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Functional Anatomy of the Thyroid and Parathyroid Glands
The thyroid gland is located in the ____, in close approximation to
the first part of the trachea.
In humans, the thyroid gland has a "butterfly" shape, with two
lateral lobes that are connected by a narrow section called the
isthmus.
Most animals, however, have ____separate glands on either side of
the trachea.
Thyroid glands are __________________ in color.
Close examination of a ______ gland will reveal one or more small,
light-colored nodules on or protruding from its surface - these are
_________glands (meaning "beside the thyroid").
The image shows a canine thyroid gland and one attached parathyroid
gland.
Occasionally, a person is born with one or more of the parathyroid
glands embedded in the thyroid, the thymus, or elsewhere in the
chest. In most such cases, however, the glands function normally.
Though their names are similar,
the thyroid and parathyroid glands are
_________________glands,
each producing distinct hormones with specific
______________.
Parathyroid hormone
____ is the most important endocrine
regulator of ______ and __________
concentration in extracellular fluid.
This hormone is secreted from cells of the
parathyroid glands and finds its major target
cells in ____and _____. Another hormone,
______________________________, binds to
the same receptor as parathyroid hormone
and has major effects on ________.
Parathyroid hormone
Like most other protein hormones,____ is synthesized as a
________hormone.
After intracellular processing, the mature hormone is
packaged within the Golgi into secretory vesicles, the
secreted into blood by ________.
PTH is secreted as a
linear protein of ___ aa.
Although the __ parathyroid glands are quite small- have a
very rich _______ supply.
IMPORTANTthey are required to monitor the calcium level in the blood
____hours a day.
As the blood filters through the parathyroid glands, they
detect the amount of ______ present in the blood and react
by making more or less parathyroid hormone (__). When
the calcium level in the blood is too low, the cells of the
parathyroids sense it and make more PTH
Once PTH is released into the blood, it circulates to act in
a # of places to increase the amount of calcium in the
blood.
When the _____ level in the blood is too high, the
cells of the parathyroids make less ____ (or stop
making it altogether), thereby allowing ______
levels to decrease.
This feed-back mechanism runs constantly, thereby
maintaining _____ (and PTH) in a very narrow
"normal" range.
In a normal person with normal parathyroid
glands, their parathyroid glands will turn on and
off _________ times per day...in an attempt to keep
the _______ level in the normal range so our brain
and muscles function properly.
Physiologic Effects of Parathyroid Hormone
Function for ____ is straightforward:
if _______ ion concentrations in extracellular
fluid fall below normal, bring them back
within the normal range.
In conjunction with increasing calcium
concentration, the concentration of
________ ion in blood is _______.
Parathyroid Hormone Receptors
PTH and its cousin _________ are critical
controllers of c_____and p______ balance.
The receptors for these ___ hormones are of high
interest to drug companies, because such
understanding may facilitate development of
antagonists for treatment of a number of
important diseases, including _________and
hypercalcemia associated with some types of
_______.
Parathyroid Hormone Receptors
Type __ PTH receptor:
PTH and
____________
peptides of PTHrP.
G protein-coupled
receptor
Type __ PTH receptor: Binds
PTH, but has very
____affinity for PTHrP. only
expressed in a few tissues- its
structure and physiologic
significance are poorly
characterized. Like the type 1
receptor, it is coupled to
______ and ligand binding
induces a rise in intracellular
concentration of _______.
Physiologic Effects of Parathyroid Hormone
Parathyroid hormone accomplishes its job by stimulating at least
three processes:
Mobilization of _____ from _____: Although the
mechanisms remain obscure, a well-documented
effect of parathyroid hormone is to stimulate
__________to reabsorb bone mineral, liberating
calcium into _______.
Physiologic Effects of Parathyroid Hormone
Enhancing absorption of ______ from the
___________: Facilitating calcium absorption
from the small intestine would clearly serve to
elevate blood levels of calcium.
Parathyroid hormone stimulates this process, but
indirectly by stimulating production of the active
form of ________ in the kidney. Vitamin D
induces synthesis of a calcium-binding protein in
intestinal epithelial cells that facilitates efficient
absorption of calcium into ______.
