Table Of ContentProstaglandins
•
In
Bone Resorption
Authors
Wilson Harvey, Ph.D.
Principal Biochemist and
Honorary Senior Lecturer
Department of Oral and Maxillo-Facial Surgery
Institute of Dental Surgery
Eastman Dental Hospital
London, England
Alan Bennett, Ph.D., D.Sc.
Professor of Pharmacology
Department of Surgery
King's College Hospital Medical School
Rayne Institute
London, England
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INTRODUCTION
A week may be a long time in politics, but research takes a little longer.
Nowhere was this more true than in the area of bone physiology where, with the exception
of some notable milestones, progress has been slow. In the 1960s things began to change
and the growth of knowledge increased exponentially. This was associated with a dramatic
swing from morphological and histological studies to a biochemical approach. Although
many things influenced this and indeed made it possible, a crucial turning point was the
discovery of the role of the nucleotide cyclic 3',5'-adenosine monophosphate (cAMP) in
the action of some hormones on their target cells, with Sutherland and colleagues1 formally
proposed as the “Second Messenger Hypothesis” in 1965. This led to the demonstration
that parathyroid hormone (PTH) appeared to exert its effect on the skeleton by activation
of adenylate cyclase.2 Meanwhile, prostaglandins (PGs) also had been found to cause ele-
vation of cAMP levels in a wide range of tissues from mouse ovaries and adipose tissue to
kidney and placenta.
The stage was set to see if PGs mimicked the bone resorbing activity of PTH, as both
agents appeared to share a common “second messenger” in their action on target cells. In
1970 Klein and Raisz3 did just that and found that PGs, notably of the E series, were potent
bone resorbers in tissue culture. Later Raisz claimed, somewhat modestly, that the importance
of this observation was not apparent until it was demonstrated by Tashjian et al.4 that PGs
were synthesized by the VX2 carcinoma and appeared to mediate the hypercalcemia it
produces in animals. That report was a sign of things to come, and in the mid-1970s a
positive rash of investigations into the role of PGs in the hypercalcemia of malignancy was
noted. This reflected a natural response of scientists in many areas to identify situations —
mainly pathological — where abnormal bone resorption occurred, and to ask “Are pros-
taglandins involved?” As you will see, this was a very productive response and, of course,
led to the question “Where do they come from and how do they act?” It is this problem,
the involvement of PGs in the complex interactions between the cells involved in bone
resorption, which still occupies many researchers.
A glance at the Table of Contents will tell you that the relevant research involves a
spectrum of approaches from the clinical, through animal and tissue culture models, to
investigation at the subcellular level. This diversity is healthy, as an interdisciplinary ap-
proach helps keep the subject and the goals in perspective. It does, however, pose problems
for a reviewer. To present the subject in terms of cells, factors, and mechanisms with
sporadic illustrations of pathological or physiological bone resorption would be one way.
This, however, would frustrate those seeking an accessible account of the role of PGs in a
particular situation, e.g., rheumatoid arthritis. Moreover, it would destroy the temporal
continuity of progress in that area of research; not only does such a sequence often make
an interesting story but also gives a valuable insight into how research does progress, what
kind of deductions are made and what kind of approach leads to advances in that area of
knowledge. Conversely, a series of self-contained reviews of discrete topics largely would
defeat the main purpose of this book, which is to make, as far as possible, a coherent story
of the role that PGs play in bone resorption. I therefore have combined the two approaches,
retaining the “story” of research into specific areas, but putting them in the context of the
mechanisms which appear to underlie them.
Let me introduce a little perspective. Bone resorption is the term given to the cellular
removal of mineral and matrix from bone. In healthy adult bone, it is in overall equilibrium
with the formation of new bone, and the two processes constitute bone “turnover”. Dis-
turbance of this equilibrium will lead either to a net increase or a net decrease of bone.
Unfortunately, the net loss of bone, whether localized or generalized often is referred to as
resorption, which is incorrect. However, because of the importance of this balance between
formation and resorption, I also have considered the effects of prostaglandins on bone
formation in this book.
Where and when does bone resorption occur? As I have implied above it is part of the
normal physiological remodeling of bone, a process that is somewhat more rapid in cancellous
than in dense cortical bone. Bone remodeling is under the control of several hormones
including PTH, vitamin D metabolites, calcitonin, “sex” steroids, glucocorticoids, growth
hormone, and others. It also is influenced by local factors such as mechanical stress and,
as we shall see, probably by PGs as well. It is true to say that bone resorption attracts
attention only when it goes wrong! This is when the process is defective, such as in osteo-
petrosis, or when its rate is greater than that of new bone formation and there is net loss of
bone. This may be generalized, when it is termed osteoporosis, or local. As you will see
throughout this book, PGs often are implicated in localized bone destruction, and their role
in generalized bone loss is somewhat equivocal. This partly may reflect their true role in
bone metabolism but also may be a result of the attention that local bone loss has received
in laboratories around the world.
