Osteoimmunology: Interactions of the Immune and Skeletal Systems
470
Osteoimmunology: Interactions of the Immune and Skeletal Systems
470eBook
Related collections and offers
Overview
Product Details
| ISBN-13: | 9780123756718 |
|---|---|
| Publisher: | Elsevier Science |
| Publication date: | 09/24/2010 |
| Sold by: | Barnes & Noble |
| Format: | eBook |
| Pages: | 470 |
| File size: | 6 MB |
About the Author
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.
Dr. Choi is Professor of Pathology and Laboratory Medicine, University of Pennsylvania; Investigator, The Leonard and Marilyn Abramson Family Cancer Research Institute, Philadelphia, PA.
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.
Read an Excerpt
Osteoimmunology: Interactions of the Immune and Skeletal Systems
Academic Press
Copyright © 2011 Elsevier Inc.All right reserved.
ISBN: 978-0-12-375671-8
Chapter One
Overview: The Developing Field of OsteoimmunologyJoseph Lorenzo, Yongwon Choi, Mark Horowitz, Hiroshi Takayanagi
It has been almost 40 years since the first observations that cells of the immune system could influence the functions of bone cells. Since that time, significant strides have been made in our understanding of the interactions between hematopoietic, immune, and bone cells, which is now known as the field of "osteoimmunology". In this introductory chapter, we will briefly establish some of the key features of osteoimmunology, which are described in greater detail in the subsequent chapters of this book.
Bone cells derive from two lineages. Osteoclasts, which are responsible for bone resorption, are large, multinucleated cells that are uniquely capable of removing both the organic and mineral components of bone. Osteoclasts share a common origin with cells of the myeloid dendritic cell and macrophage lineages and, as such, respond to and produce many of the cytokines that regulate macrophage and dendritic cell function. The discovery of a tumor necrosis factor (TNF) family member, receptor activator of NF-κB ligand (RANKL), on activated T cells and its subsequent identification as one of the key differentiation and survival factors for osteoclasts, provided critical evidence for a potential link between normal immune responses and bone metabolism.
Bone is formed by osteoblasts, which originate from mesenchymal stem cells (MSC). Osteoblast-lineage cells carry out at least three major functions: (1) they secrete bone matrix, which mineralizes over time to form new bone; (2) they regulate osteoclast differentiation; (3) they support hematopoietic cell growth and differentiation. It is now well accepted that MSC can differentiate into a variety of lineages including osteoblasts, adipocytes, muscle cells, and hematopoiesis-supporting stromal cells. Osteoblastlineage cells, which are sometimes referred to as stromal cells, produce avariety of cytokines that are critical for hematopoietic cell differentiation.
The first observation that immune cells could influence the activity of bone cells came from the finding that supernatants from phytohemagglutinin-stimulated peripheral blood monocytes of normal humans contained factors that stimulated bone resorption [2]. This activity was named osteoclast-activating factor (OAF). When it was eventually purified and sequenced, the principal stimulator of bone resorption in these crude OAF preparations was identified as the cytokine interleukin-1 (IL-1). In addition to its ability to stimulate osteoclast formation and resorbing activity, IL-1 is a mediator of a variety of inflammatory responses and a potent stimulus of prostaglandin synthesis, which independently increases bone resorption. It also is an inhibitor of osteoblast activity and bone formation.
Subsequent to the identification of IL-1 as a bone resorption stimulus, tumor necrosis factor (TNF) and interleukin-6 (IL-6) were also found to have this activity. Like IL-1, these cytokines are critical mediators of inflammatory responses. It has now been demonstrated that a long list of cytokines can have both positive and negative effects on bone mass and bone cell activity.
Production of cytokines by immune cells has been linked to human diseases that involve bone. Perhaps the most extensive studies have been of the role of cytokines in the development of the bone loss and lytic lesions that occur in inflammatory arthritis, inflammatory bowel disease, and periodontal disease. Here, production of RANKL from a variety of cell types mediates osteolysis by stimulating osteoclastic activity. In addition, production of proinflammatory cytokines such as IL-1, TNF, and IL-6 enhances the response of osteoclasts to RANKL.