Physiologic Effects of Parathyroid Hormone
Parathyroid hormone accomplishes its job by stimulating at least
three processes:
Suppression of ______ loss in urine: In addition to
stimulating fluxes of calcium into blood from
____ and _____, parathyroid hormone puts a
brake on __________________ in urine, thus
conserving ______in blood. This effect is
mediated by stimulating tubular reabsorption of
calcium. Another effect of parathyroid hormone
on the kidney is to stimulate loss of _______ ions
in urine.
Control of Parathyroid Hormone Secretion
PTH is released in response to ___________
concentrations of free ________
Changes in blood phosphate concentration can be
associated with changes in PTH secretion, but
this appears to be an indirect effect and
phosphate per se is __ a significant ________of
this hormone.
Control of Parathyroid Hormone
Secretion
When calcium concentrations fall below
the normal range, there is a steep
______in secretion of PTH. Low
levels of the hormone are secreted
even when blood calcium levels are
____. The figure depicts PTH release
from cells cultured in vitro in
differing concentrations of calcium.
The parathyroid cell monitors
extracellular free
______concentration via an integral
membrane protein that functions as
a ___________________
Extracellular Calcium-Sensing Receptor
Maintaining tight control over the concentration of c_______ in
blood and extracellular fluid is a critical task.
It stands to reason that a calcium sensor would evolve as a
component of the system responsible for calcium _________.
Considering its involvement in modulating so many physiologic
processes, calcium itself can be thought of as a type of ______,
and the __________ as its receptor.
The DNA sequence encoding the extracellular calcium sensor was
originally isolated from bovine ____________. Since then,
corresponding sequences have been isolated from a broad range
of species, enabling serious study of this intriguing membrane
protein.
The ____________ receptor is a member of the G protein-coupled
receptor family. Like other family members, it contains
______and is present in___. The large (~600 amino acids)
extracellular domain is known to be critical to interactions with
____________________. The receptor also has a rather large
(~200 amino acids) cytosolic tail.
-intracellular domain has _________________________ sites.
The __________ is expressed in a broad range of
cells, including _______ and __ cells in the
thyroid gland, indicating its involvement in
controlling the synthesis and secretion of ______
and _________.
Functional studies and investigation of animals
with mutations in the calcium sensor gene have
confirmed that the _________ directly affects
secretion of these two hormones.
Calcitonin
_______ is a hormone involved in calcium and phosphorus
metabolism.
In mammals, the major source of ________ is from the
parafollicular or __ cells in the _______gland, but it is
also synthesized in a wide variety of other tissues.
Calcitonin is a __ aa peptide cleaved from a larger
___hormone.
It contains a single disulfide bond, which causes the amino
terminus to assume the shape of a ring.
Calcitonin
Calcitonin is a hormone involved in calcium and phosphorus
metabolism.
Alternative splicing of the calcitonin pre-mRNA can yield
a mRNA encoding calcitonin gene-related peptide; that
peptide appears to function in the nervous and vascular
systems.
The _________ receptor has been cloned and shown to be a
member of the _______________________ receptor
family.
Calcitonin
Physiologic Effects of Calcitonin
A large and diverse set of effects has been attributed to
___________, but in many cases, these were seen in
response to pharmacologic doses of the hormone, and
their physiologic relevance is ________.
It is clear however, that calcitonin plays a role in _______
and ___________ metabolism.
Calcitonin
Physiologic Effects of Calcitonin
calcitonin has the ability to ________blood calcium levels
at least in part by effects on two well-studied target
organs:
_______: Calcitonin suppresses resorption of _____ by
inhibiting the activity of ___________, a cell type that
"digests" bone matrix, releasing calcium and
phosphorus into blood.
_______: Calcium and phosphorus are prevented from
being lost in urine by reabsorption in the __________.
Calcitonin inhibits tubular reabsorption of these two
____, leading to increased rates of their loss in _____.
Calcitonin
There are ______ differences in the importance of
calcitonin as a factor affecting calcium homeostasis.
