Chapter 6
Hormonal Control of Calcium
Homeostasis
Nam Deuk Kim, Ph.D.
1
1. Calcium and Bone Physiology
• Plasma Ca2+ must be closely regulated to prevent changes in
neuromuscular excitability
– Also plays vital role in a number of essential activities
• Neuromuscular excitability
• Stimulus-secretion coupling
• Excitation-contraction coupling in cardiac and smooth muscle
• Maintenance of tight junctions between cells
• Clotting of blood
– Hypercalcemia
• Reduces excitability
– Hypocalcemia
• Brings about overexcitability of nerves and muscles
• Severe overexcitability can cause fatal spastic contractions of
respiratory muscles
2
Endocrine Control of Calcium Metabolism
• Three hormones regulate plasma
concentration of Ca2+ (and PO43-)
– Parathyroid hormone (Parathormone, PTH)
– Calcitonin
– Vitamin D
3
Ca++:
PTH
V-D3
Ca++:
Calcitonin
Hydroxyapatite: Ca10(PO4)6(OH)2
4
Bone continuously undergoes remodeling.
5
Osteocyte
Osteon
Blood vessel
from marrow
Central
canal
Vessel in central canal
Canaliculi
Lamella
Central
canal
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7
• Role of osteoblasts in governing
osteoclast development and activity
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Osteoblast
Outer
surface
Osteocyte
Canaliculi
Osteocytic–
osteoblastic bone
membrane
Mineralized
bone
Bone fluid
Osteoblast
Blood vessel
Central canal
Lamellae
Relationship of mineralized bone, bone cells,
bone fluid, and the plasma
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In canaliculi In central canal
Mineralized bone:
stable pool of Ca2+
Bone fluid:
labile pool
of Ca2+
Plasma
Fast exchange
Slow exchange
(Bone
dissolution)
= Membrane-bound
Ca2+ pump
Relationship of mineralized bone, bone cells,
bone fluid, and the plasma
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Endocrine Control of Calcium Metabolism
• Parathyroid hormone (PTH)
– Secreted by parathyroid glands
– Primary regulator of Ca2+
• Raises free plasma Ca2+ levels
by its effects on bone kidneys,
and intestines
– Essential for life
• Prevents fatal consequences of
hypocalcemia
– Facilitates activation of Vitamin D
11
Fig. 9-1: Posterior (left) and transverse (right) views of
the human thyroid with attached parathyroids.
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2. Parathormone
“Chief Cells”:
(주세포)
Parathyroid
Hormones
(Parathormone, PTH)
혈중 칼슘 농도
증가 유지
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Fig. 9-2: Comparative structures of parathormone (PTH).
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• Synthesis, chemistry, and metabolism of PTH
- A polypeptide 84 aa long, derived from a precursor
molecule of 115 aa.
- Preproparathyroid hormone (115 aa preproPTH) 90
aa proPTH 84 aa PTH
• Control of PTH secretion
- Release of PTH from the gland is controlled by
circulating levels of Ca2+
- Ca2+-sensing receptor [calcium-sensing receptor
(CaSR)] : a typical seven-spanning membrane G-
protein–coupled receptor
- Human Ca2+-sensing receptor: 1,018 aa with 93%
sequence similarity to the bovine receptor
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Rough Endoplasmic Reticulum
consitutive synthesis Parathyroid Chief Cells
Pre Pro PTH PreproPTH
-31 -6 1 84 Cisternal space of RER
signal peptidase action
ProPTH
Golgi Apparatus
processing
PTH
Granules
packaging
Secretion
Low Ca2+
Prepro-PTH and its processing to secreted PTH in the parathyroid chief cells.
Negative numbers indicate the number of amino acids prior to the first amino
acid in PTH 16
• PTH acts to raise plasma
Ca2+ levels
- Bone mineral metabolism
- Renal reabsorption of
calcium
- Renal excretion of phosphate
- Intestinal absorption of
calcium
- Control of vitamin D
synthesis
- Other possible actions of
PTH: increases the mitotic
rate of red cell progenitors
(reticulocytes) and thymic
lymphocytes.
