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Intro Tothe Function of Parathyroid Gland, Concise
Intro Tothe Function of Parathyroid Gland, Concise
Phosphate Metabolism
M. Djauhari Widjajakusumah
Faculty of Medicine
University of Indonesia
Introduction
Three hormones are primarily concerned with the regulation of
calcium
metabolism:
1,25-Dihydroxycholecalciferol
o a steroid hormone formed from vitamin D
o increases calcium absorption from the intestine.
Parathyroid hormone (PTH)
o mobilizes calcium from bone, increases urinary phosphate
excretion.
Calcitonin,
o secreted primarily by cells in the thyroid gland
o inhibits bone resorption
All three hormones operate in concert to maintain the constancy of
the
Ca2+ level in the body fluids
Control of bone Ca
PTH & Calcitonin
Calcium Metabolism
o The body of a young adult human contains about 1100 g
(27.5 mol) of calcium
o 99% of the calcium is in the skeleton
o The plasma calcium, normally about 10 mg/dL (5 meq/L,
2.5 mmol/L), is partly bound to protein and partly
diffusible
o Free, ionized calcium in the body fluids:
a vital second messenger
necessary for blood coagulation, muscle contraction,
and nerve function
o The extent of Ca2+ binding by plasma proteins is
proportionate to the plasma protein level it is
important to know the plasma protein level when
evaluating the total plasma calcium.
o Other electrolytes and pH also affect the free Ca2+ level.
Ganongs Review of Medical Physiology, 23rd
ed, 2010
Calcium
Calcium Distribution
Distribution
Total Calcium
1100 g 1.5% BW
Bone Calcium
99% total
Plasma Calcium
1% total
10 mg/dL-2.5 mmol/l
Diffusible
1.34 mmol/l
59% plasma calcium
calcium
Nondiffusible
1.16 mmol/l
41% plasma
(protein-bound)
Ionized (Ca++)
1.18 mmol/l
Bound to
50% plasma calcium
globulin
Bound to
albumin
0.92 mmol/l
0.24 mmol/l
Fig 23-14. Total body calcium, an index of bone mass, at various ages in
men and women. Note the rapid increase to young adult levels (phase I)
followed by the steady loss of bone with advancing age in both sexes (phase III)
and the superimposed rapid loss in women after menopause (phase II).
Ganongs Review of Medical Physiology,
Calcium in Bone
o The calcium in bone is of two types:
a readily exchangeable reservoir and ,
a much larger pool of stable calcium that is only
slowly exchangeable.
o Two independent but interacting homeostatic systems
affect the calcium in bone.
(1000 mg)
Figure 231
Calcium metabolism in an adult human. A typical daily intake of 25 mmol Ca2+
(1000 mg) moves through many body compartments.
Robert M. Berne,
Matthew N. Levy,
Bruce M. Koeppen,
Bruce A. Stanton:
Physiology, 5th
ed, 2007
Figure 42-1 Average daily calcium turnover in humans. Note both the external
balance between intake and excretion and the internal balance between entry into
and exit from bone.
Phosphorus
Metabolism
Robert M. Berne,
Matthew N. Levy,
Bruce M. Koeppen,
Brice A. Stanton:
Physiology, 5th ed, 2007
Figure 42-2 Average daily phosphate turnover in humans. Note both the external
balance between intake and excretion and the internal balance between entry into
and exit from bone.
Parathyroid Gland
Figure 219.
Figure 219.
Parathyroid Gland
PTH Actions
Figure 237
Signal transduction pathways activated by PTH or PTHrP binding to the
hPTH/hPTHrP receptor. Intracellular cAMP is increased via Gs and adenylyl
cyclase (AC). Diacylglycerol and IP3 (1,4,5-InsP3) are increased via Gq and
phospholipase C (PLC).
OSTEOBLASTOGENESIS - OSTEOCLASTOGENESIS
Bone Marrow Culture
Fibroblast ColonyForming Unit
(Osteoprogenitor cells)
Osteoblast, Fibroblast
Chondrocytes, Adipocytes
Progenitors
PTH
Calcitriol
RANK-L
Osteoblastic
precursor cells
(+)
Late pre-osteoclast
Estrogen
(+)
(+)
Androgen
Osteoblast
IGF-1
Granulocyte-Macrophag
Colony Forming Unit
(Hematopoetic cells)
Osteoclast, Monocytes
Macrophage Progenitors
(-)
Early pre-osteoclast
(+)
Osteoclast
Bone Resorption
Osteoblast
Osteoblast Osteoclast
Osteoclast Communication
Communication
osteoblast (& osteoblast precursors)
estrogens
glucocorticoids
PTH
osteoprotegerin (OPG)
free-floating decoy receptor
osteoclast precursors
RANK receptor
+
estrogens
OPG-ligand
(RANK ligand)
osteoclast +
RANK receptor
osteoclast activity
RANK ligand
(osteoblast) +
bone resorption
PTH, DHC (vit D3), IL 1- 4 - 6-11-17, TNF-alfa
Regulation of Secretion
o Circulating ionized calcium acts directly on the parathyroid
glands in a negative feedback fashion to regulate the
secretion of PTH.
o Activation of this G-protein coupled receptor, a cell
membrane Ca2+ receptor, CaR, inhibits PTH secretion.
when the plasma Ca2+ level is high, PTH secretion is
inhibited and the Ca2+ is deposited in the bones.
when the plasma Ca2+ level is low, secretion is increased
and Ca2+ is mobilized from the bones.
o 1,25-dihydroxycholecalciferol acts directly on the parathyroid
glands to decrease preproPTH mRNA.
o Increased plasma phosphate stimulates PTH secretion by
lowering plasma levels of free Ca2+ and inhibiting the
formation of 1,25-dihydroxycholecalciferol.
o Magnesium is required to maintain normal parathyroid
secretory responses.
o Impaired PTH release along with diminished target organ
responses to PTH account for the hypocalcemia that
occasionally occurs in magnesium deficiency.