In ___, rodents and some domestic animals, calcitonin
appears to play a __________ role in calcium
homeostasis.
In humans, ______ has at best a _______ role in regulating
blood concentrations of calcium. One interesting piece
of evidence to support this statement is that humans
with chronically increased (medullary thyroid cancer)
or decreased (surgical removal of the thyroid gland)
levels of calcitonin in blood usually do not show
alterations from normal in serum calcium
concentration.
Calcitonin
Control of Calcitonin Secretion
The most prominent factor controlling calcitonin secretion
is the extracellular concentration of ionized calcium.
Elevated blood calcium levels strongly __________
calcitonin secretion, and secretion is suppressed when
calcium concentration falls below normal.
A number of other _________ have been shown to
stimulate calcitonin release in certain situations, and
nervous controls also have been demonstrated.
Calcitonin
Disease States
A large number of diseases are associated with
abnormally increased or decreased levels of
calcitonin, but ____________ effects of abnormal
calcitonin secretion per se are not generally
recognized.
Endocrine Control of Calcium and
Phosphate Homeostasis
It would be very difficult to name a
physiologic process that does not
depend, in one way or another, on
________
critical to maintain blood calcium
concentrations within a ______ normal
range.
Deviations above or below the normal
range frequently lead to _______disease.
Endocrine Control of Calcium and Phosphate Homeostasis
_________ refers to low blood calcium concentration.
Clinical signs of this disorder reflect increased
neuromuscular excitability and include muscle spasms,
tetany and cardiac dysfunction.
_______ indicates a concentration of blood calcium higher
than normal. The normal concentration of calcium and
phosphate in blood and extracellular fluid is near the
saturation point; elevations can lead to diffuse
precipitation of calcium phosphate in tissues, leading to
widespread organ dysfunction and damage.
Preventing hypercalcemia and hypocalcemia is largely the
result of robust _________ control systems.
Body Distribution of Calcium and Phosphate
3 major pools of calcium in the body:
__________: A large majority of calcium within cells is
sequestered in _______and ____. Intracellular free
calcium concentrations fluctuate greatly, from roughly
100 nM to greater than 1 uM, due to release from
cellular stores or influx from extracellular fluid. These
fluctuations are integral to calcium's role in
intracellular signaling, enzyme activation and muscle
contractions.
Body Distribution of Calcium and Phosphate
3 major pools of calcium in the body:
_______________: Roughly ____ of the calcium in
blood is bound to proteins. The concentration of ionized
calcium in this compartment is normally almost
invariant at approximately 1 mM, or 10,000 times the
basal concentration of free calcium within cells. Also,
the ___________of phosphorus in blood is essentially
identical to that of calcium.
______: A vast majority of body calcium is in ____. Within
bone, ___% of the calcium is tied up in the mineral
phase, but the remaining __% is in a pool that can
rapidly exchange with ___________ calcium.
Endocrine Control of Calcium and Phosphate Homeostasis
Fluxes of Calcium and Phosphate
Maintaining constant concentrations of calcium in blood requires
frequent adjustments, which can be described as fluxes of
calcium between blood and other body compartments.
Three organs participate in supplying calcium to blood and
removing it from blood when necessary:
The _________ is the site where dietary ______ is absorbed.
Importantly, efficient absorption of calcium in the small intestine
is dependent on expression of a calcium-binding protein
Bone serves as a _______ of calcium. Stimulating net resorption of
bone mineral releases calcium and phosphate into blood, and
suppressing this effect allows calcium to be deposited in bone.
Endocrine Control of Calcium and Phosphate Homeostasis
Fluxes of Calcium and Phosphate
The ____ is critically important in
_______homeostasis. Under normal blood
calcium concentrations, almost all of the calcium
that enters glomerular filtrate is reabsorbed
from the tubular system back into blood, which
preserves blood calcium levels.
If tubular reabsorption of calcium decreases,
calcium is lost by excretion into _________.