Finally, the question of terminology. As you will see in Chapter 1, the term “prostanoids”
includes the PGs and thromboxanes, and “eicosanoids” would include the lipoxygenase
products as well. However, “prostaglandins” is widely — if inaccurately — used and
“eicosanoids” would be unfamiliar to many readers; I have therefore used “prostaglandins”
(abbreviated to PG) as a generic term throughout the book.
REFERENCES
1. Sutherland, E. W., Oye, I., and Butcher, R. W., The action of epinephrine and the role of the adenyl
cyclase system in hormone action, Recent Prog. Horm. Res., 21, 623, 1965.
2. Chase, L. R., Fedak, S. A., and Aurbach, G. D., Activation of skeletal adenyl cyclase by parathyroid
hormone in vitro, Endocrinology, 84, 761, 1969.
3. Klein, D. C. and Raisz, L. G., Prostaglandins: stimulation of bone resorption in tissue culture, Endocri
nology, 86, 1436, 1970.
4. Tashjian, A. H., Jr., Voelkel, E. F., Levine, L., and Goldhaber, P., Evidence that the bone resorption-
stimulating factor produced by mouse fibrosarcoma cells is prostaglandin E2: a new model for the hyper-
calcaemia of cancer, J. Exp. Med., 136, 1329, 1972.
THE AUTHORS
Wilson Harvey is Principal Biochemist and Senior Lecturer at the Institute of Dental
Surgery, London University. His first degree was in Applied Biology, Brunei University,
awarded in 1970. An interest in tissue culture led to a Ph.D. in 1974 at the Department of
Medicine, Guy’s Hospital Medical School, investigating the effects of antiarthritic drugs on
fibroblast metabolism. This interest in connective tissue was continued during a postdoctoral
Fellowship at the University of Southern California School of Medicine on the changes in
collagen types synthesized by chondrocytes in culture.
He returned to Guy’s Hospital in 1976 to continue research in the control of fibroblast
activity, and then in 1979 joined the Department of Oral Surgery where he has helped to
build up a program of basic and applied connective tissue research. His main publications
have been in the field of bone resorption — notably the role of prostaglandins, the interaction
of ultrasound with cells and tissues, and mechanisms which lead to collagen accumulation
in oral submucous fibrosis, a scarring disease of the mouth.
Alan Bennett has the unique position of Professor of Pharmacology in the Department
of Surgery in King’s College Hospital School of Medicine and Dentistry. He received a B.
Pharm. with First-Class Honours from London University in 1958, and was awarded a Ph.D.
in Pharmacology in 1963 by the same University. In 1976 he received the degree of D.Sc.
from the University of London for his work in Pharmacology. The title of Professor of
Pharmacology was conferred on him in 1976, and in 1984 he was awarded a Fellowship of
the Pharmaceutical Society.
Prof. Bennett’s interest in prostaglandins dates back to the mid-1960s, and has ranged
over several areas. Initially the work was restricted to the gastrointestinal tract, but in 1971
he studied the ability of prostaglandins to resorb bone, and this led to research on the role
of prostaglandins in the formation of bone metastases in breast cancer. Subsequent studies
concerned prostaglandins and their synthesis inhibitors in malignancy in other human tumors,
in animal cancers, and malignant cells in culture. Work in gastroenterology continued
simultaneously, particularly in regard to gastrointestinal motility, innervation, prostaglandins
and various other substances.
His main scientific contributions have been studies on the control of gastrointestinal
motility, the actions of prostaglandins and their antagonists in various tissues, and several
aspects of cancer.
Prof. Bennett is on the editorial board of several specialist journals. He is on the Committee
of the Society for Drug Research, and was previously Chairman. He is a member of the
British Pharmacological Society, the British Society of Gastroenterology, the Physiological
Society, and the British Association for Cancer Research.
TABLE OF CONTENTS
Chapter 1
The Formation of Prostaglandins and Related Substances..................................................... 1
Alan Bennett
Chapter 2
Methodology...............................................................................................................................11
Wilson Harvey
Chapter 3
Source of Prostaglandins and Their Influence on Bone Resorption and Formation........27
Wilson Harvey
Chapter 4
Prostaglandins and the Mechanism of Bone Resorption......................................................43
Wilson Harvey
Chapter 5
Inflammation, Cytokines, and Prostaglandins........................................................................57
Wilson Harvey
Chapter 6
Periodontal Disease and Osteomyelitis....................................................................................73
Wilson Harvey
Chapter 7
The Dental Cyst...........................................................................................................................91
Wilson Harvey
Chapter 8
Mechanical Stress and Bone Remodeling...............................................................................103
Wilson Harvey
Chapter 9
Prostaglandins and Bone Resorption in Cancer.....................................................................115
Wilson Harvey
Index 127
1
Chapter 1
THE FORMATION OF PROSTAGLANDINS AND RELATED SUBSTANCES
Alan Bennett
TABLE OF CONTENTS
I. Introduction.........................................................................................................................2
II. Prostaglandins ...................................................................................................................2
A. Inhibition of Prostaglandin Synthesis.................................................................2
B. Prostaglandin Precursors......................................................................................2
C. Classes...................................................................................................................2
D. Prostaglandin Metabolites...................................................................................3
III. Thromboxanes...................................................................................................................3
A. Inhibitors of Thromboxane Synthesis.................................................................6
IV. Leukotrienes.......................................................................................................................6
V. Other Lipoxygenese Products..........................................................................................6
VI. Nomenclature.....................................................................................................................6
VII. Cautionary Notes..............................................................................................................8
A. Eicosanoid Formation..........................................................................................8
B. Sources...................................................................................................................8
C. Identification.........................................................................................................8
D. Assays.....................................................................................................................9
E. Drug Actions.........................................................................................................9
References......................................................................................................................................9
2 Prostaglandins in Bone Resorption
I. INTRODUCTION
There are numerous accounts of the types of prostaglandins (PGs) and related substances
and how their formation is affected by drugs. One reason for yet another description is to
introduce the basic aspects of the subject to those who have so far avoided them, but who
need the information to understand the biological topics of this book. Other reasons are to
describe recent advances and to point out some of the pitfalls in drawing conclusions from
experimental evidence. As the subject is becoming increasingly more complex, this account
starts from basic principles and builds up to produce a general overview of our current
knowledge. Details of aspects not covered here can be found in many reviews, good examples
being those by Samuelsson et al.1 and Hammarstrom.2
Several of the important facts about PGs and other fatty acid derivatives follow.