Estrogen withdrawal after menopause is also associated with a rapid and sustained increase in the rate of bone loss. This phenomenon seems to result from an increase in bone resorption, which is not met by an equivalent increase in bone formation. It was initially demonstrated that conditioned medium from cultured peripheral blood monocytes from osteoporotic women with rapid bone turnover contained more IL-1 activity than did conditioned medium from the cells of women with slow bone turnover or normal controls. In rodents, treatment with inhibitors of IL-1 and TNF prevented the bone loss that occurred with ovariectomy. In addition, ovariectomy was not associated with bone loss in mice that were genetically prevented from responding to IL-1 and TNF or unable to produce IL-6. These findings strongly link the bone loss of estrogen withdrawal to effects of estrogen on the production or activity of proinflammatory cytokines. Most recently it was shown that inhibitors of IL-1 and TNF reduced the rate of bone resorption in postmenopausal women.
The role of cytokines in the bone disease that occurs with malignancy has also been studied extensively. In hematological malignancies such as lymphomas or multiple myeloma, which are associated with increased osteoclast formation and activity, a variety of cytokines have been implicated as mediating the bone loss that can occur in these conditions. Unlike the bone disease of solid tumors, which is typically mediated by parathyroid-hormone-related protein (PTHrP), hematological malignancies are often characterized by an uncoupling of resorption from formation and the development of purely lytic bone lesions.
The immune system is also involved in normal fracture healing and the response of bone to infections (osteomyelitis). Understanding the interactions of bone and immune cells during these events is best accomplished by an osteoimmunologic approach, which integrates an appreciation of the crosstalk between these two organ systems.
The question of whether the immune system influences normal skeletal development and function is not well answered. Ontogenically, skeletal development precedes early immune system development. Therefore, it is unlikely that the immune system influences early skeletal formation. However, bone homeostasis and remodeling occur throughout life. Anatomically, bone marrow spaces are loosely compartmentalized, which allows immune and bone cells to interact and influence each other. Hence, bone homeostasis is often regulated by immune responses, particularly when the immune system has been activated or becomes pathologic.
It is not difficult to imagine that crosstalk occurs throughout life between activated lymphocytes and bone cells because all mammals are constantly challenged by a variety of infectious agents, which produce some level of sustained low-grade immune system activation. Furthermore, as we age, there is an accumulation in the bone marrow of memory T cells, which can express RANKL on their surface. The role that these cells play in skeletal homeostasis is unknown. However, it is conceivable that they might influence bone turnover and be responsible for some of the changes that occur in the skeleton with aging.
Immunologists and hematologists are well aware that, at least in adult mammals, the development of the immune system depends on the normal function of hematopoietic stem cells (HSCs), which are now known to reside in close association with bone cells. It is not surprising to learn that the development of the immune system in the bone marrow is dependent on the production of a facilitative microenvironment by bone cells. This fact was made clearer by data demonstrating that osteoblast-lineage cells provide key factors that regulate HSC development. There is also accumulating evidence that bone continues to play a role in adaptive immunity, beyond its influence on lymphocyte development. It is now known that long-lived memory T and B cells return to specialized niches in the bone marrow. These cells are capable of circulating throughout the organism. However, the questions of why they remain in specific areas of bone marrow and what factors draw them there remain unanswered. It is likely that the answers to these questions will come from experiments that are designed in the context of osteoimmunology by investigators who have knowledge of both the immune system and bone.
We are quite honored to have obtained 14 outstanding contributions for this book. The chapters of this book span the breadth and depth of our current knowledge of osteoimmunology. In this volume, the contributions are organized according to their scientific messages, though these connections are not absolute.
The initial chapters deal with the development of osteoblasts, osteoclasts, hematopoietic stem cells, T and B lymphocytes, and communications between thesecellular elements. There is also a detailed chapter on 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 and the development of pathologic conditions, which involve osteoimmunology, like osteoporosis and the bone loss of inflammatory arthritis, inflammatory bowel disease, periodontal disease, and hematologic malignancies. The book concludes with chapters on the role that immune and bone cell interactions have in osteomyelitis and fracture healing.
