Interactions of the Immune and Skeletal Systems

2nd Edition - September 23, 2015

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  • Editors: Joseph Lorenzo, Mark Horowitz, Yongwon Choi, Hiroshi Takayanagi, Georg Schett
  • eBook ISBN: 9780128006276
  • Hardcover ISBN: 9780128005712

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Osteoimmunology: Interactions of the Immune and Skeletal Systems, Second Edition, explores the advancements that have been made in the field during the last 40 years, including valuable information on our understanding of the interactions between hematopoietic, immune, and bone cells, now known as the field of osteoimmunology. This comprehensive work offers the most extensive summaries of research trends in the field and their translation into new therapeutics. Early chapters deal with the development of osteoblasts, osteoclasts, hematopoietic stem cells, T and B-lymphocytes, and communications between these cellular elements, while later sections contain discussions of the signaling pathways by which RANKL influences osteoclast development and function. Subsequent chapters explore the effects that estrogen has on bone and the immune system, the development of pathologic conditions, and the growing research around osteoporosis, Paget’s disease, the genetics of bone disease, and bone cancer metastasis.

Key Features

  • Explains the intricate interaction between the immune system and bone
  • Features detailed discussions of the key cellular and molecular mechanisms governing the homeostasis of the individual systems
  • Facilitates greater understanding of osteoimmunologic networks, their environments, and how this understanding leads to better treatments for human diseases involving both systems


Academic, medical, and pharmaceutical researchers in bone biology, immunology, rheumatology, endocrinology, hematology, and periodontia

