Table Of Contentm:~ Endocrinology and Metabolism
Progress in Research and Clinical Practice
Piero P. Faa
Series Editor
Endocrinology and Metabolism
Progress in Research and Clinical Practice
Piero P. Foa
Series Editor
Cohen and Foa (eds.): Hormone Resistance and Other Endocrine
Paradoxes (Vol. 1)
Jovanovic (ed.): Controversies in Diabetes and Pregnancy (Vol. 2)
Cohen and Foa (eds.): The Brain as an Endocrine Organ (Vol. 3)
Ginsberg-Fellner and McEvoy (eds.): Autoimmunity and the
Pathogenesis of Diabetes (Vol. 4)
Foa (ed.): Humoral Factors in the Regulation of Tissue Growth (Vol. 5)
Forthcoming volumes:
Foa (ed.): Ion Channels and Ion Pumps: Metabolic and Endocrine Relationships
in Biology and Clinical Medicine (Vol. 6)
Grossman (ed.): Bilateral Communication Between the Endocrine and
Immune Systems (Vol. 7)
Piero P. Foa
Editor
Humoral Factors in
the Regulation of
Tissue Growth
Blood, Blood Vessels,
Skeletal System, and Teeth
With 43 Figures
Springer-Verlag
New York Berlin Heidelberg London Paris
Tokyo Hong Kong Barcelona Budapest
l>iero P. Foa, M.D., Sc.D.
Professor Emeritus
Department of Physiology
Wayne State University
Detroit, MI
Mailing address:
2104 Rhine Road
West Bloomfield, MI 48323 USA
Library of Congress Cataloging-in-Publication Data
Humoral factors in the regulation of tissue growth: blood, blood vessels, skeletal system,
and teeth/Piero P. Foa, editor.
p. cm.-(Endocrinology and metabolism; 5)
Includes bibliographical references and index.
ISBN -13: 978-1-4613-9274-3 e-ISBN -13: 978-1-4613-9272-9
DOl: 10.1007/978-1-4613-9272-9
1. Growth factors. 2. Neovascularization. 3. Erythropoiesis.
4. Musculoskeletal system-Growth-Regulation. I. Foa, Piero P.
(Piero Pio), 1911- . II. Series: Endocrinology and metabolism
(New York, N.Y.); 5.
[DNLM: 1. Growth Substances-physiology. 2. Muscles-growth &
development. WI EN396SN v.5/WE 500 H925]
QP552.G76H86 1992
612.4-dc20
DNLM/DLC
for Library of Congress
92-20284
Printed on acid-free paper.
© 1993 Springer-Verlag New York, Inc.
Softcover reprint of the hardcover 1st edition 1993
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ISBN -13: 978-1-4613-9274-3
Preface
More than 70 years have elapsed since H.M. Evans and J.A. Long
discovered the growth-promoting effect of crude saline extracts of the
anterior pituitary and almost exactly 40 years from Rita Levi-Montalcini's
discovery that the growth and differentiation of neurons is stimulated in
the presence of mouse S-180 tumor transplants. Since then, the pace
setting observations of Evans and Long were followed by the prepara
tion of ever more potent pituitary extracts, by the isolation of pure
growth hormone (GH), by its molecular identification and, finally, by its
biosynthesis by recombinant DNA technology: a wondrous, even if
now familiar sequence of events. Similarly, Levi-Montalcini's work and
the subsequent observation that snake venom and extracts of mouse
submaxillary gland shared the growth-promoting powers of sarcomatous
cells led her and Stanley Cohen to the discovery of the nerve growth
factor (NGF). GH and NGF are but two representatives of a rapidly
increasing number of organ and tissue-specific growth-stimulating
substances whose discovery created a revolution in medicine and blurred
the frontiers of endocrinology. Indeed, any distinction between growth
factors and hormones was rendered obsolete by the observation that the
insulin-like growth factor 1 (IGF-1) is identical to the GH-dependent
somatomedin C and by the realization that circulating hormones often
exert their effect by releasing local target-specific factors which in an
autocrine or paracrine fashion activate receptor-mediated mechanisms of
signal transduction.