17
Interaction
between PTH
and V-D in
controlling
plasma calcium
18
Fig. 9-3: Aligned sequences of the 1–34 region of PTH and PTHrP
from various species. Conserved residues are outlined in black.
Note the lack of substantial sequence identity between PTH and
PTHrP from amino acid residue 14 through the C terminus.
3. Parathormone-related Peptide (PTHrP) • PTHrP: isolated from human tumor cells or tissues obtained
from patients with humoral hypercalcemia of malignancy
• PTHrP: 139-173 aa resides, depending upon the species.
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Fig. 9-4: Primary structure of human calcitonin.
4. Calcitonin • Calcitonin
– Hormone produced by C cells of thyroid gland
– Negative-feedback fashion
• Secreted in response to increase in plasma Ca2+
concentration
– Acts to lower plasma Ca2+ levels by inhibiting activity
of bone osteoclasts
– Unimportant except during hypercalcemia
20
C cell (Calcitonin)
21
Fig. 9-5: Comparative structures of some calcitonins. Three
molecular species (isoforms) of salmon CT exist; the structure of
salmon I calcitonin is shown, which differs from eel CT at only
three residues (eel: 26, Asp; 27, Val; 29, Ala).
22
• Calcitonin acts to lower plasma Ca2+ levels
- Bone mineral metabolism:
- Calcitonin as a satiety hormone: Subcutaneous (s.c.)
injections of CT inhibit the 24-hour food intake of rats and
rhesus monkeys. Intracerebroventricular injections of CT in
the rat are also inhibitory to feeding. In humans, significant
reduction in body weight is observed 24 to 36 hours
following a single s.c. injection of CT.
- Vitamin D regulation: CT directly stimulates V-D metabolism
and indirectly stimulates it by lowering plasma Ca2+ levels,
resulting in the release of PTH, which activates renal
vitamin D synthesis and secretion.
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Negative-feedback Loops Controlling Parathyroid
Hormone (PTH) and Calcitonin Secretion
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25
26
5. Vitamin D
• Stimulates Ca2+ and PO43- absorption from
intestine
• Can be synthesized from cholesterol derivative
when exposed to sunlight
• Often inadequate source
• Amount supplemented by dietary intake
• Must be activated first by liver and then by kidneys
before it can exert its effect on intestines
27
Precursor in skin
(7-dehydrocholesterol) Dietary vitamin D
Vitamin D3
Hydroxyl group (OH)
Liver enzymes
25-OH D3
Hydroxyl group PTH Plasma Ca2+
Kidney enzymes
Plasma PO4 3-
1, 25-(OH)2 D3
(active vitamin D)
Promotes intestinal absorption of Ca2+ and PO4
+
3-
Sunlight
Activation of
Vitamin D
28
Fig. 9-6: Photic stimulation of integumental cholecalciferol
(vitamin D3) formation and subsequent transfer to the general
circulation by a cholecalciferol-binding protein.
29
Fig. 9-7: Production of ergosterol and ergocalciferol from
their precursors.
30
Fig. 9-8: Sequential
steps in the
biosynthesis of
vitamin D.
31
Fig. 9-9: Feedback control of vitamin D biosynthesis. 32
• V-D promotes Ca2+
absorption in the gut and
Ca2+ reabsorption in the
kidney.
- Intestine:
- Bone:
- Kidney:
- Other putative roles:
33
Interaction
between PTH
and V-D in
controlling
plasma calcium
34
Control of
plasma
phosphate
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36
6. Hormone Mechanisms of Action in
Calcium Homeostasis
Fig. 9-10: Cell-surface receptors for PTH are coupled to two classes of G proteins. Gs
mediates stimulation of adenylyl cyclase (AC) and the production of cAMP, which in turn
activates protein kinase A (PKA). Gq stimulates phospholipase C (PLC) to form the second
messengers inositol-(1,4,5)-triphosphate (IP3) and diacylglycerol (DAG) from membrane-
bound phosphatidyl-inositol-(4,5)-biphosphate. IP3 increases intracellular calcium (Ca2+) and
DAG stimulates protein kinase C (PKC) activity. Each G protein consists of a unique chain
and dimer.
