The molecular biology of pagets disease

www.pdflobby.com www.pdflobby.com MEDICAL INTELLIGENCE UNIT THE MOLECULAR BIOLOGY OF PAGET'S DISEASE Paul T Sharpe University of London London Bridge, England n1n ~ Springer-Verlag Berlin Heidelberg GmbH R.G.LANDES COMPANY AuSTIN www.pdflobby.com MEDICAL INTELLIGENCE UNIT THE MOLECULAR BIOLOGY OF PAGET'S DISEASE R.G LANDES COMPANY Austin, Texas, U.S.A International Copyright © 1996 Springer-Verlag Berlin Heidelberg Originally published by Springer-Verlag, Heidelberg, Germany 1996 Softcover reprint of the hardcover 1st edition 1996 All rights reserved No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher 'Springer International ISBN 978-3-662-22507-3 While the authors, editors and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein Library of Congress Cataloging-in-Publication Data The molecular biology of Paget's disease I [edited by} Paul T Sharpe p em - (Medical intelligence unit) Includes bibliographical references and index ISBN 978-3-662-22507-3 ISBN 978-3-662-22505-9 (eBook) DOI 10.1007/978-3-662-22505-9 Osteitis deformans Molecular aspects I Sharpe, Paul T II Series [DNLM: Osteitis Deformans physiopathology Osteitis Deformans etiology Molecular Biology WE 250 M718 1996} RC931.065M65 1996 616.7'12 -dc20 DNLM/DLC 96-32383 for Library of Congress CIP www.pdflobby.com PuBLISHER's NoTE R.G Landes Company publishes six book series: Medical Intelligence Unit, Molecular Biology Intelligence Unit, Neuroscience Intelligence Unit, Tissue Engineering Intelligence Unit, Biotechnology Intelligence Unit and Environmental Intelligence Unit The authors of our books are acknowledged leaders in their fields and the topics are unique Almost without exception, no other similar books exist on these topics Our goal is to publish books in important and rapidly changing areas of the biosciences for sophisticated researchers and clinicians To achieve this goal, we have accelerated our publishing program to conform to the fast pace in which information grows in the biosciences Most of our books are published within 90 to 120 days of receipt of the manuscript We would like to thank our readers for their continuing interest and welcome any comments or suggestions they may have for future books Shyamali Ghosh Publications Director R.G Landes Company www.pdflobby.com DEDICATION This book is dedicated to the memory of Jean Stevens, founder of the Salford Paget's Appeal, who died in June 1995 www.pdflobby.com The Pathology of Paget's Disease • Anthony J Freemont Introduction Clinical Features General Pathophysiology Complications 16 Summary 19 The Epidemiology of Paget's Disease; Clues to the Cause? 21 David C Anderson Introduction 21 The Function of the Normal Osteoclast in Relation to that in Paget's Disease 22 Behavior of Paget's Disease in the Individual 22 Epidemiological Implications of the Behavior of the Disease in the Individual 25 The Epidemiology of Paget's Disease 26 Worldwide Distribution of the Disease 27 Familial Paget's Disease 32 Evidence for Diversity of the Disease Between Different Populations 33 Evidence for a Decline in the Incidence of Paget's Disease 38 Overall Conclusions, and the Need for Further Studies! 39 Pagetic Osteoclasts 45 G David Roodman, Linda M McManus and Anne Demulder Pathology and Ultrastructure ofPagetic Osteodasts 45 Pathophysiology of the Osteoclast in Paget's Disease 48 Abnormalities in Osteoclast Precursors in Pagetic Marrow Samples 53 Summary 54 Paramyxoviruses and Their Possible Role in Paget's Disease 59 Andrew P Mee Introduction 59 The Paramyxoviruses 59 Paramyxovirus Persistence and Disease in Humans 68 Evidence for a Paramyxoviral Etiology of Paget's Disease 71 Canine Distemper Virus in Dogs 78 How Might Paramyxoviruses Cause Paget's Disease? 86 Conclusions 89 Cytokines and Growth Factors in Paget's Disease 101 Mark A Birch and fames A Gallagher Introduction 101 Cytokines and Growth Factors in Normal Bone Remodeling 102 www.pdflobby.com Cytokines and Growth Factors Which Regulate Bone Resorption Regulation of Osteoclastogenesis Activation of Mature Osteoclasts Bone Formation Osteoblast Proliferation/Differentiation Mature Osteoblast Activity Production of Cytokines and Growth Factors in Bone The Role of Cytokines and Growth Factors in Abnormal Bone Remodeling Cytokines in Paget's Disease 103 103 107 108 108 111 112 117 119 A Molecular Model of Paget's Disease 135 Paul T Sharpe Introduction 135 The Pagetic Osteoclast 136 Pagetic Osteoblasts 141 A Multifactorial Disease? 142 Testable Predictions 143 Mechanisms of Action ofBisphosphonates as Inhibitors of Bone Resorption 147 Michael J Rogers and R Graham G Russell Antimineralization and Antiresorptive Properties ofBisphosphonates 147 Direct Effects of Bisphosphonates on Osteoclasts 154 Inhibition of Osteoclast Development 160 Effects ofBisphosphonates on Other Bone Cells 162 Models for Identifying the Molecular Mechanisms of Action ofBisphosphonates 164 Conclusions 168 Familial Expansile Osteolysis: A Genetic Model of Paget's Disease 179 Anne E Hughes and R john Barr Introduction 179 Familial Expansile Osteolysis 181 Pathology 182 Genetics ofFEO 188 Candidate Genes 19 Overview 196 Index 20 www.pdflobby.com r.