The chapters of this book were selected not to cover the waterfront, as
only a series of monographs could do justice to that purpose, but rather
to discuss the nature and mechanism of action of growth-stimulating
substances whose biologic and clinical activities in man have been demon
strated or are being investigated. Thus, the book starts with a chapter on
angiogenesis in health and disease, discussing the various factors that
regulate blood vessel growth during embryologic development, follicle
maturation, menstrual cycle, implantation of the embryo and formation
of the placenta, and such pathologic events as joint inflammation and
v
vi Preface
inflammatory processes associated with wound healing, tumor growth
and diabetic retinopathy. The normal vascularization and pathologic
neovascularization of the retina is dealt with in greater detail in a separate
chapter that discusses the identity, mechanism of action and clinical
significance of angiogenic factors and their relationship to the pathogenesis
of potentially blinding retinal disease. A chapter on the humoral regula
tion of erythropoiesis discusses the nature, secretion, mode of action and
clinical usefulness of erythropoietin, interleukin-3, erythroblast-enhancing
factor, and other stimulatory and inhibiting substances. This is followed
by a chapter on the role of the colony-stimulating factors and the inter
leukins in leukopoiesis, which includes a discussion of pilot studies
carried out at the Sloan-Kettering Cancer Center and elsewhere attempt
ing to boost blood cell production in patients with AIDS, with lymphoid
malignancies, or undergoing bone marrow transplantation and suffer
ing the hematologic consequences of chemotherapy. The normal and
pathologic roles of the lymphokinins are discussed separately in greater
detail, while another chapter discusses inhibitory rather than stimulatory
effects on cell proliferation, emphasizing the role of transforming growth
factor B, interferon and the cytokines and their possible role as anti
neoplastic agents. Another chapter discusses how the cytokines regulate
hypothalamic and pituitary hormone secretion, an example of interaction
between growth factors and hormones that reaches the highest degree of
complexity in the case of the humoral agents (parathyroid hormone,
calcitonin, vitamin D, growth factors and prostaglandins) that regulate
bone growth, remodeling and repair. This discussion provides the neces
sary information required to understand the numerous endocrine, nutri
tional, and iatrogenic factors involved in the pathogenesis of osteopenia
and the special problems of bone mineral metabolism associated with
the menopause. Physical inactivity causes loss of bone mass, a problem
extensively investigated during space flight in a gravity-free environment,
an interesting model of unloading and immobilization described in a
chapter based on the experience of the Russian space program. The
rapidly growing body of knowledge on the role of growth factors in the
physiology of joints and in the pathogenesis of arthritis is the topic of
another chapter, and the monograph ends with a dissertation on the
control of tooth and periodontal tissue growth and repair.
Considering the scope and variety of the subject matter, I believe
that this book represents a good sampler of current basic and applied
knowledge and a tantalizing inducement to further reading. A rich
bibliography will guide the reader in this effort.
PIERO P. FoA
Preface vii
References
1. Evans HM, Long JA. The effect of the anterior lobe of the hypophysis
administered intraperinoteneally upon growth, maturity, and oestrus cycles of
the rat (Abstr). Anat Rec. 1921;21:61.
2. Levi-Montalcini R. Effect of mouse tumor transplants on the nervous system.
Am NY Acad Sci. 1952;55:330-344.
3. Cohen S. Purification of a nerve-growth promoting protein from the mouse
salivary gland and its neurocytotoxic antiserum. Proc Natl Acad Sci USA.
1960:46:302-316.
