histomorphometry Structural parameters Bone formation Bone mineralization Bone resorption Bone remodeling dynamics Cortical bone histomorphometry Histomorphometric measurement of longitudinal bone growth Microdamage measurement technique Histomorphometry of rodent models of bone healing Histomorphometry of bone loss rodent models Histomorphometry of pharmacological efficacy in rodents Conclusion References 83. Bone strength testing in rodents Introduction Whole-bone mechanical testing Specimen preparation Standard three-point and four-point bending to failure Torsion to failure Compression testing Whole-bone testing in preclinical drug development Fracture toughness testing Finite element analysis Microscale and nanoscale bone material assessment Cyclic reference point indentation Nanoindentation Summary and discussion References 84. Regulation of energy metabolism by bone-derived hormones Introduction Osteocalcin: a bone-derived hormone regulating glucose metabolism GPRC6A osteocalcin receptor in β cells Regulation of the endocrine function of osteocalcin by gamma-carboxylation Osteocalcin decarboxylation and activation during bone resorption Regulation of osteocalcin by the proprotein convertase furin A role for osteocalcin in adaptation to exercise Osteocalcin regulation of skeletal muscle energy metabolism during exercise Modulating adaptation to exercise through bone and skeletal muscle cross talk Bone as a regulator of appetite: the anorexigenic function of osteoblast-derived lipocalin-2 Are there additional osteocalcin- or lipocalin-2-independent endocrine functions of bone? Concluding remarks Acknowledgments References Index for Volumes 1 and 2 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 Back Cover