After reading this book, one will hopefully appreciate the intricate interaction between the immune system and bone. However, despite the progress that has already been made towards understanding the cross-regulation between bone and the immune system, the biological implications of such interactions are only beginning to be identified. The fields of immunology and bone biology have matured sufficiently so that key cellular and molecular mechanisms governing the homeostasis of the individual systems are extensively described. Hence, progress toward understanding osteoimmunologic networks will likely be greatly facilitated by creating an environment conducive to its study. It is hoped that this endeavor will lead to better treatments for human diseases involving both systems.
Many of the pathologic processes of the skeletal and immune systems are major targets for therapeutic intervention. However, the search for novel treatments for these conditions is often pursued in the absence of a solid scientific understanding of the molecular and cellular pathways that underlie these processes. According to the U.S. Surgeon General Report on Bone Health and Osteoporosis, by 2020 one in two Americans over the age of 50 will be at risk for fractures from osteoporosis or low bone mass. These health concerns become more prominent as people live longer and expect to remain active as they age. Future interventions to prevent and treat bone diseases will require a high degree of specificity, especially because these therapies are often tailored for a segment of the population that is already suffering from or is vulnerable to other age-related ailments. These issues place osteoimmunology in a position of uniqueclinical significance and make its study highly relevant.
Chapter Two
Origins of OsteoclastsDeborah L. Galson G. David Roodman
CHAPTER OUTLINE
Introduction: osteoclasts 8 Hematopoietic origins of osteoclasts – insights from osteopetrosis 11 Hematopoietic cells 11 Osteoclast precursors are in the monocyte–macrophage lineage 11
Generation of osteoclasts 17 External signals/receptors 18 M-CSF/c-fms (Csf1R) 18 RANKL/RANK/OPG 18 Signal transduction molecules 19 TRAF6 20 DAP12/FcR&gamma and their co-receptors TREM-2, PIR-A, OSCAR, and SIRPβ1 20 CaMKIV and calcineurin 21
Transcription factors 21 Spi1/PU1 21 NF-κB/IKKα (IKK1), IKKβ (IKK2), IKKγ (IKK3, NEMO) 22 PPARg 23 c-Fos 23 NFATc1 24 MITF 24
Regulation of pre-osteoclast fusion 24 CD47/TSP1/SIRPα (MFR) 24 DC-STAMP 26 Multi-subunit V-ATPase (oc/oc (Atp6i) and Atp6v0d2) 26 CD44 27 ADAM8/α9β1-integrin 27 CTR 28
More than one type of osteoclast? 28 Distinctive morphological and biochemical characteristics of mature osteoclasts that suggest the presence of osteoclast subtypes 29 Carbonic anhydrase II (CAII) 29 Anion exchangers (Ae2 and Slc4a4) 30 Cathepsin K (CatK) 30 Matrix metalloproteinase (MMP9) 30 Different osteoclasts in different bone sites: trabecular vs cortical, long bones vs jaw and calvarial sites 31
Other OCL precursors 32 Other macrophage lineage cells 32 Dendritic cells 32 Alveolar macrophages 33 B cells 33 Multiple myeloma cells 33
Conclusion 34
References 34
Introduction: osteoclasts
Bone remodeling is an essential process, which creates the marrow space utilized for hematopoietic stem cell differentiation, shapes and sculpts the bones during growth, enables tooth eruption, is critical for maintaining bone quality and strength, and is part of the system generating calcium homeostasis. Excessive bone remodeling is a feature of a number of pathological states, such as rheumatoid arthritis, hypercalcemia of malignancy, Paget's disease, and osteoporosis, while defective bone remodeling is seen in osteopetrosis. Mammalian bone undergoes continuous remodeling to remove old bone and stress-induced microfractures, which involves a process of bone resorption at selected sites followed by bone formation at the previous site of resorption. Without remodeling the skeleton would eventually collapse. Humans remodel their skeleton at different rates depending upon the bone location and the number of additional factors, including mechanical forces, autocrine and paracrine hormone status, and immunological influences. However, on average, during normal bone remodeling in the adult human skeleton, 5-10% of the existing bone is replaced every year.