Hormonal Control Systems
Maintaining normal blood calcium and phosphorus
concentrations is managed through the
concerted action of
_____________________
that control fluxes of calcium in and out of blood
and extracellular fluid:
Hormonal Control Systems
____ serves to increase blood concentrations of calcium.
Mechanistically, ____ preserves blood calcium by several major
effects:
Stimulates production of the biologically-active form of _____ within
the kidney.
Facilitates mobilization of _____ and phosphate from bone. To
prevent detrimental increases in phosphate, _____ also has a
potent effect on the kidney to eliminate phosphate (phosphaturic
effect).
Maximizes tubular reabsorption of ________ within the kidney.
This activity results in minimal losses of ______ in _______.
Hormonal Control Systems
_______ acts also function to increase blood concentrations of
calcium. It is generated through the activity of PTH within
the kidney.
Far and away the most important effect of ________ is to
facilitate absorption of calcium from the _______. In
concert with PTH, vitamin D also enhances fluxes of
calcium out of bone.
_______ is a hormone that functions to reduce blood
calcium levels.
Vitamin D (Cholecalciferol, Calcitriol)
________ is a steroid hormone that has long been known
for its important role in regulating body levels of
calcium and phosphorus, and in mineralization of bone.
More recently, it has become clear that receptors for
vitamin D are present in a wide variety of cells, and that
this hormone has biologic effects which extend
____________________________________
Structure and Synthesis-Vitamin D
The term vitamin D actually refers to a ___________ molecules.
Vitamin D3, also known as cholecalciferol is generated in the
s___of animals when light energy is absorbed by a
precursor molecule 7-dehydrocholesterol.
_______ is thus not a true vitamin, because individuals with
adequate exposure to ________ do not require dietary
supplementation.
There are dietary sources of vitamin D, including ____, fish oil and a
number of _____.
The plant form of vitamin D is called vitamin D2 or ergosterol.
However, natural diets typically do not contain adequate
quantities of vitamin D, and exposure to sunlight or consumption
of foodstuffs purposefully supplemented with vitamin D are
necessary to prevent deficiencies.
Vitamin D, as either D3 or D2, does not have
_________________________________________
Rather, it must be ______ within the _____ to the hormonally-active
form.
This transformation occurs in ___steps, as depicted in the diagram
on the next slide
Within the ______, cholecalciferal is hydroxylated
to 25-hydroxycholecalciferol by the enzyme 25-hydroxylase.
Within the______, 25-vitamin D serves as a substrate for 1-alphahydroxylase, yielding 1,25-dihydroxycholecalciferol, the
biologically active form of vitamin D.
Each of the forms of _______ is _________ and is
transported in blood bound to carrier proteins.
The major carrier is called, appropriately, vitamin Dbinding protein.
The half-life of 25-hydroxycholecalciferol is several
weeks, while that of 1,25-dihydroxycholecalciferol
is only a ________s.
Control of Vitamin D Synthesis
Hepatic synthesis of 25-hydroxycholecalciferol
is only loosely regulated, and blood levels of
this molecule largely reflect the amount of
amount of vitamin D produced in the ____ or
______.
In contrast, the activity of 1-alpha-hydroxylase
in the _____ is tightly regulated and serves
as the major control point in production of
the active hormone. The major inducer of 1alpha-hydroxylase is _____: it is also induced
by low blood levels of phosphate.
The Vitamin D Receptor and Mechanism of Action
The active form of vitamin D binds to intracellular
receptors that then function as ___________ to
modulate gene expression. Like steroid hormones and
thyroid hormones, the _________ receptor has
hormone-binding and DNA-binding domains.
The vitamin D receptor forms a complex with another
intracellular receptor, the retinoid-X receptor (RXR),
and that ________ is what binds to DNA.
In most cases studied, the effect is to activate transcription,
but situations are also known in which vitamin D
suppresses transcription.
The vitamin D receptor binds several forms of
cholecalciferol. Its affinity for 1,25dihydroxycholecalciferol is roughly 1000 times that for
25-hydroxycholecalciferol, which explains their relative
Physiological Effects of Vitamin D
Vitamin D is well known as a hormone involved in ______
metabolism and ______ growth.
