M EC H A NIS MS OF D IS EASE
Review Articles
Mechanisms of Disease
F R A N K L I N H . E P S T E I N , M. D. , Editor
T HE P HYSIOLOGY OF P ARATHYROID
H ORMONE –R ELATED P ROTEIN
GORDON J. STREWLER, M.D.
P
ARATHYROID hormone–related protein was
identified in the 1980s as a tumor product that
had the ability to activate parathyroid hormone
receptors and cause hypercalcemia.1 Parathyroid hor-
mone–related protein resembles parathyroid hormone
not only in terms of its genetic sequence but also in
terms of its genetic structure and is thus a second
member of the parathyroid hormone family.2 As ex-
pected of a protein that activates the parathyroid hor-
mone receptor, parathyroid hormone–related protein
causes hypercalcemia by increasing bone resorption
and renal tubular resorption of calcium.3,4 Like para-
thyroid hormone, it also has phosphaturic action.
PARATHYROID HORMONE–RELATED
PROTEIN AND HYPERCALCEMIA
Parathyroid hormone–related protein is the pre-
dominant cause of hypercalcemia in patients with can-
cer. Among patients with solid tumors and hyper-
calcemia, at least 80 percent have increased serum
concentrations of parathyroid hormone–related pro-
tein.4 Thus, hypercalcemia in patients with cancer
has predominantly a humoral basis, rather than be-
ing caused by local destruction of bone by tumor
metastases. In animals with hypercalcemia caused by
allografts of human tumors, the infusion of antibod-
ies to parathyroid hormone–related protein reverses
the hypercalcemia, thus establishing that the protein
is not just a bystander but is the cause of the hyper-
calcemia.5,6 In addition to its humoral effects, para-
thyroid hormone–related protein can also induce lo-
cal osteolysis around bone metastases, and it appears
to be important in the progression of bone metasta-
ses in patients with breast carcinoma.7,8
From the Department of Medicine, Veterans Affairs Boston Health Care
System, West Roxbury, Mass., and Harvard Medical School, Boston.
©2000, Massachusetts Medical Society.
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Despite the biochemical similarities between par-
athyroid hormone and parathyroid hormone–relat-
ed protein, the clinical abnormalities that result from
excesses or deficiencies of these two substances differ.
In contrast to primary hyperparathyroidism, which is
usually a mild, chronic disease, hypercalcemia in pa-
tients with cancer occurs abruptly, is often severe, and
carries a poor prognosis, with a median survival of
only about six weeks.
PHYSIOLOGIC ROLE OF PARATHYROID
HORMONE–RELATED PROTEIN
The discovery of a second member of the parathy-
roid hormone family immediately raised the question
of its physiologic role. This was an interesting chal-
lenge, because there was little in the way in which
parathyroid hormone–related protein was discovered
or in the physiology of parathyroid hormone to sug-
gest what its physiologic role might be. What was the
function of this new protein, which shared its receptor
with a hormone whose own physiologic role seemed
to be well understood?9
The first clues to the function of parathyroid hor-
mone–related protein came from studies of its ex-
pression in different tissues. In marked contrast to
parathyroid hormone, which is found only in the para-
thyroid glands, parathyroid hormone–related protein
is found in many tissues in both fetuses and adults,
including epithelia, mesenchymal tissues, endocrine
glands, and the central nervous system (Table 1). This
widespread distribution suggested a diversity of roles
for parathyroid hormone–related protein. Insights into
these roles are now emerging from gene-knockout
experiments and other approaches.
DEVELOPMENT OF CARTILAGE
A null mutation in the parathyroid hormone–relat-
ed protein gene in mice, achieved through homolo-
gous recombination,10 was found to be lethal in the
homozygous state. Affected mice produce no para-
thyroid hormone–related protein and die shortly
after birth from the effects of a severe defect in the
development of cartilage, or chondrodysplasia. In the
cartilage phase of endochondral bone formation, car-
tilage cells (chondrocytes) form a model of the future
bone. As part of this process, the chondrocytes pro-
liferate in an orderly fashion and lay down a specialized
extracellular matrix. When the phase of proliferation
has ended, the chondrocytes progress to a terminally
differentiated state in which they first become hyper-
trophied and change their program of matrix synthe-
sis (e.g., from type II collagen to type X collagen),
then mineralize their matrix, and finally undergo pro-
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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