Table of Contents

    • List of Contributors
    • Foreword
    • Preface
    • Chapter 1: Overview: The Developing Field of Osteoimmunology
      • Abstract
    • Chapter 2: The Origins of the Osteoclast
      • Abstract
      • First descriptions of the osteoclast
      • Early controversies: are osteoclasts capable of bone resorption?
      • Early controversies: hematopoietic or mesenchymal origin of the osteoclast?
      • Osteoclast: a hematopoietic cell
      • Osteoclasts: cells of the myeloid lineage
      • Advancing the field: culturing osteoclasts in vitro
      • Identification of RANKL and OPG
      • Defining osteoclast precursors within myeloid cell development
      • Heterogeneity among osteoclasts
      • Origins of the osteoclast through the lens of evolution
      • Conclusions
      • Acknowledgments
    • Chapter 3: Trafficking of Osteoclast Precursors
      • Abstract
      • Introduction
      • A century-long search for the identity of osteoclast precursors
      • Intravital two-photon imaging of bone tissues
      • Osteoclast precursors are motile and circulate throughout the body
      • Guidance cues sensed by osteoclast precursors in bone marrow
      • S1P-dependent migratory control of osteoclast precursors
      • Differences between osteoclast precursor and mature osteoclast migration mechanisms
      • Control of osteoclast migration and function by Rho GTPases
      • Role of integrins in osteoclast precursor migration
      • Control of osteoclast precursor differentiation by GPCR-mediated inhibition of cell migration
      • Unanswered questions in osteoclast precursor trafficking and differentiation
    • Chapter 4: Osteoclast Biology: Regulation of Formation and Function
      • Abstract
      • Introduction
      • RANKL and RANK: an osteoclastogenic cytokine and its receptor
      • TRAF6: the multifunctional signaling molecule activated by RANK
      • What happens downstream of TRAF6?
      • The role of NF-κB in osteoclast differentiation
      • The critical role of AP-1 transcription factors
      • MAPKs activated by RANKL
      • NFATc1 is a master transcription factor of osteoclast differentiation
      • Autoamplification of NFATc1 and its epigenetic regulation
      • Inhibition of NFATc1 induction
      • Transcriptional control governed by NFATc1
      • Costimulatory receptor signals for RANK: FcRγ and DAP12
      • The ligands for the costimulatory receptors
      • Importance of ITAM costimulatory signals in humans: Nasu-Hakola disease
      • Additional costimulatory signals involved in osteoclastogenesis
      • Receptors signaling through DAP12
      • The inhibitory signals for costimulatory signals
      • Src family kinases: activation of ITAM signaling
      • Syk kinase: downstream of DAP12/FcRγ?
      • PLCγ2: enzyme and adaptor molecule
      • Tec kinases: integrating RANK and ITAM signaling
      • Negative regulatory role of DAP12
      • M-CSF and c-Fms: a road to proliferation and survival
      • M-CSF signaling
      • Erk, PI3K, and c-Fos signaling
      • The osteoclast’s job: bone resorption
      • Osteoclast cytoskeleton: the podosomes and the sealing zone
      • Osteoclast cytoskeleton: the microtubules and the sealing zone
      • Osteoclast functional structure: the ruffled border
      • Osteoclast and bone matrix: role of αvβ3 integrin
      • Integrin-associated proteins
      • M-CSF and the osteoclast cytoskeleton
      • Coupling factors released in osteoclastic bone resorption
      • Stimulation of bone formation by clastokines
      • Inhibition of bone formation by clastokines
      • Coupling by cell–cell interaction between osteoclasts and osteoblasts
      • Conclusions
    • Chapter 5: Osteoimmunology and the Osteoblast
      • Abstract
      • Advantages of immune-osteoblast interaction
      • Immune-osteoblast interaction in fracture repair
      • Dual role for TNF-α
      • TNF is an inhibitor of Wnt signaling
      • Coupling of skeletal homeostasis with innate and acquired immunity
      • Osteoblast support of hematopoiesis
      • Osteoblast support of B cell differentiation
      • Osteoblasts support hematopoietic stem cells
      • Conclusions
    • Chapter 6: The Variety of Osteocyte Function
      • Abstract
      • Introduction
      • The osteocyte network
      • New tools to study osteocyte function
      • Osteocytes and bone remodeling
      • Osteocytes and mineral homeostasis
      • Osteocytes as mechanosensors
      • Osteocytes and hematopoiesis
      • Conclusions
    • Chapter 7: Bone Marrow Hematopoietic Niches
      • Abstract
      • Introduction
      • Hematopoiesis occurs within the bone marrow and is closely linked to skeletal development
      • A role for the osteoblast lineage in supporting hematopoietic stem cells
      • A perivascular niche for HSCs involves mesenchymal progenitors
      • Signaling pathways implicated in microenvironment-HSC communication
      • Perivascular osteoblast precursors support hematopoiesis
      • Other components of the hematopoietic niche
      • Clinical implications
      • The bone marrow HSC microenvironment is complex
    • Chapter 8: RANK and RANKL of Bones, T Cells, and the Mammary Glands
      • Abstract
      • RANK and RANKL in bone
      • Downstream signaling of RANK/RANKL
      • Rank/Rankl mutations in human patients
      • Osteoimmunology
      • RANK and RANKL in the organogenesis of the immune system
      • Immunotolerance
      • RANK/RANKL and metastases
      • RANK/RANKL and the mammary gland
      • RANK and RANKL and their function in mammary stem cell biology
      • Breast cancer
      • Is there even more?
      • Denosumab, a rational treatment for bone loss
      • Conclusions
    • Chapter 9: The Effects of Immune Cell Products (Cytokines and Hematopoietic Cell Growth Factors) on Bone Cells
      • Abstract
      • Receptor activator of nuclear factor-κB ligand (RANKL), receptor activator of nuclear factor-κB (RANK) and osteoprotegerin (OPG)
      • Colony-stimulating factor-1
      • Additional colony stimulating factors
      • Interleukin-1
      • Tumor necrosis factor
      • Additional TNF superfamily members
      • Interleukin-6
      • Additional interleukin-6 family members
      • Interleukin-7
      • Interleukin-8 and other chemokines
      • Interleukin-10
      • Interleukin 12
      • Interleukin 15
      • Interleukin 17, Interleukin 23, and Interleukin 27
      • Interleukin 18 and interleukin 33
      • Interferons
      • Additional cytokine
      • Conclusions
    • Chapter 10: Coupling: The Influences of Immune and Bone Cells
      • Abstract
      • Introduction: bone remodeling and the concept of coupling
      • Modeling and remodeling in anabolic therapy for the skeleton
      • Osteoclast-derived factors that promote osteoblast differentiation
      • What is the target cell of osteoclast-derived factors that may promote bone formation?
      • How do osteocytes contribute to coupling?
      • Promotion of bone formation in the BMU during the reversal phase
      • The influences of T and B lymphocytes on the coupling process
      • Signals between the bone surface and the vasculature
      • Isolation of the remodeling site by the bone remodeling canopy
      • Conclusions
    • Chapter 11: The Role of the Immune System in the Development of Osteoporosis and Fracture Risk
      • Abstract
      • Introduction
      • Connections between bone and the immune system
      • Bone remodeling
      • Periarticular bone structure and bone loss in inflammatory arthritis
      • Bone involvement in rheumatic diseases
      • From fracture risk evaluation to fracture prevention: a 5-step plan
      • Differential diagnosis
      • Fracture prevention in inflammatory joint diseases
      • Follow up
      • Conclusions
      • Key messages
    • Chapter 12: The Role of Sex Steroids in the Effects of Immune System on Bone
      • Abstract
      • Introduction
      • Estrogen and other sex steroids
      • Interactions of sex steroids and immune cells
      • Effects of sex steroid-modulated immune cells on bone cells
      • Conclusions
    • Chapter 13: The Role of the Immune System in the Local and Systemic Bone Loss of Inflammatory Arthritis
      • Abstract
      • Introduction
      • Bone disease associated with RA
      • Bone changes in spondyloarthritis and psoriatic arthritis
      • Conclusions
      • Acknowledgments
    • Chapter 14: Osteoarthritis and the Immune System
      • Abstract
      • Introduction
      • Physiological structural organization of periarticular bone
      • Periarticular bone changes in osteoarthritis
      • Regulatory mechanisms involved in OA bone pathology
      • Bone marrow lesions and targeted bone remodeling
      • Calcified cartilage, bone, and articular cartilage interactions in OA
      • Osteophytes
      • The role of synovium in OA cartilage and bone pathology
      • Conclusions
    • Chapter 15: Inflammatory Bowel Disease and Bone
      • Abstract
      • Introduction
      • Pathophysiology of IBD and osteo-immune connections
      • IBD and osteoimmunology
      • Conclusions
    • Chapter 16: The Role of the Immune System and Bone Cells in Acute and Chronic Osteomyelitis
      • Abstract
      • Introduction
      • Mechanism of microbial infection in the pathogenesis in osteomyelitis
      • Bacterial persistence in chronic osteomyelitis
      • The host response to osteomyelitis
      • Osteoblasts and their multiple roles in bone infections
      • Cellular responses to acute and chronic osteomyelitis
      • Osteoclast mobilization
      • Osteoclasts as immune cells
      • DCs and osteoclasts in infection
      • The role of B-cells in bone infection and the potential of passive immunization
    • Chapter 17: The Role of the Immune System in Fracture Healing
      • Abstract
      • Bone repair as a postnatal regenerative process
      • Fracture healing cascade
      • Role of mesenchymal stem cells in the modulation of immune function
      • Cytokines involved in fracture healing
      • RANK, RANKL, and OPG
      • Phase-specific roles of cytokines in fracture healing
      • Role of nonsteroidal anti-inflammatory drugs in fracture healing
      • Biological effects of COX-2 inhibition
      • Clinical effects of COX inhibitors on fracture healing
    • Chapter 18: The Role of the Immune System in the Effects of Cancer on Bone
      • Abstract
      • Introduction
      • The vicious cycle of bone metastasis
      • Bone as the preferred site for metastasis
      • Role of mesenchymal stromal cells in bone metastasis
      • T lymphocytes and bone metastasis
      • T regulatory cells
      • Role of macrophages and macrophage-derived cells in bone metastasis
      • Tumor associated macrophages
      • Myeloid derived suppressor cells (MDSC)
      • Dendritic cells (DC)
      • B Cells
      • Conclusions
    • Chapter 19: Osteoimmunology in the Oral Cavity (Periodontal Disease, Lesions of Endodontic Origin, and Orthodontic Tooth Movement)
      • Abstract
      • Introduction
      • Periodontal diseases
      • Lesions of endodontic origin
      • Orthodontic tooth movement
      • Conclusions
      • Acknowledgment
    • Chapter 20: Marrow Adipose Tissue and its Interactions with the Skeletal, Hematopoietic, and Immune Systems
      • Abstract
      • Introduction
      • Adipose development and expansion
      • Measurement of marrow adipose tissue
      • The cellular origin of bone marrow adipocytes
      • Molecular regulation of BM adipogenesis
      • Cellular interactions between adipocytes, bone, hematopoietic and immune cells
      • Conclusions
      • Acknowledgments
    • Subject Index

