Download Chapter 6 Hormonal Control of Calcium Homeostasis

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
Central
canal
Osteocyte
Lamella
Canaliculi
Osteon
Blood vessel
from marrow
Central
canal
Vessel in central canal
6
7
• Role of osteoblasts in governing
osteoclast development and activity
8
Relationship of mineralized bone, bone cells,
bone fluid, and the plasma
Osteocyte
Osteoblast
Osteocytic–
osteoblastic bone
membrane
Osteoblast
Mineralized
bone
Outer
surface
Blood vessel
Central canal
Bone fluid
Canaliculi
Lamellae
9
Relationship of mineralized bone, bone cells,
bone fluid, and the plasma
In canaliculi
Mineralized bone:
stable pool of Ca2+
In central canal
Bone fluid:
labile pool
of Ca2+
Plasma
Fast exchange
Slow exchange
(Bone
dissolution)
= Membrane-bound
Ca2+ pump
10
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.
12
2. Parathormone
“Chief Cells”:
(주세포)
Parathyroid
Hormones
(Parathormone, PTH)
혈중 칼슘 농도
증가 유지
13
Fig. 9-2: Comparative structures of parathormone (PTH).
14
• 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 Gprotein–coupled receptor
- Human Ca2+-sensing receptor: 1,018 aa with 93%
sequence similarity to the bovine receptor
15
Rough Endoplasmic Reticulum
consitutive synthesis
Parathyroid Chief Cells
Pre
-31
Pro
-6
PTH
PreproPTH
1
84
Cisternal space of RER
signal peptidase action
ProPTH
Golgi Apparatus
processing
PTH
Granules
packaging
 Low Ca2+
Secretion
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
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.
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
19
PTHrP from amino acid residue 14 through the C terminus.
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
Fig. 9-4: Primary structure of human calcitonin.
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.
23
Negative-feedback Loops Controlling Parathyroid
Hormone (PTH) and Calcitonin Secretion
24
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
Sunlight
Vitamin D3
Hydroxyl group (OH)
Liver enzymes
25-OH D3
PTH
Hydroxyl group
+
Plasma Ca2+
Kidney enzymes
Activation of
Vitamin D
Plasma PO4
3-
1, 25-(OH)2 D3
(active vitamin D)
Promotes intestinal
absorption
of Ca2+ and PO4 3-
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
35
36
6. Hormone Mechanisms of Action in
Calcium Homeostasis
1) PTH
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 membranebound 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.
37
• Ultimately, these two messengers result
in a release of calcium from intracellular
Secretion of parathyroid hormone is
stores and a subsequent flux of
controlled chiefly by serum [Ca2+] through
extracellular calcium into the cytoplasmic
negative feedback.
space.
Calcium-sensing receptors located on
• The effect of this signaling of high
parathyroid cells are activated when
extracellular calcium results in an
[Ca2+] is low.
intracellular calcium concentration that
The G-protein coupled calcium receptors
inhibits the secretion of preformed PTH
(CaR) sense extracellular calcium and
from storage granules in the parathyroid
may be found on the surface on a wide
gland.
variety cells distributed in the brain, heart,
• In contrast to the mechanism that most
skin, stomach, C cells, and other tissues.
secretory cells use, calcium inhibits
In the parathyroid gland, sensation of
vesicle fusion and release of PTH.
high concentrations of extracellular
calcium result in activation of the Gq Gprotein coupled cascade through the
action of phospholipase C.
This hydrolyzes phosphatidylinositol 4,5bisphosphate (PIP2) to liberate
intracellular messengers IP3 and
diacylglycerol (DAG).
Regulation of PTH secretion
•
•
•
•
•
38
• Stimulators of PTH secretion
• In the parathyroids, magnesium
- Decreased serum [Ca2+].
serves this role in stimulus- Mild decreases in serum [Mg2+].
secretion coupling.
- An increase in serum phosphate
• Magnesium: a natural calcium
(increased phosphate causes it to
antagonist
complex with serum calcium, forming
• Hypomagnesia inhibits PTH
calcium phosphate, which reduces
secretion and also causes
stimulation of Ca-sensitive receptors
resistance to PTH, leading to a
(CaSr) that do not sense calcium
phosphate, triggering an increase in PTH) form of hypoparathyroidism that is
reversible.
• Inhibitors of PTH secretion
• Hypermagnesemia also results in
- Increased serum [Ca2+].
inhibition of PTH secretion when a
- Severe decreases in serum [Mg2+], which
moderate low calcium
also produces symptoms of
concentration is present.
hypoparathyroidism (such as
hypocalcemia).
- Hypermagnesemia
- Calcitriol
39
“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 alphasubunits 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
40
system.
2) Calcitonin (CT): Receptors for CT are present in skeletal tissue,
kidney, and testicular Leydig cells.
Osteoblast
Bone constructor
PTH
Gs  cAMP  PKA
Osteoclast
Bone destructor
IL-6; other
cytokines
IL-6

activation
inactivation
PKA cAMP  Gs
CT
ODF
• 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
Control of bone remodeling by PTH and calcitonin
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.
Uses of calcitonin
• 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
3) Vitamin D
Fig. 9-11: Mechanism of action and general functions of 1,25(OH)2D3 in target cells.
43
7. Hormone Integration in Calcium Homeostasis
Fig. 9-12: Generalized model of the role of hormones controlling bone
mineralization and demineralization.
44
8. Hormonal Regulation of Intracellular Calcium
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,
45
Tyr.
Calcium release in excitation-contraction coupling.
46
Fig. 9-14:
Model for the
mechanism of action of
calmodulin.
47
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
48
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
49
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
50
Completed Picture of Updated Calcium/Parathyroid Hormone
Normogram (http://www.parathyroid.com/hyperparathyroidismdiagnosis.htm, 2014.4.6)
51
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
52
원발성 부갑상샘 기능항진증
(Primary Hyperparathyroidism)
: PTH 과다분비
원인:
1. 샘종(80%)
2. 원발성 증식증(10~15%)
3. 샘암종(5% 이하)
53
부갑상샘 기능항진증
조직학적 변화
1. Adenoma
2. Primary hyperplasia:
Chief cell
3. Primary hyperplasia:
Clear cell
4. Secondary hyperplasia
5. Carcinoma
54
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
55
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
56
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
58
부갑상샘기능저하증
(Hypoparathyroidism)
임상증상:
•
•
•
•
•
•
•
•
•
저칼슘혈증
근-신경 흥분성
Trousseau’s sign
Chvostek’s sign
Convulsion
Laryngeal spasm
Choked disk
정서불안
정신병
59
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
60
•골연화증
(Osteomalacia)
•구루병(Rickets)
61
62
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 bonespecific alkaline phosphatase test, bone scan, or X-ray can be performed.
63
뼈의 파제트병 Paget Disease of Bone
64
65
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
67
68
69
70
골다공증
May 4, 2003
It was a dramatic end to a 5 1/2month space station mission for
Ken Bowersox, who served as the
commander, astronaut Donald
Pettit and cosmonaut Nikolai
Budarin.
Russian spotters carry astronaut Ken Bowersox at the landing
site of the Soyuz space capsule that returned him and two
others to Earth.
71
72
73