TABLE 1. SITES AND PROPOSED ACTIONS OF PARATHYROID A

Periarticular cells
HORMONE–RELATED PROTEIN.

Proliferating
SITE PROPOSED ACTIONS
chondrocytes
Mesenchymal tissues
Cartilage Promotes proliferation of chondrocytes; inhibits
terminal differentiation and apoptosis of chon-
drocytes
Bone Stimulates or inhibits bone resorption
Smooth muscle Released in response to stretching; relaxes
Vascular system smooth muscle Parathyroid
Myometrium hormone–related
Urinary bladder protein receptors
Cardiac muscle Positive chronotropic stimulus; indirect positive Transitional
inotropic stimulus zone
Skeletal muscle Unknown
Epithelial tissues
Mammary Induces branching morphogenesis; secreted in Perichondrial
milk; possible roles in lactation Hypertrophic cells
Epidermis Unknown chondrocytes
Hair follicle Inhibits anagen Indian
Intestine Unknown hedgehog
Tooth enamel Induces osteoclastic resorption of overlying bone
Endocrine tissues
Parathyroid glands Stimulates placental transport of calcium?
Pancreatic islets Stimulates insulin secretion and somatic growth
Pituitary Unknown
Placenta Calcium transport? B Parathyroid
Central nervous system Released from cerebellar granular neurons in re- hormone–related
sponse to activation of L-type calcium chan- protein
nels; receptors in cerebellum, hippocampus,
hypothalamus

grammed cell death, or apoptosis (Fig. 1). Subse-
quently, the mineralized rudiment is invaded by bone
cells, which resorb the cartilaginous scaffolding and
replace it with bone.
In the absence of parathyroid hormone–related
protein, chondrocytes do not proliferate normally, giv-
ing rise to shortened bones. Their differentiation is
accelerated, so that their extracellular matrix is miner-
alized prematurely, and they undergo early apopto-
sis10-12 (Fig. 1). A mirror-image disorder is produced
in mice by targeted overexpression of parathyroid
hormone–related protein, using the cartilage-specific
type II collagen promoter to direct the expression of
the protein to chondrocytes. In mice that overexpress
parathyroid hormone–related protein in cartilage, the
maturation of chondrocytes is severely delayed, apop-
tosis is suspended, and islands of chondrocytes per-
sist within mature bone.13 Thus, the results of both
loss-of-function approaches (knockout of the para-
thyroid hormone–related protein gene) and gain-of-
function approaches (the targeted overexpression of
the protein in cartilage) lead to the conclusion that the
physiologic action of parathyroid hormone–related
protein in cartilage is to accelerate the growth of car-
tilage cells and to oppose their progression to a ter-
minally differentiated state.
How do the proliferative effects of parathyroid hor-
mone–related protein determine the size and shape
+ -
Parathyroid hormone–
related protein receptor
Indian hedgehog
Figure 1. The Expression and Action of Parathyroid Hormone–
Related Protein and Indian Hedgehog Protein during Endo-
chondral Bone Formation.
In Panel A, the transitional zone of the cartilaginous bone rudi-
ment is present between proliferating chondrocytes and hyper-
trophic chondrocytes. Indian hedgehog protein (red) is expressed
in the transitional zone, just proximal to a band of parathyroid
hormone–related protein receptors (green). By means of its
own receptors on perichondrial cells (blue), Indian hedgehog
initiates the secretion of parathyroid hormone–related protein
from periarticular cells (orange). In Panel B, Indian hedgehog is
secreted from committed early hypertrophic cells and induces
the secretion of parathyroid hormone–related protein (indicat-
ed by the plus sign), which binds to its receptor in late prolifer-
ating cells, which are not yet committed to differentiation, and
blocks the differentiation of these cells to hypertrophic chon-
drocytes (indicated by the minus sign). Thus, committed hyper-
trophic cells regulate the entry of cells into the hypertrophic
compartment.