Product details

  • No. of pages: 376
  • Language: English
  • Copyright: © Academic Press 2015
  • Published: September 23, 2015
  • Imprint: Academic Press
  • eBook ISBN: 9780128006276
  • Hardcover ISBN: 9780128005712

About the Editors

Joseph Lorenzo

Dr. Lorenzo is Professor of medicine in the Division of Endocrinology and Metabolism and Director of Bone Biology Research at the University of Connecticut Health Center. He is a nationally renowned expert on bone remodeling and its effect on bone health.

Affiliations and Expertise

Professor of medicine in the Division of Endocrinology and Metabolism and Director of Bone Biology Research at the University of Connecticut Health Center

Mark Horowitz

Dr. Horowitz is Professor of Orthopaedics and Rehabilitation at the Yale University School of Medicine. His research interests include the interactions between the skeletal, immune, and hematopoietic systems as they relate to normal and pathologic bone remodeling.

Affiliations and Expertise

Professor of Orthopaedics and Rehabilitation at the Yale University School of Medicine.

Yongwon Choi

Dr. Choi is Professor of Pathology and Laboratory Medicine, University of Pennsylvania; Investigator, The Leonard and Marilyn Abramson Family Cancer Research Institute, Philadelphia, PA.

Affiliations and Expertise

Professor of Pathology and Laboratory Medicine, University of Pennsylvania; Investigator, The Leonard and Marilyn Abramson Family Cancer Research Institute, Philadelphia, PA.

Hiroshi Takayanagi

Dr. Takayanagi is Professor in the Department of Cell Signaling, Tokyo Medical and Dental University. His group studies the mechanism of bone destruction in rheumatoid arthritis, which focuses on the regulation of osteoclasts by T cells. This interdisciplinary field, osteoimmunology, covers various research on shared mechanisms and interactions between immune and bone systems.

Affiliations and Expertise

Professor in the Department of Cell Signaling, Tokyo Medical and Dental University

Georg Schett

Affiliations and Expertise

University of Erlangen-Nuremberg, Germany

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