chapter 6 hormonal control of calcium...
TRANSCRIPT
![Page 1: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/1.jpg)
Chapter 6
Hormonal Control of Calcium
Homeostasis
Nam Deuk Kim, Ph.D.
1
![Page 2: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/2.jpg)
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
![Page 3: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/3.jpg)
Endocrine Control of Calcium Metabolism
• Three hormones regulate plasma
concentration of Ca2+ (and PO43-)
– Parathyroid hormone (Parathormone, PTH)
– Calcitonin
– Vitamin D
3
![Page 4: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/4.jpg)
Ca++:
PTH
V-D3
Ca++:
Calcitonin
Hydroxyapatite: Ca10(PO4)6(OH)2
4
![Page 5: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/5.jpg)
Bone continuously undergoes remodeling.
5
![Page 6: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/6.jpg)
Osteocyte
Osteon
Blood vessel
from marrow
Central
canal
Vessel in central canal
Canaliculi
Lamella
Central
canal
6
![Page 7: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/7.jpg)
7
![Page 8: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/8.jpg)
• Role of osteoblasts in governing
osteoclast development and activity
8
![Page 9: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/9.jpg)
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
9
![Page 10: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/10.jpg)
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
10
![Page 11: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/11.jpg)
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
![Page 12: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/12.jpg)
Fig. 9-1: Posterior (left) and transverse (right) views of
the human thyroid with attached parathyroids.
12
![Page 13: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/13.jpg)
2. Parathormone
“Chief Cells”:
(주세포)
Parathyroid
Hormones
(Parathormone, PTH)
혈중 칼슘 농도
증가 유지
13
![Page 14: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/14.jpg)
Fig. 9-2: Comparative structures of parathormone (PTH).
14
![Page 15: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/15.jpg)
• 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
15
![Page 16: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/16.jpg)
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
![Page 17: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/17.jpg)
• 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
![Page 18: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/18.jpg)
Interaction
between PTH
and V-D in
controlling
plasma calcium
18
![Page 19: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/19.jpg)
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.
19
![Page 20: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/20.jpg)
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
![Page 21: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/21.jpg)
C cell (Calcitonin)
21
![Page 22: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/22.jpg)
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
![Page 23: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/23.jpg)
• 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
![Page 24: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/24.jpg)
Negative-feedback Loops Controlling Parathyroid
Hormone (PTH) and Calcitonin Secretion
24
![Page 25: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/25.jpg)
25
![Page 26: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/26.jpg)
26
![Page 27: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/27.jpg)
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
![Page 28: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/28.jpg)
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
![Page 29: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/29.jpg)
Fig. 9-6: Photic stimulation of integumental cholecalciferol
(vitamin D3) formation and subsequent transfer to the general
circulation by a cholecalciferol-binding protein.
29
![Page 30: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/30.jpg)
Fig. 9-7: Production of ergosterol and ergocalciferol from
their precursors.
30
![Page 31: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/31.jpg)
Fig. 9-8: Sequential
steps in the
biosynthesis of
vitamin D.
31
![Page 32: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/32.jpg)
Fig. 9-9: Feedback control of vitamin D biosynthesis. 32
![Page 33: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/33.jpg)
• V-D promotes Ca2+
absorption in the gut and
Ca2+ reabsorption in the
kidney.
- Intestine:
- Bone:
- Kidney:
- Other putative roles:
33
![Page 34: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/34.jpg)
Interaction
between PTH
and V-D in
controlling
plasma calcium
34
![Page 35: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/35.jpg)
Control of
plasma
phosphate
35
![Page 36: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/36.jpg)
36
![Page 37: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/37.jpg)
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
37
![Page 38: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/38.jpg)
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.
38
![Page 39: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/39.jpg)
• 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
39
• 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.
![Page 40: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/40.jpg)
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.
![Page 41: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/41.jpg)
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
![Page 42: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/42.jpg)
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
![Page 43: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/43.jpg)
Fig. 9-11: Mechanism of action and general functions of 1,25(OH)2D3 in target cells.
3) Vitamin D
43
![Page 44: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/44.jpg)
Fig. 9-12: Generalized model of the role of hormones controlling bone
mineralization and demineralization.
7. Hormone Integration in Calcium Homeostasis
44
![Page 45: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/45.jpg)
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
45
![Page 46: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/46.jpg)
Calcium release in excitation-contraction coupling.
46
![Page 47: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/47.jpg)
Fig. 9-14:
Model for the
mechanism of action of
calmodulin.
47
![Page 48: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/48.jpg)
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
![Page 49: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/49.jpg)
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
![Page 50: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/50.jpg)
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
![Page 51: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/51.jpg)
51
Completed Picture of Updated Calcium/Parathyroid Hormone
Normogram (http://www.parathyroid.com/hyperparathyroidism-
diagnosis.htm, 2014.4.6)
![Page 52: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/52.jpg)
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
![Page 53: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/53.jpg)
원발성 부갑상샘 기능항진증
(Primary Hyperparathyroidism)
: PTH 과다분비
원인:
1. 샘종(80%)
2. 원발성 증식증(10~15%)
3. 샘암종(5% 이하)
53
![Page 54: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/54.jpg)
부갑상샘 기능항진증
조직학적 변화
1. Adenoma
2. Primary hyperplasia:
Chief cell
3. Primary hyperplasia:
Clear cell
4. Secondary hyperplasia
5. Carcinoma
54
![Page 55: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/55.jpg)
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
![Page 56: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/56.jpg)
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
![Page 57: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/57.jpg)
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
![Page 58: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/58.jpg)
부갑상샘기능저하증
(Hypoparathyroidism)
: 혈중 저칼슘증 발생
1. 갑상샘 절제술
2. 특발성
3. 가족성
4. 가성: PTH에 대한 무감응
58
![Page 59: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/59.jpg)
임상증상:
• 저칼슘혈증
• 근-신경 흥분성
• Trousseau’s sign
• Chvostek’s sign
• Convulsion
• Laryngeal spasm
• Choked disk
• 정서불안
• 정신병
부갑상샘기능저하증
(Hypoparathyroidism)
59
![Page 60: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/60.jpg)
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
![Page 61: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/61.jpg)
•골연화증 (Osteomalacia) •구루병(Rickets)
61
![Page 62: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/62.jpg)
62
![Page 63: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/63.jpg)
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.
63
![Page 64: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/64.jpg)
뼈의 파제트병 Paget Disease of Bone
64
![Page 65: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/65.jpg)
65
![Page 66: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/66.jpg)
Urinary
hydroxyproline
elevated
66
![Page 67: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/67.jpg)
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
![Page 68: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/68.jpg)
68
![Page 69: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/69.jpg)
69
![Page 70: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/70.jpg)
70
![Page 71: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/71.jpg)
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
71
![Page 72: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/72.jpg)
72
![Page 73: Chapter 6 Hormonal Control of Calcium Homeostasiscontents.kocw.net/KOCW/document/2015/pusan/kimnamdeuk/6.pdf · Hormonal Control of Calcium ... Endocrine Control of Calcium Metabolism](https://reader030.vdocument.in/reader030/viewer/2022021704/5b321b327f8b9a2c328d198f/html5/thumbnails/73.jpg)
73