Osteoclasts are large multinucleated giant cells that contains between 3 and 100 nuclei per cell, but usually contain 10-20 nuclei per cell and are highly motile. They form by fusion of mononuclear precursors and become adherent to bone. Osteoclasts are polarized cells that have a basolateral domain that doesn't face bone and a resorptive surface that forms a characteristic sealing zone and F-actin ring at sites of bone contact (Figure 2-1). The integrin αvβ3 (also known as vitronectin receptor (VNR) and CD51+CD61+) mediates the attachment of the sealing zone to the bone surface by binding Arg-Gly-Asp (RGD)-containing extracellular matrix proteins such as osteopontin. Activation of Src kinase by αvβ3 is required to form the actin ring structure and create a sealing zone. Inside the sealing zone, the resorptive surface of the osteoclast forms a unique and specialized ruffled border at the interface with bone from which proteolytic enzymes and hydrogen ions are released to degrade and resorb both the mineral and organic components of the bone matrix. This feature distinguishes osteoclasts from macrophage polykaryons. When osteoclasts are plated on bone surfaces, a characteristic "resorption pit" is formed below the cell within the sealing zone. These resorption lacunae are never seen in the absence of osteoclasts and are not produced by macrophages or macrophage polykaryons. The capability to efficiently excavate bone is a unique function of osteoclasts and requires many specialized systems as well as exquisite regulation to maintain healthy bone.
(Continues...)
Excerpted from Osteoimmunology: Interactions of the Immune and Skeletal Systems Copyright © 2011 by Elsevier Inc.. Excerpted by permission of Academic Press. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.
Table of Contents
Contents
Contributors....................viiForeword....................xi
Preface....................xiii
1. Overview: The Developing Field of Osteoimmunology Joseph Lorenzo, Yongwon Choi, Mark Horowitz, and Hiroshi Takayanagi....................1
2. Origins of Osteoclasts Deborah L. Galson and G. David Roodman....................7
3. The Adaptive Immune Response David G. Hesslein, Hector L. Aguila, and Mark C. Horowitz....................43
4. The Role of Bone Cells in Establishing the Hematopoietic Stem Cell Niche Joy Y. Wu and Henry M. Kronenberg....................81
Gravallese, and Gary S. Stein....................101
6. The Osteoclast: The Pioneer of Osteoimmunology Roberta Faccio, Yongwon Choi, Steven L. Teitelbaum, and Hiroshi Takayanagi....................141
7. The Effects of Immune Cell Products (Cytokines and Hematopoietic Cell Growth Factors) on Bone Cells Joseph Lorenzo....................187
8. Interactions Among Osteoblasts, Osteoclasts, and Other Cells in Bone T. John Martin, Natalie A. Sims, and Julian M. W. Quinn....................227
9. The Role of the Immune System in the Development of Osteoporosis Ulrike I. Mödder, B. Lawrence Riggs, and Sundeep Khosla....................269
10. The Role of the Immune System in the Bone Loss of Inflammatory Arthritis Steven R. Goldring and Georg Schett....................301
11. Inflammatory Bowel Disease and Bone Francisco A. Sylvester and Anthony T. Vella....................325
12. The Role of the Immune System in Fracture Healing Brandon M. Steen, Louis C. Gerstenfeld, and Thomas A. Einhorn....................343
13. The Role of the Immune System and Bone Cells in Acute and Chronic Osteomyelitis Brendan F. Boyce, Lianping Xing, and Edward M. Schwarz....................369
14. The Role of the Immune System in Hematologic Malignancies that Affect Bone Jessica A. Fowler, Claire M. Edwards, and Gregory R. Mundy....................391
15. Osteoimmunology in the Oral Cavity (Periodontal Disease, Lesions of Endodontic Origin and Orthodontic Tooth Movement) Dana T. Graves, Rayyan A. Kayal, Thomas Oates, and Gustavo P. Garlet....................411
Index....................443
What People are Saying About This
Comprehensive translational reference focusing on the interactions of bone and immune cells and their development into bone and immunological diseases