MEDICAL INTELLIGENCE UNIT

THE MOLECULAR BIOLOGY OF PAGET'S DISEASE

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Paul T. Sharpe University of London

London Bridge, England

Springer-Verlag Berlin Heidelberg GmbH R.G.LANDES COMPANY

AuSTIN

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 1. Osteitis deformans--Molecular aspects. I. Sharpe, Paul T. II. Series.

[DNLM: 1. Osteitis Deformans--physiopathology. 2. Osteitis Deformans--etiology. 3. Molecular Biology. WE 250 M718 1996} RC931.065M65 1996 616.7'12---dc20 DNLM/DLC 96-32383 for Library of Congress CIP

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DEDICATION This book is dedicated to the memory of Jean Stevens,

founder of the Salford Paget's Appeal, who died in June 1995.

1. The Pathology of Paget's Disease ......................•........................ 1 Anthony J Freemont Introduction ......................................................................................... 1 Clinical Features .. . . .. . .. .. . . . . . . .. . .. .. .. . . . . .. .. .. .. .. . . . . . . . . . . . . .. .. .. .. . .. .. .. . . .. .. . .. .. .. . . . 1 General Pathophysiology ....................................................................... 2 Complications ..................................................................................... 16 Summary ............................................................................................ 19

2. 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

3. 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

4. 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

5. Cytokines and Growth Factors in Paget's Disease .................. 101 Mark A. Birch and fames A. Gallagher Introduction ..................................................................................... 1 01 Cytokines and Growth Factors in Normal Bone Remodeling ............ 102

Cytokines and Growth Factors Which Regulate Bone Resorption ..... 103 Regulation of Osteoclastogenesis ....................................................... 103 Activation of Mature Osteoclasts ....................................................... 107 Bone Formation ................................................................................ 108 Osteoblast Proliferation/Differentiation ............................................ 108 Mature Osteoblast Activity ............................................................... 111 Production of Cytokines and Growth Factors in Bone ...................... 112 The Role of Cytokines and Growth Factors

in Abnormal Bone Remodeling ..................................................... 117 Cytokines in Paget's Disease ............................................................. 119

6. 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

7. Mechanisms of Action ofBisphosphonates as Inhibitors of Bone Resorption ................................................................. 14 7 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

8. 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 3 Overview ........................................................................................... 196

Index .............................................................................................. 20 1

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 5

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 1

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 5

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 3

Andrew P. Mee Department of Medicine Manchester Royal Infirmary Manchester, England Chapter4

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 7

=====PREFACE=====

Paget'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 2 details the highly unusual epidemiology and introduces the idea of

a viral cause. Chapter 3 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 5 discusses

the role of cytokines and growth factors and is followed in chapter 6 by the piecing together of many of the molecular findings into the first molecular model of the biology of Pagetic bone cells.

Chapter 7 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.

====INTRODUCTION=====

PAGET'S IS AN OLD DISEASE The condition now known as Paget's disease was first reported by Wilks in

18691 but it was a few years later before the disease was classically described as Osteitis deformam (Paget's disease) by Sir James Paget in 1877 working in London.2 The disease itself is certainly much older, with pagetic lesions being found in skeletons from ancient Egypt,3 the Galla-Roman era4 and Anglo Saxon burial grounds of around AD950.5 Paget's is primarily a disease of the elderly affecting between 5-8% of the population over 40 in Europe and the United States.6

PAGET'S ISAN ENIGMA TIC DISEASE While the scientific literature is increasingly filled with great excitement of

genes being identified causing diseases that affect a few thousand people, Paget's, a debilitating disease that may affect up to five million people worldwide, receives scant attention. There is no single reason for this anomaly but a combination of several features that together make Paget's a "Cinderella" of diseases. Paget's disease is not Mendeally inherited and so there is not a single "Paget's disease gene" to be searched for. Paget's is primarily a disease of the elderly population. Paget's disease is non-infectious. Excellent new treatments are available that if not cure, certainly alleviate much of the suffering. Paget's disease is rarely lethal. Bal­anced against these features are the inescapable facts that Paget's is often very a painfol severely debilitating disease that can lead to serious incurable complications such as osteosarcoma. Paget's disease is a "Western" disease with a unique epidemiol­ogy that has no proven cause despite being .first described over 100 years ago.

PAGET'S IS NOT AN IDIOSYNCRATIC DISEASE Paget's disease research has a great deal to offer the bone field: a fact that has

not been fully appreciated by researchers, pharmaceutical companies and fund­ing bodies alike. Unlike "normal" bone and bone in diseases such as osteoporosis, pagetic bone is very cellular. It is a very active tissue with many osteoclasts and osteoblasts carrying out their functions in an uncontrolled fashion. So much basic bone research has been carried out with cultured cells that the bone field often feels like an unreal world where the tissue itself is forgotten. The search for the mysterious "coupling factor" that communicates osteoblasts and osteoclasts still occupies much of the basic research on bone. In pagetic tissue, coupling is abnormal and can provide a unique environment to study basic bone biology in VIVO.

PAGET'S IS NOT A CONTROVERSIAL DISEASE The only major controversy is whether or not it is caused by a virus infection.

Sadly the controversy ends there because if viral infection is not the cause there are no feasible alternative ideas. This book is not meant to be an all encompass­ing work on Paget's disease but rather to highlight the molecular and cell biology of the disease. The aim of this book is to provide a forum for top researchers in the field to be controversial and express their own ideas. From the onset I have encouraged all authors to be speculative. In truth there is so little hard informa­tion on the molecular biology of Paget's disease that almost any speculation can fit with what is known. There is some degree of duplication between chapters which I have deliberately chosen not to edit so that authors' different interpreta­tions can be appreciated. Above all I hope this book will stimulate new ideas.

REFERENCES

1. Wilks S. Case of osteoporosis or spongy hypertrophy of the bones (calvaria, clavice, os femoris and rib exhibited at the society). Transactions of the Pathological Society of London 1869; 20:273-277.

2. Paget J. On a form of chronic inflammation of bones (osteitis deformans). Medico­Chirurgical Transactions of London 1877; 60:37-63.

3. Hutchinson J. On osteitis deformans. Illustrated Medical News 1889; 2:169- 180. 4. Astre G. Maladie osseuse pagetoide d'un gallo-romain. Revue Pathologie Generale et

Comparee 1957; 57:955-961. 5. Wells C, Woodhouse NJY. Paget's disease in an Anglo-Saxon. Medical History 1975;

19:396-400. 6. Kanis JA. Pathophysiology and Treatment of Paget's Disease of Bone. London: Martin

Dunitz Ltd, 1991.

FURTHER INFORMATION ON PAGET'S DISEASE CAN BE OBTAINED FROM:

National Association for the Relief of Paget's Disease 1 Church Road Eccles Manchester M30 ODL, UK Tel. 0161 707 9225.

The Paget Foundation 200 Varick Street- Suite 1004 New York, NY, USA 10014-4810 Tel. 212 229 1592 Fax. 212 229 1502. Email. pagetfdn@aol.com

AcKNOWLEDGMENTS

My thanks go to all the contributors for making the editing of this book an enjoyable and interesting experience. My per­sonal special thanks also go to the three charitable organizations who have provided and hopefully will continue to provide in­valuable support for all kinds of matters relating to Paget's disease. The National Association for the Relief of Paget's Dis­ease, The Paget Foundation (USA) and the Salford Paget's Ap­peal. Thank you.