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 M EC H A NIS MS OF D IS EASE
of the skeleton? To pattern bones, parathyroid hor-
mone–related protein works with the products of oth-
er patterning genes. One of them is Indian hedge-
hog (Ihh), a descendant found in vertebrates of the
drosophila gene hedgehog. In the fruit fly Drosophila
melanogaster, hedgehog encodes a secreted protein that
interacts with the products of other genes to set up
the pattern of the limbs and trunk. In vertebrates,
the Indian hedgehog protein is secreted by prehyper-
trophic chondrocytes. By means of its own receptors
in the perichondrial layer surrounding developing
bone, Indian hedgehog initiates the secretion of para-
thyroid hormone–related protein, which in turn stim-
ulates the proliferation of cartilage cells and prevents
the terminal differentiation of these cells.14,15 Recep-
tors for the parathyroid hormone–related protein are
present on proliferating chondrocytes, and levels are
highest in cells in the transitional zone, which lies
between the zones of proliferation and hypertrophy;
at these sites the cells are slightly less mature than
those that express Indian hedgehog (Fig. 1). At this
location, the system is situated to regulate a cross-
road in the life of a chondrocyte, the point at which
a cell either continues to proliferate or terminally dif-
ferentiates, becomes hypertrophied, and prepares to
mineralize the cartilaginous matrix, thereby complet-
ing its work.
The feedback effects of the Indian hedgehog pro-
tein are absent in animals in which the parathyroid
hormone–related protein gene has been knocked out,
establishing that parathyroid hormone–related pro-
tein acts downstream of hedgehog protein in the sys-
tem. The effect of these two proteins is to relay a
signal from mature cells to the crossroad at which pro-
liferation or maturation is chosen. This feedback loop
regulates the balance between the proliferation and
entry of chondrocytes into the differentiation path-
way and thereby ensures that the proliferation and
maturation of chondrocytes are balanced, so that the
linear growth of bone is orderly. Events that disrupt
the feedback lead to disordered formation of bone, as
illustrated by the disruption of growth-plate architec-
ture when cells lacking receptors for parathyroid hor-
mone or parathyroid hormone–related protein are
introduced into wild-type growth plates in chimeric
mice.16 The system could also be used to shut off the
linear growth of bone, and it may do so during pu-
berty. Thus, parathyroid hormone–related protein has
become linked during evolution to an enduring sys-
tem for the control of limb development.
The addition of either parathyroid hormone–relat-
ed protein or parathyroid hormone itself to cartilage
explants from mice with a homozygous deletion of
the gene for parathyroid hormone–related protein re-
verses the proliferative defect. The observation that
parathyroid hormone mimics the proliferative effect
of parathyroid hormone–related protein suggests that
the latter acts through shared receptors for parathy-
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roid hormone and parathyroid hormone–related pro-
tein in cartilage.
This mechanism has been confirmed by studies of
the receptor. Mice with targeted ablation of the re-
ceptor have the same phenotype as parathyroid hor-
mone–related protein knockout mice.15 (The recep-
tor knockout mice have a high incidence of early fetal
death, suggesting that the receptor for parathyroid
hormone and parathyroid hormone–related protein
also has an important role at an earlier stage of devel-
opment.) Patients with a rare chondrodysplasia, the
Blomstrand type, who have mutations of the receptor,
have a similar phenotype.17-19
In addition, a mutation of the gene for the receptor
for parathyroid hormone and parathyroid hormone–
related protein, which constitutively activates the re-
ceptor without a requirement for a ligand, gives rise
to a rare form of chondrodysplasia called Jansen’s dis-
ease or metaphyseal chondrodysplasia.20 Patients with
constitutively active parathyroid hormone receptors
in bone and kidney have hypercalcemia, as would be
expected, but they also have a marked delay in the
maturation of chondrocytes. Their bones have the
appearance of bones with an excess of parathyroid
hormone–related protein, as confirmed by targeting
of the causative mutation to cartilage in transgenic
mice,21 and are the mirror image of those resulting
from knockout of the parathyroid hormone–related
protein and the receptor for parathyroid hormone
and parathyroid hormone–related protein in mice.
The shared receptor is clearly responsible for the ac-
tions of parathyroid hormone–related protein in car-
tilage, yet circulating parathyroid hormone cannot
ameliorate the effects on cartilage of a deficiency of
parathyroid hormone–related protein.
The early death of mice with a homozygous dele-
tion of the gene for parathyroid hormone–related
protein meant that the effects of a deficiency of this
protein could not be studied in the various tissues in
which it is expressed in adults. Fortunately, a way of
preventing death in the neonatal period has been de-
vised. Mice that are heterozygous for the gene for par-
athyroid hormone–related protein have been crossed
with transgenic mice in which parathyroid hormone–
related protein is overexpressed in cartilage under the
control of the cartilage-specific type II collagen pro-
moter22 or, in separate experiments, with mice in which
the expression of the constitutively active receptor
for parathyroid hormone and parathyroid hormone–
related protein receptor is directed to cartilage.21 The
genetic crosses yield animals that have a homozygous
deletion of parathyroid hormone–related protein and
thus have a deficiency of the protein everywhere ex-
cept in cartilage, in which they express either parathy-
roid hormone–related protein or constitutively active
receptors for parathyroid hormone and parathyroid
hormone–related protein from the transgene, there-
by ensuring endochondral bone formation.
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A B C D
Epithelial Nipple Epithelial
Epithelium swelling Breast bud rudiment degeneration