II. PROSTAGLANDINS
Almost all cells in the body can make PGs, but the types formed vary with the cell type.
These PGs may contribute to physiology and pathology.
A. Inhibition of Prostaglandin Synthesis
PG formation is inhibited by many commonly used drugs, mainly the anti-inflammatory
drugs such as aspirin, indomethacin, and other similar nonsteroidal compounds. These drugs
inhibit cyclooxygenase, which is part of the enzyme complex called PG synthase (PG
synthetase) (Figure 1).
PG formation is also inhibited by corticosteroid anti-inflammatory drugs such as hydro-
cortisone, but in this case the mechanism is a reduction of PG precursor release. Cortico-
steroids inhibit the hydrolysis of cell membrane phospholipids by phospholipase A2 (Figure
1). They do so indirectly by stimulating the synthesis and/or release of polypeptide(s) called
lipocortin (formerly called macrocortin, lipomodulin, and renocortin by different groups).
The extent to which corticosteroids inhibit phospholipase A2 in vivo has been questioned
by recent experiments.
B. Prostaglandin Precursors
The main PG precursor is arachidonic acid (arachidonate at body pH) which chemically
is eicosatetraenoic acid (eicosa means 20 carbon atoms, and tetraenoic means that the carbon
skeleton contains 4 double bonds). This precursor gives rise to PGs with two double bonds,
one in each of the side chains attached to the ring (a cyclopentane ring), shown by the
subscript 2, e.g., PGE2. In communities where the diet is almost entirely fish, the precursor
is mainly eicosapentaenoic acid, which produces PGs with three double bonds in the side
chains. Eicosatrienoic acid has three unsaturated bonds and gives rise to PGs with one double
bond.
C. Classes
There are ten classes of PGs, given letters (A to J), based on the ring structures. These
classes may have widely differing activities and potencies. PGD, E, F, G, H, and I are the
3
FIGURE 1. A simple scheme of PG formation, and the inhibition of
enzyme activity by anti-inflammatory drugs.
most important biologically. PGE and F were the first to be classified, the letters being
based on their solubilities (E in ether, F in phosphate buffer, spelled with an f in Swedish).
The other letters were then assigned by starting at the beginning of the alphabet. PGG and
PGH compounds are intermediates in the formation of the other PGs (Figure 2). Aspirin
and many other nonsteroidal anti-inflammatory drugs inhibit the formation of PGG2 and
PGH2 from arachidonate, but not their conversion by other enzymes into other PGs.
Often the members of each class, i.e., having one, two, or three double bonds, possess
similar types of biological activity but different potencies, although sometimes the type of
biological activity may alter with the number of double bonds. With natural PGF compounds,
the -OH group on the ninth carbon atom has a stereochemical configuration denoted as a,
e.g., PGF2ü.
D. Prostaglandin Metabolites
PGs lose their biological activities in tbe body mainly by the enzymic conversion of the
C-15 hydroxyl to a keto group. The enzyme responsible for removing this hydroxyl is
therefore called PG-15-hydroxydehydrogenase. Various other metabolites are then formed,
but they are not discussed here because the information is not important for the understanding
of PG biology, and they are not targets for drugs. PGI2 (also known as prostacyclin) degrades
spontaneously at body pH into the much less active 6-keto-PGFla (also called 6-oxo-PGFla),
as well as undergoing enzymic conversion to the 15-keto compounds.
III. THROMBOXANES
PGG and PGH also give rise to thromboxanes (TXs), whose ring structure (an oxacy-
clohexane) differs from those of the PGs (Figure 3). The name thromboxane reflects the
finding that blood platelets are a major source. TXA2, also with a double bond in each of
the side chains because it is formed from arachidonate, has a very potent action on several
tissues and cell types (e.g., in aggregating platelets). It degrades rapidly (half-life of about
30 sec) into the much less active TXB2.