1) PTH
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Regulation of PTH secretion • Secretion of parathyroid hormone is
controlled chiefly by serum [Ca2+] through
negative feedback.
• Calcium-sensing receptors located on
parathyroid cells are activated when
[Ca2+] is low.
• The G-protein coupled calcium receptors
(CaR) sense extracellular calcium and
may be found on the surface on a wide
variety cells distributed in the brain, heart,
skin, stomach, C cells, and other tissues.
• In the parathyroid gland, sensation of
high concentrations of extracellular
calcium result in activation of the Gq G-
protein coupled cascade through the
action of phospholipase C.
• This hydrolyzes phosphatidylinositol 4,5-
bisphosphate (PIP2) to liberate
intracellular messengers IP3 and
diacylglycerol (DAG).
• Ultimately, these two messengers result
in a release of calcium from intracellular
stores and a subsequent flux of
extracellular calcium into the cytoplasmic
space.
• The effect of this signaling of high
extracellular calcium results in an
intracellular calcium concentration that
inhibits the secretion of preformed PTH
from storage granules in the parathyroid
gland.
• In contrast to the mechanism that most
secretory cells use, calcium inhibits
vesicle fusion and release of PTH.
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• Stimulators of PTH secretion
- Decreased serum [Ca2+].
- Mild decreases in serum [Mg2+].
- An increase in serum phosphate
(increased phosphate causes it to
complex with serum calcium, forming
calcium phosphate, which reduces
stimulation of Ca-sensitive receptors
(CaSr) that do not sense calcium
phosphate, triggering an increase in PTH)
• Inhibitors of PTH secretion
- Increased serum [Ca2+].
- Severe decreases in serum [Mg2+], which
also produces symptoms of
hypoparathyroidism (such as
hypocalcemia).
- Hypermagnesemia
- Calcitriol
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• In the parathyroids, magnesium
serves this role in stimulus-
secretion coupling.
• Magnesium: a natural calcium
antagonist
• Hypomagnesia inhibits PTH
secretion and also causes
resistance to PTH, leading to a
form of hypoparathyroidism that is
reversible.
• Hypermagnesemia also results in
inhibition of PTH secretion when a
moderate low calcium
concentration is present.
40
“Magnesium and the parathyroid”
• Curr Opin Nephrol Hypertens. (2002)
11(4): 403-410.
• The serum levels of parathyroid hormone
and magnesium depend on each other in
a complex manner.
• The secretion of parathyroid hormone by
the parathyroid is physiologically
controlled by the serum calcium level, but
magnesium can exert similar effects.
• While low levels of magnesium (mild
decrease) stimulate parathyroid hormone
secretion, very low serum concentrations
(hypomagnesemia) induce a paradoxical
block.
• This block leads to clinically relevant
hypocalcemia in severely
hypomagnesiemic patients.
• The mechanism of this effect has recently
been traced to an activation of the alpha-
subunits of heterotrimeric G-proteins.
“Magnesium modulates parathyroid
hormone secretion and upregulates
parathyroid receptor expression at
moderately low calcium concentration”
• Nephrol Dial Transplant (2014) 29: 282–
289
• Results:
I. Increasing Mg concentrations from 0.5 to
2 mM produced a left shift of PTH–Ca
curves.
II. With Mg 5 mM, the secretory response
was practically abolished. Mg was able
to reduce PTH only if parathyroid glands
were exposed to moderately low Ca
concentrations; with normal–high Ca
concentrations, the effect of Mg on PTH
inhibition was minor or absent.
• Conclusions. Mg reduces PTH secretion
mainly when a moderate low calcium
concentration is present; Mg also
modulates parathyroid glands function
through upregulation of the key cellular
receptors CaR, VDR and FGF23/Klotho
system.
IL-6 Gs cAMP PKA
IL-6; other
cytokines
ODF
Osteoblast
Bone constructor
Osteoclast
Bone destructor
Control of bone remodeling by PTH and calcitonin
activation CT PKA cAMP
inactivation PTH
Gs
• Calcitonin (CT) secreted by thyroid C-cells in response to hypercalcemia.