Mesenchyme

Fat pad Fat Breast

pad rudiment

Figure 2. Development of Breast Rudiments in Mice with the Wild-Type Gene for the Parathyroid Hormone–Related Protein Receptor
and in Mice with a Homozygous Deletion of the Gene.
The breast bud begins as a swelling in the epithelium (Panel A). As the mammary bud grows into the underlying mesenchyme (on
embryonic day 15), bidirectional signals between epithelium and mesenchyme (arrows in Panel B) are required to maintain growth.
At this stage there is no developmental difference between wild-type mice and mice with a homozygous deletion of the gene for
parathyroid hormone–related protein. Panel C shows mammary development on embryonic day 18 in a wild-type mouse. The mam-
mary rudiment has grown into the fat pad and begun branching. The overlying epithelial swelling is the nipple rudiment. Panel D
shows mammary development on embryonic day 18 in a mouse with homozygous deletion of the gene for parathyroid hormone–
related protein. The development of the nipple rudiment has been arrested, epithelial cells are degenerating, mesenchymal cells
are tightly clustered around the invaginating rudiment (arrows), and the epithelial swelling has disappeared.

These so-called rescued knockout mice survive the
perinatal period. They have a complex developmen-
tal disorder that highlights a variety of postnatal ac-
tions of parathyroid hormone–related protein. These
include premature closure of the growth plates (epiph-
yses), failure of mammary glands to develop, absence
of tooth eruption, and abnormalities of the skin. These
mice can therefore be used to study the consequences
of a postnatal deficiency of parathyroid hormone–
related protein.
The finding that the growth plates disappear in res-
cued knockout mice suggests that the protein has a
physiologic role in the normal process of epiphyseal
closure. The closure of epiphyses at the time of pu-
berty, which ends linear growth and thus determines
a person’s ultimate height, is now recognized as be-
ing the direct result of the pubertal increase in estro-
gen secretion in women and in men as well. It is thus
possible that estrogen induces the closure of growth
plates by inhibiting the system of Indian hedgehog
protein and parathyroid hormone–related protein in
cartilage.
MAMMARY DEVELOPMENT
Mammary development in mice with a homozy-
gous deletion of the gene for parathyroid hormone–
related protein or of the gene for its receptor does
not progress beyond the earliest stages of ingrowth
of the mammary epithelial rudiment, which normal-
ly expresses parathyroid hormone–related protein, into
the underlying mesenchyme, which normally express-
es receptors for the protein 22 (Fig. 2). This finding
suggests that parathyroid hormone–related protein is
one of the signals in the complex interactions of ep-
ithelium and mesenchyme that underlie breast devel-
opment. Parathyroid hormone–related protein can be
reestablished in mammary epithelium by crossing res-
cued knockout mice with mice that express parathy-
roid hormone–related protein constitutively in the
mammary epithelium,23 creating mice that produce
parathyroid hormone–related protein only in car-
tilage (thus ensuring their survival) and the ingrow-
ing mammary rudiment. This strategy restores the
ingrowth of the breast bud, but the nipple still does
not develop normally.22
LACTATION
The role of parathyroid hormone–related protein
in breast tissue is not confined to the developmental
period. Glandular epithelial cells of the lactating breast
as well as myoepithelial cells produce large amounts
of parathyroid hormone–related protein. This find-
ing has led to the proposal that the protein may be
the long-postulated signal that is responsible for the
adaptation of maternal calcium metabolism to the
stress of lactation. A nursing mother secretes gram
quantities of calcium into milk to mineralize the skel-
eton of her offspring; lactation presents a particular