========EDITORS=======]l Paul T Sharpe Department of Craniofacial Development United Medical and Dental Schools of Guy's and St Thomas's Hospitals University of London London Bridge, England Chapter6 ~====CONTRIBUTORS=====! David C Anderson Hong Kong Chapter2 R John Barr Department of Orthopaedic Surgery Musgrave Park Hospital Belfast, Northern Ireland ChapterS Mark A Birch Human Bone Cell Research Group Department of Human Anatomy and Cell Biology The U niversiry of Liverpool Faculty of Medicine Liverpool, England Chapter Anne Demulder University ofTexas Health Science Center at San Antonio San Antonio, Texas, U.S.A Chapter3 Anthony J Freemont Department of Rheumatology The University of Manchester Manchester, England Chapter James A Gallagher Human Bone Cell Research Group Department of Human Anatomy and Cell Biology The University of Liverpool Faculty of Medicine Liverpool, England Chapter Anne E Hughes Department of Medical Genetics The Queens University of Belfast Belfast, Northern Ireland ChapterS Linda M McManus University of Texas Health Science Center at San Antonio San Antonio, Texas, U.S.A Chapter Andrew P Mee Department of Medicine Manchester Royal Infirmary Manchester, England Chapter4 www.pdflobby.com Michael] Rogers, Ph.D The University of Sheffield Medical School Department of Human Metabolism and Clinical Biochemistry Sheffield, England Chapter7 G David Roodman UniversityofTexas Health Science Center at San Antonio San Antonio, Texas, U.S.A Chapter3 R Graham G Russell, M.D., Ph.D The University of Sheffield Medical School Department of Human Metabolism and Clinical Biochemistry Sheffield, England Chapter www.pdflobby.com =====PREFACE===== P aget's disease ofbone is a "Cinderella" of human diseases Although it can be severely debilitating and affects around 5% of the elderly population of Europe and the United States it receives scant recognition from clinicians, pharmaceutical companies and the general public Add to this fact that the disease is probably caused by a viral infection and can occasionally lead to such fatal complications as osteosarcoma, it is remarkable that Paget's disease appears to attract so little attention There is a great deal of ignorance in the general medical profession regarding the diagnosis and treatment of Paget's disease and the two major Paget's disease charities-the Paget's Foundation, USA and the National Association for the Relief of Paget's Disease, UK-which are very active in educating physicians and patients An excellent monograph on the pathophysiology of Paget's Disease by Professor John Kanis, M.D., (University of Sheffield, UK) was published in 1991 The aim of this new text is to complement that text by concentrating on areas not covered by John Kanis, namely the molecular and cellular rather than clinical aspects of the disease Leading researchers in different aspects of Paget's disease biology have contributed a total of eight chapters that together summarize the current status of knowledge and thinking The book is written for both researchers and physicians and aims to stimulate further research into the fascinating disease The book begins with a chapter of the basic pathology of the disease Chapter details the highly unusual epidemiology and introduces the idea of a viral cause Chapter describes the cell and molecular biology ofPagetic osteoclasts, the cells at the heart of the disease which are responsible for the initial lesion In chapter 4, the viral etiology is discussed in great detail Chapter discusses the role of cytokines and growth factors and is followed in chapter by the piecing together of many of the molecular findings into the first molecular model of the biology of Pagetic bone cells Chapter concerns the mechanism of the action of the drugs used to treat the disease, and the book ends with an insight into a fascinating inherited form of Paget's Disease, Familial Expansile Osteolysis www.pdflobby.com Familial Expansi/e Osteolysis: A Genetic Model of Paget's Disease 797 region, and interrogation of Genethon YAC data available by Internet The large size of the YACs is an advantage for contig formation, but they suffer from a high rate of chimerism and rearrangement We have eliminated YACs which are known to be highly chimeric from the contig which has at least 4-fold depth in most regions and encompasses the highly polymorphic markers D18S483, D18S68, D18S42, D18S55, GATA26C03, D18S51, Dl8S60, D18S499 and D18S64 We are currently constructing a restriction map of this contig which is approximately 5-6.5 Mb in 21.1 21.2 21.31 21.32 21.33 22.1 22.2 ~ 01.8541 01.85383 01.8564 01.8538 01.85499 01.8560 01.8551 01.8555 01.8542 01.85875 01.85483 01.85495 22.3 01.8561 23 Fig 8.4 Map of genetic markers in the FEO gene region on chromosome IBq c:: •.-t C> (J) L w LL ted from the affected parent are shown on the left of each pair and the haplotype linked to the disease gene is shaded Analysis of recom· bination suggests that the FEO gene lies b etween 01 8564 and 78551 018564, 0185499, 018560, 018551 , 078542 and 185483 in order from top to bottom Alleles transmit· Fig 8.5 Pedigree of part of the FEO kindred showing types for markers 185383, II I v IV I I I I I 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