Contents
Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. Xlll
1. Angiogenesis: Its Regulation in Health and Disease 1
NIRMAL K. BANSKOTA and GEORGE L. KING
Angiogenesis in the Embryo .................................... 1
Angiogenesis in the Postnatal State .............................. 2
Diffusion Chambers and Avascular Tissues. . . . . . . . . . . . . . . . . . . . . . . . 3
Growth and Inhibitory Factors in Capillary Growth ................ 3
Other Endothelial Cell Mitogens ................................ 5
The Role of the Extracellular Matrix on Angiogenesis . . . . . . . . . . . . . . 6
Inhibitors of Angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Angiogenesis in Health and Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Summary..................................................... 10
2. Growth Factors and the Retina: Normal Vascularization and
Pathologic Neovascularization . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 18
ROBERT N. FRANK and LAURA B. SOTOLONGO
Normal and Pathologic Anatomy of the Retinal and Choroidal
Blood Vessels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
The Role of Growth Factors in Normal and Pathologic Retinal
Vascularization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
The Role of Ancillary Factors in Retinal Vascular Growth. . . . . . . . . . 31
Models of Retinal and Subretinal Neovascularization . . . . . . . . . . . . . . . 34
Localization of Growth Factors in the Eye . . . . . . . . . . . . . . . . . . . . . . . . 37
Summary..................................................... 39
3. The Humoral Regulation of Normal and Pathologic
Erythropoiesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 47
ALBERTO GROSSI, ALESSANDRO M. VANNUCCHI, DANIELA
RAFANELLI, and PIER LUIGI ROSSI FERRINI
Erythropoietin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
IX
x Contents
Interleukin-3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Granulocyte Macrophage-Colony Stimulating Factor .............. 56
Erythroblast-Enhancing Factor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Platelet-Derived Growth Factor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Prostaglandins ................................................ 58
Other Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 60
4. Colony-Stimulating Factors in Leukopoiesis . . . . . . . . . . . . . . . .. 71
MARY ANN BONILLA and ANN JAKUBOWSKI
Granulocyte Macrophage-Colony Stimulating Factor .............. 73
Granulocyte-Colony Stimulating Factor. . . . . . . . . . . . . . . . . . . . . . . . . . 76
Macrophage-Colony Stimulating Factor. . . . . . . . . . . . . . . . . . . . . . . . . . 78
Interleukin-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Interleukin-3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Future Clinical Uses of CSFs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
5. Regulation of Lymphocyte Proliferation, Differentiation, and
Functional Activity by Peptide Growth Factors .............. 94
JOSEPH KAPLAN
Interleukin-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Interleukin-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
Interleukin-3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
Interleukin-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Interleukin-S. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 100
Interleukin-6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 101
Interleukin-7. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 102
Interleukin-8. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 102
Interleukin-9. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 102
Transforming Growth Factor-~ ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 103
Summary..................................................... 105
Biomedical Perspective. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 105
6. The Inhibitory Effects of Growth Factors and Cytokines on
Cell Proliferation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 110
DAVID GOLDSTEIN and GEORGE WILDING
Inhibitory Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 112
Cytokines .................................................... 118
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 124
7. Cytokine Regulation of Hypothalamic and Pituitary
Hormone Secretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 139
MICHAEL D. LUMPKIN
Background .................................................. 140
Relationships Between IL-1, Stress, ACTH, and GH Secretion. . . . .. 141
Contents xi
IL-l, the Hypothalamus, and Releasing Factor Hormones. . . . . . . . . .. 141
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 151
8. Bone Growth, Remodeling, and Repair: Interactions
of Parathyroid Hormone, Calcitonin, Vitamin D, Growth
Factors, and the Prostaglandins. . . . . . . . . . . . . . . . . . . . . . . . . . .. 160
JOSEPH E. ZERWEKH
Macroscopic Structure of Bone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 160
Microscopic Structure of Bone .................................. 161
Composition of Bone Matrix. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 163
Bone Growth, Modeling, and Remodeling........................ 168
Bone Healing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 178
Hormonal Regulation of Bone Growth and Remodeling . . . . . . . . . . .. 179
9. Endocrine, Iatrogenic, and Nutritional Causes of Osteopenia .. 194
ADEL B. KORKOR
Endocrine Osteopenia ......................................... 194
Iatrogenic Causes of Osteopenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 201
Other Causes of Osteopenia .................................... 203
10. Bone Mineral Metabolism at the Menopause:
Determinants and Markers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 211
IAN A. KATZ and SOL EpSTEIN
Calcitropic Hormones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 213
"Epicalcitropic" Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 217
Biochemical Markers .......................................... 224
Serum Markers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 224
Urine Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 228
Local Factors ................................................. 229
Body Weight. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 230
Genetic Factors ............................................... 230
Conclusion ................................................... 231
11. Influence of Hypokinesia and Weightlessness on Jaw
Bones and Teeth ........................................ 244
BERND-MICHAEL KLEBER and KARL HECHT
Hypokinesia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 245
Influence of Hypokinesia on Mandibular Bone and Teeth:
Personal Investigations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 247
Results. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 248
Discussion and Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 251
Weightlessness. . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . .. 255
Some Effects of Weightlessness on Behavior and Metabolic
Processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 257
Effects on Jaw Bones and Teeth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 258
Final Comments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 261