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 M EC H A NIS MS OF D IS EASE
challenge to calcium homeostasis in multiparous an-
imals. Yet the adaptation to this challenge does not
seem to require any of the hormones of calcium ho-
meostasis; a mother can successfully suckle her off-
spring despite having a calcium deficiency, hypopara-
thyroidism, or vitamin D deficiency, sacrificing a large
portion of her skeletal mineral to do so.24 Mothers
with hypoparathyroidism can even maintain normo-
calcemia without treatment during lactation, but they
must resume vitamin D supplementation thereafter.25
Parathyroid hormone–related protein is detectable
in the serum of nursing mothers.26,27 However, con-
clusive evidence that it is the long-sought lactation-
al signal is lacking. Nevertheless, mammary parathy-
roid hormone–related protein probably has systemic
effects, because serum concentrations of the protein
are high in women with the rare syndromes of hy-
percalcemia associated with lactation 28 and massive
mammary hypertrophy.29
During lactation, parathyroid hormone–related
protein is released on the stimulus of suckling30 and
secreted into the milk in quantities that are about
10,000 times as high as those in serum.31 This re-
creates for the nursing newborn the environment of
its developing gut in utero, because amniotic fluid
swallowed by the fetus also contains high concentra-
tions of parathyroid hormone–related protein.32
Receptors for parathyroid hormone–related pro-
tein are present in the intestinal epithelium.33 It is
possible that the protein has a physiologic role in the
developing alimentary tract or is absorbed to fulfill
other functions. However, infants raised on soy-based
formulas that do not contain parathyroid hormone–
related protein are healthy. It therefore appears that
parathyroid hormone–related protein in milk is not
essential.
TOOTH DEVELOPMENT
The failure of tooth eruption in rescued knockout
mice can also be attributed to epithelial–mesenchy-
mal interaction. The formation of the teeth appears to
be normal, but parathyroid hormone–related protein
is absent from the enamel epithelium, which caps the
tooth rudiment as it pushes its way through the over-
lying alveolar bone to erupt. Restoration of parathy-
roid hormone–related protein to enamel epithelium
in these mice, by directing the protein to this cell
layer with use of a tissue-specific promoter, restores
tooth eruption.34 This finding implies that parathyroid
hormone–related protein secreted by the epithelial
layer is normally targeted to receptors in the overly-
ing bone, where it activates resorption of alveolar
bone by osteoclasts to allow passage of the tooth. The
signaling circuit in alveolar bone is distinctive, be-
cause there is no general defect in osteoclast function
in transgenic mice. If present, a generalized impair-
ment in osteoclast function would result in general-
ized osteopetrosis or marble bone disease.
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EFFECTS ON SKIN AND HAIR FOLLICLES
One prominent site of the normal production of