Its most dramatic effect is to facilitate _______ absorption
of calcium, although it also stimulates absorption of
phosphate and magnesium ions.
In the absence of vitamin D, dietary calcium is not
absorbed at all efficiently. Vitamin D stimulates the
expression of a number of proteins involved in
transporting calcium from the lumen of the intestine,
across the epithelial cells and into blood. The beststudied of these calcium transporters is _______, an
intracellular protein that ferries calcium across the
intestinal epithelial cell.
Physiological Effects of Vitamin D
Numerous effects of vitamin D on bone have been demonstrated.
As a transcriptional regulator of bone matrix proteins, it induces the
expression of osteocalcin and suppresses synthesis of type I
collagen. In cell cultures, vitamin D stimulates differentiation of
osteoclasts. However, studies of humans and animals with
vitamin D deficiency or mutations in the vitamin D receptor
suggest that these effects are perhaps not of major physiologic
importance, and that the crucial effect of vitamin D on bone is to
provide the proper balance of calcium and phosphorus to
support mineralization.
vitamin D receptors are present in most if not all cells in the body.
Additionally, experiments using cultured cells have demonstrated
that vitamin D has potent effects on the growth and
differentiation of many types of cells. Hence, vitamin D has
physiologic effects much ______ that a role in mineral
Disease States
Vitamin D deficiency: The classical manifestations of vitamin D
deficiency is ________, which is seen in children and results in
bony deformaties including bowed long bones.
Disease States
Deficiency in adults leads to the disease osteomalacia. Both rickets
and osteomalacia reflect impaired mineralization of newly
synthesized bone matrix, and usually result from a combination
of inadequate exposure to ______and decreased dietary intake of
_________________.
Disease States
Vitamin D deficiency or insufficiency occurs in several other
situations, which you might predict based on the synthetic
pathway described above:
Genetic defects in the ________ receptor: a number of different
mutations have been identified in humans that lead to hereditary
________ resistance.
Severe_____ or ______ disease: this can interfere with generation
of the biologically-active form of vitamin D.
Disease States
Vitamin D deficiency or insufficiency occurs in several other
situations, which you might predict based on the synthetic
pathway described above:
Insufficient exposure to _________: Elderly people that stay inside
and have poor diets often have at least subclinical deficiency.
Disease States
Ironically, it appears that hypovitaminosis D is very
common in some of the most sunny countries in the
world - the cause of this problem is the cultural dictate
that women be heavily veiled when outside in public.
Sunscreens, especially those with SPF ratings greater than
8, effectively block synthesis of vitamin D in the skin.
However, people that use such sunscreens usually live in
industrial countries where many foods are
supplemented with vitamin D, and vitamin D deficiency
is thereby averted by dietary intake.
Disease States
Vitamin D toxicity: Excessive exposure to sunlight does not
lead to overproduction of ________. Vitamin D toxicity
is inevitably the result of overdosing on vitamin D
_______. Don't do this! Ingestion of milligram
quantities of vitamin D over periods of weeks of months
can be severely ______ to humans and animals. In fact,
baits laced with vitamin D are used very effectively as
_____________.
Disease States
Both
and
secretion of PTH are
recognized as causes of serious disease in
man and animals.
Excessive secretion of parathyroid hormone
is seen in ______ forms:
______
Is the result of parathyroid gland disease, most commonly
due to a parathyroid tumor (adenoma) which secretes
the hormone without proper regulation.
Common manifestations of this disorder are chronic
elevations of blood ______ concentration
(hypercalcemia), ______ and decalcification of bone.
hypercalcemia is what usually signals the doctor that something
may be wrong with the parathyroid glands.
In ______ of people with this disorder, a benign tumor (adenoma)
has formed on one of the parathyroid glands, causing it to
become overactive.
In most other cases, the excess hormone comes from two or more
enlarged parathyroid glands, a condition called hyperplasia.
Very rarely, hyperparathyroidism is caused by cancer of a
parathyroid gland.