• CT gene can yield calcitonin gene-related peptide (CGRP) if processed
differently (alternative mRNA splicing).
• CGRP = a potent vasodilator
2) Calcitonin (CT): Receptors for CT are present in skeletal tissue,
kidney, and testicular Leydig cells.
41
Receptor for calcitonin
• The calcitonin receptor, found on
osteoclasts, and in kidney and
regions of the brain.
• G protein-coupled receptor, which
is coupled by Gs to adenylate
cyclase and thereby to the
generation of cAMP in target cells.
• It may also affect the ovaries in
women and the testes in men.
• Calcitonin can be used
therapeutically for the treatment
of hypercalcemia or osteoporosis.
• Oral calcitonin may have a
chondroprotective role in
osteoarthritis (OA) How
calcitonin affects osteoarthritis
(OA)?
Calcitonin acts both directly on
osteoclasts, resulting in inhibition of
bone resorption and following
attenuation of subchondral bone
turnover, and directly on
chondrocytes, attenuating cartilage
degradation and stimulating
cartilage formation
42
Uses of calcitonin
Fig. 9-11: Mechanism of action and general functions of 1,25(OH)2D3 in target cells.
3) Vitamin D
43
Fig. 9-12: Generalized model of the role of hormones controlling bone
mineralization and demineralization.
7. Hormone Integration in Calcium Homeostasis
44
Fig. 9-13: Primary structure of calmodulin (CaM), an intracellular
calcium receptor. The following are one-letter codes for amino acid
residues: A, Ala; D, Asp; E, Glu; F, Phe; G, Gly; H, His; I, Ile; K, Lys; L,
Leu; M, Met; N, Asn; P, Pro; Q, Gln; R, Arg; S, Ser; T, Thr; V, Val; Y,
Tyr.
8. Hormonal Regulation of Intracellular Calcium
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Calcium release in excitation-contraction coupling.
46
Fig. 9-14:
Model for the
mechanism of action of
calmodulin.
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9. Pathophysiology 1) Hypoparathyroidism results in hypocalcemia.
2) Hyperparathyroidism results in hypercalcemia.
3) Hypercalcemia can accompany some malignancies.
4) Osteomalacia is a condition of inadequate bone mineralization.
5) Paget’s disease is characterized by excess osteoclastic activity.
6) Osteoporosis is a condition of decreased bone mineral density.
a. Postmenopausal (Type I) osteoporosis
b. Senile (Type II) osteoporosis
7) New pharmacological therapies for diseases of Ca2+ homeostasis
are available.
a. Bisphosphonates
b. Selective estrogen receptor modulators (SERMs)
c. Pharmaceutical preparations of vitamin D.
d. Dietary calcium and osteoporosis
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Parathyroid Glands
Calcium Metabolism
• Blood calcium is in equilibrium with calcium in the bone
• Calcium level is regulated by the parathyroid glands
– Reduced calcium in blood: tetany (increases neuromuscular excitability, causing spasm of skeletal muscle)
– Elevated calcium in blood: reduces neuromuscular excitability
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Calcium Disorders
• PTH hypersecretion (hyperparathyroidism)
– Characterized by hypercalcemia and
hypophosphatemia
• PTH hyposecretion (hypoparathyroidism)
– Characterized by hypocalcemia and
hyperphosphatemia
• Vitamin D deficiency
– Children – rickets
– Adults – osteomalacia
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51
Completed Picture of Updated Calcium/Parathyroid Hormone
Normogram (http://www.parathyroid.com/hyperparathyroidism-
diagnosis.htm, 2014.4.6)
Hyperparathyroidism
• Usually a result of hormone-secreting
parathyroid adenoma
• Blood calcium rises
• Excessive calcium withdrawn from bone
• Excessive calcium excreted in urine
• Treated by removal of tumor
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원발성 부갑상샘 기능항진증
(Primary Hyperparathyroidism)
: PTH 과다분비
원인:
1. 샘종(80%)
2. 원발성 증식증(10~15%)
3. 샘암종(5% 이하)