parathyroid hormone–related protein is the epidermis.
The activation of the gene in epidermal keratinocytes
probably accounts for the frequency of hypercalce-
mia induced by parathyroid hormone–related protein
in patients with squamous carcinomas, which arise
from this type of cell. The level of expression of para-
thyroid hormone–related protein seems to control
the size of the proliferative pool of basal keratino-
cytes, from which keratinocytes exit to undergo ter-
minal differentiation, keratinization, and apoptosis.
This pool is increased when parathyroid hormone–
related protein is overexpressed in the skin but is di-
minished in rescued knockout mice, with a reciprocal
increase in granular cells that have entered the differ-
entiation pathway. These findings suggest that, after
birth, parathyroid hormone–related protein regulates
epidermal cell traffic in mice in much the same way
that it does in endochondral ossification prenatally.35
Parathyroid hormone–related protein is also pro-
duced by cells of the inner root sheath of the hair fol-
licle. The receptor for parathyroid hormone and par-
athyroid hormone–related protein is present in the
underlying dermis. Treatment with an antagonist of
parathyroid hormone–related protein increases the
number of hair follicles in anagen, the active phase of
hair growth.36 Skin is excessively keratinized and the
hair coat is shaggy in rescued knockout mice; con-
versely, alopecia results when parathyroid hormone–
related protein is overexpressed in the skin.37 These
effects provide another example of epithelial–mes-
enchymal interactions in which parathyroid hormone–
related protein serves as the messenger.
EXPRESSION IN THE CENTRAL
NERVOUS SYSTEM
Parathyroid hormone–related protein and its re-
ceptors are both expressed widely in the central nerv-
ous system.38 The protein protects neurons against
glutamate-induced excitotoxicity in cerebellar gran-
ule cells. This form of excitotoxicity results from the
activation of voltage-dependent calcium channels by
glutamate receptors of the kainate class. The activa-
tion of voltage-dependent calcium channels marked-
ly increases the expression of parathyroid hormone–
related protein,39 which in turn inhibits the entry of
calcium and promotes the survival of neurons. As
might be predicted from this observation, there is a
striking age-dependent decrease in neurons in mice
with a homozygous deletion of the gene for parathy-
roid hormone–related protein, particularly in areas
of the cerebral cortex and hippocampus.40
SPECIFICITY OF ACTION
Parathyroid hormone and parathyroid hormone–
related protein have different biologic roles. Parathy-
roid hormone is a circulating hormone that carries
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1 13 37 88–91 102–106 139

Parathyroid
hormone–related
protein

1 36 38 94 107 139

Peptides PTH-like Midregion Osteostatin

Site of Cartilage Placental calcium transport Bone resorption

effect Breast Renal bicarbonate transport? Brain
Skin

Figure 3. Structural Features of Parathyroid Hormone–Related Protein.