This excess ______ triggers the release of too much calcium into the
bloodstream. The bones may lose calcium, and too much calcium
may be absorbed from food. The levels of calcium may increase
in the urine, causing kidney stones. PTH also acts to lower blood
phosphorous levels by increasing excretion of phosphorus in the
______.
Why Are Calcium and Phosphorous So Important?
Calcium is essential for good health.
It plays an important role in ______
development and in
maintaining bone strength.
It is also important in ______
Phosphorous is found in ______
Combined with calcium, it gives strength and rigidity to your bones
and teeth.
What Causes Hyperparathyroidism?
In most cases ______.
The vast majority of cases occur in people with no family
history of the disorder.
Only about ______ % of cases can be linked to an
inherited problem. Familial (multiple) endocrine
neoplasia type I is one rare inherited syndrome that
affects the parathyroids as well as the pancreas and the
pituitary gland.
Another rare genetic disorder, familial hypocalciuric
hypercalcemia, is sometimes confused with typical
hyperparathyroidism.
How Common Is Hyperparathyroidism?
In the U.S., about 100,000 people develop the
disorder each year. Women outnumber men
______ to 1, and risk increases with ______. In
women 60 years and older, 2 out of 1,000 will get
hyperparathyroidism.
What Are the Symptoms of Hyperparathyroidism?
may have ______ symptoms, subtle ones, or none at all.
Increasingly, routine blood tests that screen for a wide range of
conditions including ______ levels are alerting doctors to people
who, though symptom-free, have mild forms of the disorder.
When symptoms do appear, they are often mild and nonspecific,
such as a feeling of weakness and fatigue, depression, or aches
and pains. With more severe disease, a person may have a loss of
______, nausea, vomiting, constipation, confusion or impaired
thinking ______, and increased ______
. Patients may
have thinning of the bones without symptoms, but with risk of
fractures.
Increased calcium and phosphorous excretion in the urine may cause
______. Patients with hyperparathyroidism may be more likely
to develop peptic ulcers, high blood pressure, and pancreatitis.
How Is Hyperparathyroidism Diagnosed?
Hyperparathyroidism is diagnosed when tests show that blood levels
of calcium as well as PTH are too high.
Other diseases can cause high blood calcium levels, but only in
hyperparathyroidism is the elevated calcium the result of too
much PTH.
______ has simplified the diagnosis of hyperparathyroidism.
Once the diagnosis is established, other tests may be done to assess
complications.
Because high PTH levels can cause bones to weaken from calcium
loss, a measurement of ______ may be done to assess bone loss
and the risk of fractures. Abdominal radiographs may reveal the
presence of kidney stones and a 24-hour urine collection may
provide information on kidney damage and the risk of stone
formation.
How Is Hyperparathyroidism Treated?
Surgery to remove the enlarged gland(s) is the only
treatment for the disorder and cures it in ______ of
cases.
However, some patients who have mild disease may not
need immediate treatment, according to a panel of
experts convened by the National Institutes of Health in
1990.
Patients who are symptom-free, whose blood ______ is
only slightly elevated, and whose kidneys and bones are
normal, may wish to talk to their doctor about longterm monitoring.
How Is Hyperparathyroidism Treated?
In the panel's recommendation, monitoring would consist of clinical
evaluation and measurement of ______ levels and ______
function every 6 months, annual abdominal x-ray, and bone mass
measurement after 1 to 2 years.
If the disease shows no signs of worsening after 1 to 3 years, the
interval between exams may be lengthened.
If the patient and doctor choose long-term followup, the patient
should try to ______, and get plenty of exercise. Immobilization
and gastrointestinal illness with vomiting or diarrhea can cause
calcium levels to rise, and if these conditions develop, patients
with hyperparathyroidism should seek medical attention
Are There Any Complications Associated With Parathyroid
Surgery?
Surgery for hyperparathyroidism is highly successful with a low
complication rate when performed by surgeons experienced with
this condition. About 1 % of patients undergoing surgery have
damage to the nerves controlling the vocal cords, which can
affect speech.
