The Molecular Biology of Paget’s Disease

213 Pages·1996·7.426 MB·English

by  Paul T. Sharpe (auth.)

MEDICAL
INTELLIGENCE
UNIT
THE MOLECULAR BIOLOGY
P
OF AGET'S DISEASE
Paul T. Sharpe
University of London
London Bridge, England
n1n
~
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, elec
tronic 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 recommend
ations 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
NoTE
PuBLISHER's
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 infor
mation 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
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 ................................................................. 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
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
James A. Gallagher
Hong Kong
Human Bone Cell Research Group
Chapter2
Department of Human Anatomy
and Cell Biology
R. John Barr
The University of Liverpool
Department of Orthopaedic Surgery
Faculty of Medicine
Musgrave Park Hospital
Liverpool, England
Belfast, Northern Ireland
Chapter 5
ChapterS
Anne E. Hughes
Mark A. Birch
Department of Medical Genetics
Human Bone Cell Research Group
The Queens University of Belfast
Department of Human Anatomy
Belfast, Northern Ireland
and Cell Biology
ChapterS
The U niversiry of Liverpool
Faculty of Medicine
Linda M. McManus
Liverpool, England University of Texas Health Science
Chapter 5 Center at San Antonio
San Antonio, Texas, U.S.A.
Anne Demulder Chapter 3
University ofTexas Health Science
Center at San Antonio Andrew P. Mee
San Antonio, Texas, U.S.A. Department of Medicine
Chapter3 Manchester Royal Infirmary
Manchester, England
Anthony J. Freemont Chapter4
Department of Rheumatology
The University of Manchester
Manchester, England
Chapter 1
Michael]. Rogers, Ph.D. R. Graham G. Russell, M.D., Ph.D.
The University of Sheffield Medical The University of Sheffield Medical
School School
Department of Human Metabolism Department of Human Metabolism
and Clinical Biochemistry and Clinical Biochemistry
Sheffield, England Sheffield, England
Chapter7 Chapter 7
G. David Roodman
UniversityofTexas Health Science
Center at San Antonio
San Antonio, Texas, U.S.A.
Chapter3
=====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 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.