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부갑상샘 기능항진증
조직학적 변화
1. Adenoma
2. Primary hyperplasia:
Chief cell
3. Primary hyperplasia:
Clear cell
4. Secondary hyperplasia
5. Carcinoma
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부갑상샘 기능항진증
임상 증상
1. 혈중 PTH 상승
2. 고칼슘혈증
3. 저인산염혈증
4. 낭종섬유성 골염
5. 신장결석
6. 정서적 불안
7. 기억력 감퇴
8. 근 약화
9. 전이성 칼슘 침착
10. 위장의 소화성 궤양
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고칼슘증 감별 진단법
1. Hyperparathyroidism
2. Milk-Alkali syndrome
3. V-D intoxication
4. Sarcoidosis
5. Multiple myeloma
6. Metastatic ca.
7. Primary ca, not involving
bone
8. Disuse atrophy
(osteoporosis)
9. Thyrotoxicosis
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Hypoparathyroidism
• Usually result of removal of parathyroid glands
during thyroid surgery
• Blood calcium falls precipitously
• Leads to neuromuscular excitability and tetany
• Treated with high-calcium diet and
supplementary vitamin D
57
부갑상샘기능저하증
(Hypoparathyroidism)
: 혈중 저칼슘증 발생
1. 갑상샘 절제술
2. 특발성
3. 가족성
4. 가성: PTH에 대한 무감응
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임상증상:
• 저칼슘혈증
• 근-신경 흥분성
• Trousseau’s sign
• Chvostek’s sign
• Convulsion
• Laryngeal spasm
• Choked disk
• 정서불안
• 정신병
부갑상샘기능저하증
(Hypoparathyroidism)
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골연화증/구루병
• 골연화증(Osteomalacia): 새로이 형성된 뼈 기질에 미네랄화가 부적절한 것을 특징으로 하는 성인 질환
• 구루병(Rickets): 골단이 열려 있는 어린이에서 발생하는 유사질환
• 비타민 D 대상의 비정상, 인산 결핍 상태 및 미네랄화 과정 자체의 결함 등
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•골연화증 (Osteomalacia) •구루병(Rickets)
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Paget's disease of bone • Paget's disease of the bone (other terms are Paget's disease, osteitis
deformans, osteodystrophia deformans): a chronic disorder that typically
results in enlarged and deformed bones.
• The disease is named after Sir James Paget, the British surgeon who first
described it in 1877.
• The excessive breakdown and formation of bone tissue that occurs with Paget's
disease can cause bone to weaken, resulting in bone pain, arthritis, deformities, and
fractures.
• Paget's disease is rarely diagnosed in people less than 40 years of age. Women are
more commonly affected than men.
• Prevalence of Paget's disease ranges from 1.5 to 8.0 percent, depending on age
and country of residence. Prevalence of familial Paget's disease (where more than
one family member has the disease) ranges from 10 to 40 percent in different parts
of the world.
• Because early diagnosis and treatment is important, after age 40, siblings and
children of someone with Paget's disease may wish to have an alkaline
phosphatase blood test every two or three years.
• If the alkaline phosphatase level is above normal, other tests such as a bone-
specific alkaline phosphatase test, bone scan, or X-ray can be performed.
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뼈의 파제트병 Paget Disease of Bone
64
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Urinary
hydroxyproline
elevated
66
Osteoporosis
• Generalized thinning of the bone and dimineralization of the entire skeletal system, “porous bones”
– Most common in postmenopausal women
• Loss of estrogen accelerates rate of bone resorption
– Also develops in elderly men
• Remember that osteoporosis is not the same as osteoarthritis
• Osteoarthritis is the “wear and tear” degeneration of one or more of the weight-bearing joints
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Russian spotters carry astronaut Ken Bowersox at the landing
site of the Soyuz space capsule that returned him and two
others to Earth.
It was a dramatic end to a 5 1/2-
month space station mission for
Ken Bowersox, who served as the
commander, astronaut Donald
Pettit and cosmonaut Nikolai
Budarin.
May 4, 2003
골다공증
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