1-5% of patients develop chronic low calcium levels, which may
require treatment with calcium and/or vitamin D.
The complication rate is slightly higher for hyperplasia than it is for
adenoma since more extensive surgery is needed.
.
Are Parathyroid Imaging Tests Needed Before Surgery?
NOPE
The NIH panel recommended against the use of expensive imaging
tests to locate benign tumors before initial surgery.
Research shows that such tests do not improve the success rate of
surgery, which is about ______ when performed by experienced
surgeons.
Localization tests are useful in patients having a second operation
for recurrent or persistent hyperparathyroidism.
.
Secondary hyperparathyroidism
is the situation where disease outside of the parathyroid gland leads
to excessive secretion of parathyroid hormone.
A common cause of this disorder is kidney disease - if the kidneys
are unable to reabsorb calcium, blood calcium levels will fall,
stimulating continual secretion of parathyroid hormone to
maintain normal calcium levels in blood.
Secondary hyperparathyroidism can also result from inadequate
nutrition - for example, diets that are deficient in calcium or
vitamin D, or which contain excessive phosphorus (e.g. all meat
diets for carnivores).
A prominent effect of secondary hyperparathyroidism is
decalcification of bone, leading to pathologic fractures or
"rubber bones".
There is no doubt that chronic secretion or
continuous infusion of PTH leads to
decalcification of bone and loss of bone mass.
However, in certain situations, treatment with PTH
can actually stimulate an increase in bone mass
and bone strength. This seemingly paradoxical
effect occurs when the hormone is administered
in pulses (e.g. by once daily injection), and such
treatment appears to be an effective therapy for
diseases such as osteoporosis.
Inadequate production of parathyroid hormone –
______ - typically results in decreased concentrations of
calcium and increased concentrations of phosphorus in
blood.
Common causes of this disorder include surgical removal
of the parathyroid glands and disease processes that
lead to destruction of parathyroid glands.
The resulting ______ often leads to tetany and convulsions,
and can be acutely life-threatening.
Treatment focuses on restoring normal blood calcium
concentrations by calcium infusions, oral calcium
supplements and vitamin D therapy.
Parathyroid Hormone-Related Protein
Parathyroid hormone-related protein
(PTHrP) is actually a family of protein
hormones produced by most if not all
tissues in the body.
A segment of PTHrP is closely related to
PTH, hence its name, but these peptides
have a much broader spectrum of effects.
PTH and some of the PTHrP peptides bind to
the same receptor, but PTHrP peptides also
bind to several other receptors.
Parathyroid Hormone-Related Protein
.
PTHRP was discovered as a protein secreted by certain tumors that
caused hypercalcemia (elevated blood calcium levels) in affected
patients.
It was soon shown that the uncontrolled secretion of PTHRP by
many tumor cells induces hypercalcemia by stimulating
resorption of calcium from bone and suppressing calcium loss in
urine, similar to what is seen with hyperparathyroidism.
However, it quickly become apparent that PTHRH had many
activities not seen with PTH.
Hormone Structures, Receptors and Sources
______ is encoded by a single gene that is highly conserved among
species. It should probably be described as a polyhormone,
because a family of peptide hormones are generated by ______ of
the primary transcript and through use of alternative posttranslational cleavage sites. To make matters even more complex,
some cells appear to use alternative translational initiation
codons to produce forms of the protein that are targeted either
for secretion or nuclear localization. The figure below shows one
of the characterized processing patterns of the PTHrP
preprohormone, in this case yielding 3 bioactive peptides.
Parathyroid Hormone-Related Protein
The diverse activities of PTHrP result not only from
processing of the precursor into multiple hormones, but
from use of multiple receptors. It is clear that aminoterminal peptides of PTHrP share a receptor with PTH,
but they also bind to a type of receptor in some tissues
that does not bind PTH.
Moreover, it is almost certain that the midregion and
osteostatin peptides bind other, unique receptors.
In addition to the secreted forms, there is considerable
evidence that a form of PTHrP is generated in some
cells that is not secreted and, via nuclear targeting
sequences, is translocated to the nucleus, where it
affects ______.