Effects of Parathyroidectomy
Effects of Parathyroidectomy
Chemistry
Regulation of Synthesis
o The formation of 1,25-dihydroxycholecalciferol in the kidneys,
catalyzed by the renal 1 -hydroxylase, is regulated in a
feedback fashion by plasma Ca2+ and PO43+.
o This effect of Ca2+ on production of 1,25dihydroxycholecalciferol is the mechanism that brings about
adaptation of Ca2+ absorption from the intestine.
o Expression of 1 -hydroxylase is stimulated by PTH, and when
the plasma Ca2+ level is low, PTH secretion is increased.
o The production of 1,25-dihydroxycholecalciferol is also
increased by low and inhibited by high plasma PO43 levels, by
a direct inhibitory effect of PO43 on the 1 -hydroxylase.
o Additional control
a direct negative feedback effect of the metabolite on 1hydroxylase,
a positive feedback action on the formation of 24,25dihydroxycholecalciferol,
a direct action on the parathyroid gland to inhibit PTH
expression.
Figure 232
Formation and hydroxylation of vitaminD3. 25-hydroxylation takes place in the
liver, and the other hydroxylations occur primarily in the kidneys. The formulas of 7dehydrocholesterol, vitamin D3, and 1,25-dihydroxycholecalciferol are also shown
below.
Ganongs Review of Medical Physiology,
23rd ed, 2010
Figure 796
Activation of vitamin D3 to form 1,25-dihydroxycholecalciferol and the role of vitamin D in
controlling the plasma calcium concentration.
Guyton & Hall: Textbook of Medical Physiology 11th ed
Fig 23-3.
Effects of PTH and 1,25-dihydroxycholecalciferol on whole body calcium
homeostasis. Note that these hormones are also involved in the regulation of
circulating phosphate levels.
Ganongs Review of Medical Physiology,
Prolactin
25(OH)D3
PTH
24.25(OH)2D3
1.25(OH)2 D3
Bone resorption
Kidney Ca++
reabsorbtion
plasma Ca++
+
--
reabsorption
Figure 798
Effect of plasma calcium concentration on the plasma concentration of 1,25dihydroxycholecalciferol. This figure shows that a slight decrease in calcium
concentration below normal causes increased formation of activated vitamin D,
which in turn leads to greatly increased absorption of calcium from the intestine.
Guyton & Hall: Textbook of Medical Physiology 11th ed
Neuromuscular
Neuromuscular excitability
excitability
Em
Ca++
Em
muscular
muscular excitability
excitability
Ca++
Em
Ca++
Em
muscular
muscular excitability
excitability
Ca++
cardiac
cardiac arrhythmia
arrhythmia
2.
2.
Excitation-contraction
Excitation-contraction coupling
coupling in
in cardiac
cardiac &
& smooth
smooth muscle
muscle
Ca++
myocardial,
myocardial, and
and smooth
smooth muscle
muscle contractility
contractility
Ca++
(particularly)
(particularly)
3.
3.
Stimulus-secretion
Stimulus-secretion coupling
coupling
Ca++ entry
entry into
into secreting
secreting cells
cells (endocrine
(endocrine cells,
cells, nerve
nerve cells)
cells)
Ca++
in
in response
response to
to stimulation
stimulation
secretory
secretory product
product (peptide
(peptide
hormones,
hormones, catecholamines,
catecholamines, neurotransmitters)
neurotransmitters) exocytosis
exocytosis
4.
4.
5.
5.
Blood
Blood clotting
clotting
Bone
Bone minerals
minerals
Bone
Bone growth
growth and
and maintenance
maintenance
Hydroxyapatite:
Hydroxyapatite: Ca10(PO4)6(OH)2
Ca10(PO4)6(OH)2
6.
6.
Second
Second messenger
messenger
IP3
IP3
endoplasmic
endoplasmic reticulum
reticulum
Ca
Ca ion
ion
enzyme
enzyme activation
activation
Calcitonin
Control of secretion
Secreted by the parafollicular cells
[Ca++] > 9.5 mg/dl calcitonin
Estrogen
calcitonin
Glucagon
calcitonin
Calcitonin
Effects
Effects
Kidneys
Kidneys
Calcitonin
Calcitonin membrane
membrane receptors
receptors on
on renal
renal tubules
tubules cells
cells
Calcium
Calcium reabsorption
reabsorption
Phosphate
Phosphate reabosrption
reabosrption
Bones
Bones
Calcitonin
Calcitonin membrane
membrane receptors
receptors on
on osteoclast
osteoclast
osteoclast
osteoclast activity
activity
bone
bone resorption
resorption
Ca
Ca and
and PO4
PO4 release
release
Blood
Blood
[Ca++]
[Ca++]
[PO4]
[PO4]
Calcitonin
Prevents
Prevents bone
bone resorption
resorption excess
excess in
in pregnancy
pregnancy
estrogen
estrogen
prolactin
prolactin
+
+
calcitonin
calcitonin
1.25
1.25 DHC
DHC
bone
bone resorption
resorption
[Ca
[Ca ++]
++]
+
+
---
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