The domain that is homologous with that of parathyroid hormone (amino acids 1 through 13) is shown in yellow, and potential
cleavage sites are shown in red. The peptides known or postulated to be derived from parathyroid hormone–related protein are shown
below. Three midregion peptides, terminating at amino acids 94, 95, and 101, have been identified. Proven or postulated sites of
effects of individual peptides are shown beneath each peptide. PTH denotes parathyroid hormone.

signals from a calcium sensor in the parathyroid glands
to remote target tissues; parathyroid hormone–related
protein is a local messenger within tissues. Yet they
share a receptor. There are at least two general ways in
which the specificity of hormone action could have
come about. First, circulating parathyroid hormone
may not be able to gain access to tissue receptors that
are designed to respond to parathyroid hormone–
related protein. This is true in cartilage, skin, and
breast tissue, where the shared receptor is used by par-
athyroid hormone–related protein, but circulating
parathyroid hormone cannot compensate for the ab-
sence of parathyroid hormone–related protein. The
receptor in cartilage may be relatively inaccessible to
circulating parathyroid hormone because of the avas-
cular nature of cartilage, but breast tissue and skin, at
least, are exposed to both peptides. In these tissues,
the differences in responsiveness may be due to the re-
ceptor’s sensitivity to the activating ligand. Sensitiv-
ity can be regulated by altering the number of recep-
tors or, in the case of G-protein–coupled receptors
such as the receptor for parathyroid hormone and
parathyroid hormone–related protein receptor, the
number of G proteins available to couple the receptor
to a cellular effector network. When the number of
receptors is low, a higher fraction of receptors must
be occupied to induce a response; this scenario would
require a higher hormone concentration, thus favor-
ing the local regulator.
Evolution has also forged a second strategy to pro-
vide unique roles for parathyroid hormone–related
protein in tissues: the use of additional receptors that
are not shared with parathyroid hormone. Only the
amino-terminal sequences of parathyroid hormone–
related protein and parathyroid hormone are similar,
and there are potential cleavage sites that demarcate
the homologous domain from midregion and car-
boxyl-terminal domains (Fig. 3). Within the cells that
secrete it, parathyroid hormone–related protein is
processed by members of the family of prohormone
convertases to at least three fragments.9,41 This find-
ing suggests that it is a polyhormone, the precursor
of multiple biologically active peptides, much like the
pituitary protein proopiomelanocortin, which is the
precursor not only of corticotropin but also of mel-
anocyte-stimulating hormone and endorphins. The
strongest evidence in support of the polyhormone hy-
pothesis comes from studies of the regulation of pla-
cental calcium transport.
EXPRESSION IN PLACENTA
In order to supply calcium to the mineralizing skel-
eton of the fetus, calcium is transported across the
placenta by a placental pump, which maintains higher
serum calcium concentrations in the fetus than in the
mother. This maternal–fetal gradient is abolished in
mice with a homozygous deletion of the gene for
parathyroid hormone–related protein,42 indicating
that this protein is the principal regulator of placen-
tal calcium transport. Placental transport of calcium in
sheep is sharply reduced after parathyroidectomy,43
suggesting that the source of parathyroid hormone–
related protein is, at least in part, the fetal parathy-
roid glands. The transport of calcium can be restored
by the introduction of midregion fragments of par-
athyroid hormone–related protein, but not by the
introduction of amino-terminal fragments of the pro-
tein or by parathyroid hormone.42,44,45 This effect es-