Parathyroid Hormone-Related Protein
Moreover, it is almost certain that the midregion and
osteostatin peptides bind other, unique receptors.
In addition to the secreted forms, there is considerable
evidence that a form of PTHrP is generated in some
cells that is not secreted and, via nuclear targeting
sequences, is translocated to the nucleus, where it
affects nuclear function.
The consequences of this "intracrine" mode of action are
not yet well characterized, but may modulate such
important activities as programmed cell death.
Parathyroid Hormone-Related Protein
PTHrP is secreted from a large and diverse set of cells, and
during both fetal and postnatal life.
Among tissues known to secrete this hormone are several
types of epithelium, mesenchyme, vascular smooth
muscle and central nervous system.
Although PTHrP is found in serum, a majority of its
activity appears to reflect paracrine signaling.
Physiologic Effects of Parathyroid HormoneRelated Protein
One thing to recognize about PTHrP is that its
name is ______
Like PTH, some of the effects of PTHrP result from
its effects on transepithelial fluxes of calcium,
but many of its actions have nothing to do with
______.
Most prominently, PTHrP peptides exert
significant control over the proliferation,
differentiation and death of many cell types.
They also play a major role in development of
several tissues and organs.
Physiologic Effects of Parathyroid Hormone-Related
Protein
.
Much of our understanding of the biologic effects of
PTHrP comes from experiments with ______
Mice with targeted deletions in the PTHrP gene (knockout
mice), mice that overexpress PTHrP in specific tissues
(transgenic mice), and crosses between knockout and
transgenic mice have been critical in delineating many
effects of this hormone.
Humans with mutations in the PTHrP gene or the
parathyroid receptor have also played a role in
confirming the activity of PTHrP. Some of the
physiologic effects of PTHrP garnered from these
studies are indicated on next few slides
Physiologic Effects of Parathyroid Hormone-Related
Protein
______ : Mice null for PTHrP gene die at birth, if not
earlier. A developmental defect in proliferation and
differentiation of cartilage. These and other types of
studies indicate that PTHrP stimulates the proliferation
of chondrocytes and suppresses their terminal
differentiation. These effects of PTHrP appear due to
interaction of the PTH-like peptide with the PTH
receptor.
Physiologic Effects of Parathyroid Hormone-Related
Protein
.
Mammary Development and Lactation: The mammary glands of
female mice with homozygous inactivation of the PTHrP gene fail
to develop, except for the earliest stages. Development of the
mammary gland depends upon a complex interaction between
epithelial and mesenchymal cells that apparently requires
PTHrP. In normal animals, mammary epithelial cells secrete
large amounts of PTHrP, which suggests a role of this hormone
in adapting maternal metabolism to the calcium demands of
lactation.
Placental Transfer of Calcium: The "midregion" peptide of PTHrP
(see above) has been shown to control the normal maternal-tofetal pumping of calcium across the placenta. In the absence of
fetal PTHrP, this gradient is not established.
Physiologic Effects of Parathyroid Hormone-Related
Protein
______ PTHrP is secreted from smooth muscle usually in response
to stretching. It acts to relax smooth muscle, thereby serving,
among other things, as a vasodilating hormone. Transgenic mice
that express PTHrP in vascular smooth muscle manifest
hypotension. PTHrP may also have effects on contraction of
muscle in the bladder, uterus and heart.
Physiologic Effects of Parathyroid Hormone-Related
Protein
______ : PTHrP is highly expressed in skin. Transgenic mice that
overexpress PTHrP in skin show alopecia, and treatment of mice
with a PTHrP antagonist leads to increased numbers of hair
follicles and a shaggy appearance. Another interesting defect in
PTHrP-null mice is that teeth develop normally, they fail to
erupt. Finally, both PTHrP and its receptors are widely
expressed in the CNS, and appear to influence neuronal survival
by several mechanisms. It should be clear from the above
examples that PTHrP hormones have profound effects on a large
number of physiologic processes. Ongoing research on this
polyhormone is certain to reveal additional effects in this already
complex system.