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 MECH A NIS MS OF D IS EASE
tablishes that parathyroid hormone–related protein
is a polyhormone. The fetus uses a midregion pep-
tide derived from parathyroid hormone–related pro-
tein for the regulation of systemic calcium economy,
rather than the amino-terminal domain homologous
to that of parathyroid hormone.
The receptor for midregion parathyroid hormone–
related protein, whose existence is suggested by these
results, has not yet been identified, but the family of
parathyroid hormone–related protein receptors will
almost certainly be larger than two. Brain cells,46 in-
sulinoma cells,47 and skin cells48 have receptors that
are specific for the amino-terminal fragment of para-
thyroid hormone–related protein and that do not
recognize parathyroid hormone. There is also evi-
dence of a receptor for the carboxyl-terminal frag-
ment of parathyroid hormone–related protein in the
brain49 and putatively in bone, where this fragment,
sometimes called osteostatin, appears to inhibit the
resorption of bone.50,51 Finally, as discussed below,
some effects of parathyroid hormone–related protein
may not be mediated by a cell-surface receptor at all.
EFFECTS ON SMOOTH MUSCLE
Parathyroid hormone–related protein is secreted by
a variety of smooth-muscle beds,52 in which it is re-
leased in response to mechanical stretching53,54 and in
response to vasoconstrictors such as angiotensin II.55
It acts as a smooth-muscle dilator by binding to its
receptor.56 This process sets up the circuitry for a
short-loop feedback system in which parathyroid hor-
mone–related protein responds to stretching by re-
laxing smooth muscle locally. In keeping with this
hypothesis, transgenic mice that express parathyroid
hormone–related protein in vascular smooth mus-
cle have low blood pressure.57 A similar pathway or
mechanism could also be operative in uterine smooth
muscle at the time of parturition,54 when parathy-
roid hormone–related protein may signal for cervical
dilatation to begin; in the urinary bladder53; in arte-
rial hypertension58; and even in the heart, where the
protein is released by atrial and ventricular myocytes59
and has a positive chronotropic effect, as well as a
positive inotropic effect that probably results from
coronary vasodilation.60,61
Parathyroid hormone–related protein is expressed
in proliferating vascular smooth-muscle cells in cul-
ture55 and after balloon angioplasty in vivo.62 The
concentration of the protein is increased in athero-
sclerotic coronary arteries.63 Exposure of rat vascular
smooth-muscle cells to parathyroid hormone–relat-
ed protein has an antimitotic effect, suggesting that
local release of the protein would reduce the re-
sponse to a proliferative stimulus.55 In contrast, when
transfected into A10 rat vascular smooth-muscle cells,
parathyroid hormone–related protein induces marked
proliferation.64 The proliferative response does not
occur with transfection of mutant forms from which
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polybasic amino acid sequences between residues 88
and 106 have been deleted. These sequences function
as a nuclear-localization sequence in other cells,65,66
and wild-type parathyroid hormone–related protein,
but not the mutant form, is targeted to the nucleus
of A10 cells. It thus appears possible that in addition
to binding to cell-surface receptors, parathyroid hor-
mone–related protein can have direct nuclear actions,
termed intracrine actions. Since secreted fragments
of the protein and its intracrine actions appear to have
opposing effects on proliferation, the protein could
interact in a complex fashion with other proliferative
factors in determining the response of the vascular
wall to injury or atherosclerosis.
CONCLUSIONS
The breadth of the biologic actions of parathyroid
hormone–related protein is impressive (Table 1), but
several principles are evident. Parathyroid hormone–
related protein has evolved to regulate local tissue
functions, in contrast to the systemic hormonal func-
tion of parathyroid hormone. These local functions
fall into several classes: in mesenchymal tissues such
as cartilage, the protein functions in local feedback
loops to control rates of proliferation and differenti-
ation, thus allowing local tissue organization. It is ex-
pressed by several epithelia and participates in epi-
thelial–mesenchymal interactions by activating the
receptor for parathyroid hormone and parathyroid
hormone–related protein in the underlying mesen-
chyme. To carry out its diverse biologic roles, parathy-
roid hormone–related protein functions as a poly-
hormone. It gives rise to several biologically active
peptides, each of which presumably has its own re-
ceptor. To broaden its repertoire even further, it ap-
pears to have intracrine effects in the nucleus of cells
that produce it in addition to having juxtacrine, para-
crine, and possibly, endocrine effects after secretion.
Given that parathyroid hormone–related protein was
identified as a result of the clinical investigation of
hypercalcemia in patients with cancer, the story of
the protein is an apt illustration of the adage, “Med-
icine is the tutor of biology.”
I am indebted to Dr. A.E. Broadus for sharing data before publi-
cation.
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