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Calcium.pps [compatibility mode]

9/1/2012
Calcium balance
Importance of calcium
in vertebrates plays double role:
in the form of inorganic salts (hydroxyapatite) builds
up the internal frame (skeleton)
found in the extracellular space in soluble form
calcium metabolism is strictly regulated as its
appropriate level is indispensable in many
physiological processes
sets the threshold of voltage-dependent Na+-channels
– low Ca++ level: increased excitability, spontaneous
contractions, tetanus
exocytosis – synapses, gland cells
action potentials in the heart and smooth muscles
muscle contraction
hemostasis (blood clotting)
half of the Ca++ in the blood is bound to
proteins, part of the rest is bound to anions,
free, ionized concentration is: 1,1-1,2 mmol/l
during alkalosis (e.g. hyperventilation) – more
negative charges on proteins – increased binding
of Ca++ to proteins – Ca++ level decreases -
increased excitability of neurons and muscles
9/1/2012
Calcium metabolism
external turnover
internal
turnover
intracellular
absorption
extracellular
interstitial
fluid in bones
secretion
ry
nta
e
lim

glomerulal
mineralized
filtration
reabsorption
urine 200 mg
Bone tissue
our body contains about 1-2 kg calcium, of this
99% in bones
remodeling is continuous in bones, it can restore
diminished plasma level if necessary
remodeling is regulated by several hormones:
parathyroid hormone, calcitriol (vitamin D),
calcitonin, androgens (estrogens), glucocorticoids

osteoprogenitor – osteoblast – matrix synthesis
(collagen, etc. fibers) – osteoid tissue
osteoblasts surrounded by the matrix become
osteocytes; keeping contact with each other
through thin processes

the next step is mineralization or calcification a
– hydroxyapatite precipitates on the fibers
precipitation is induced by an increase of
phosphate concentration – phosphatase and
pyrophosphatase activity of osteoblasts release
phosphate from organic and inorganic phosphates

9/1/2012
Remodeling of the bone
osteoclasts are giant, multinucleated
macrophages
they are activated by paracrine factors
released by the osteoblasts and other local
influences (TNF, IL-1, etc.)
secretion of H+-ions and hydrolyzing enzymes –
dissolution of the hydroxyapatite and the
remodeling goes according the “brick wall
model” - triggering effect is unknown
osteoclasts bore cavities into the bone (7-10
days), osteoblasts synthesize the matrix, then
mineralization follows
in young people rebuilding is 100%, later not:
osteoporosis
androgens facilitate, glucocorticoids inhibit
rebuilding
matrix contains cytokines freed during
dissolution of the bone – they inhibit this
process and facilitate rebuilding
Parathyroid hormone (PTH) 6/13
in humans produced by 4 parathyroid glands (40
mg each) located in the thyroid gland
deletion of the thyroid gland – death in humans,
in some species auxiliary parathyroid glands
cells here and in many other tissues also
produce PTH-related-peptide – paracrine role
pre-pro-PTH (115) – pro-PTH (90) – PTH (84)
production is regulated by the Ca++ level in the
blood through negative feedback (fast)
very sensitive between 1-1,3 mmol/l, higher or
lower levels cause no additional change
Ca++ level is detected by G-protein associated
7TM receptors – low level – cAMP synthesis –
PTH release

another, slower element of the regulation is
calcitriol (vitamin D)
9/1/2012
Regulation of PTH production
parathyroid
gland cell
distal tubule
in kidney
proximal tubule
1-α-hydroxylase
calcitriol
Effects of parathyroid hormone
its main effect is to increase the Ca++ level in
the blood
acts mainly on the kidneys and the bones
kidney
Ca++ reabsorption increases in distal tubules
P-reabsorption decreases in the proximal tubules
1-α-hydroxylase activity is facilitated in proximal
Ca++ permeability of osteocyte processes forming a
barrier between the capillaries and the interstitial
fluid increases (2-3 hours)
osteoblasts activate osteoclasts (they have no PTH
receptor) through paracrine mediation (after 12
hours)

immature osteoclasts differentiate into maturate
osteoclasts
high PTH level: osteolysis, low level: tetanus
9/1/2012
Parathyroid hormone effects
osteoclast precursor
osteoblast
mature osteoclast
osteocyte
permeability
P-reabsorption
in proximal
1-α-hydroxylase
in proximal
calcitriol
Ca++ reabsorption
in distal tubule
Calcitriol (vitamin D)
vitamin D is known in two forms:
ergocalciferol, D2 – uptake with food
cholecalciferol, D3 – uptake with food (cod liver oil),
or produced in the skin from 7-dehydrocolesterol
under the influence of UV irradiation (sunshine)

vitamin D is only missing, if there is no uptake
with food and there is no sunshine either
calciferols are inactive – they are transformed
in an unregulated way (possibility of overdosing)
in the liver to 25-OH-calciferol, which has
weak activity

additional OH at position 1 in the kidney in a
regulated way – calcitriol
regulation:
negative feedback at 3 points
alternate hydroxylase binding OH to position 24,
rendering the molecule inactive
9/1/2012
Effects of calcitriol
calcitriol effects can be grouped in 3
categories:
increase of blood Ca++ level
effects on bones and other tissues
inhibition of its own production and that of PTH
increase of Ca++ level mainly through
facilitating reabsorption from the alimentary
canal – in addition, weak facilitation of active
transport in the renal distal tubules

in the bones it effects osteoblasts and
immature osteoclasts, similarly to PTH
influences mineralization of osteoid tissue
in high concentration stimulates osteoclasts through
factors released by osteoblasts
facilitates the maturation of immature osteoclasts
lymphocytes and monocytes posses calcitriol
receptors – modulation of immune functions
Calcitriol effects
osteoclast precursor
osteoblast
mature osteoclast
enterocyte
absorption
calcitriol
reabsorption
in distal tubules
parathyroid
secretion
immunocytes
9/1/2012
Calcitonin
gene is present in various cells – alternate
splicing – different products:
in C-cells distributed diffusely in the thyroid gland
– calcitonin precursor
in nerve cells and other cells „calcitonin-gene-
related-peptide”, CGRP – acting as transmitter
precursor (124) – calcitonin (32)
production regulated directly by blood Ca++
level through G-protein associated 7TM
receptor – higher level – increased cAMP
synthesis – increased calcitonin secretion

calcitonin acts on 7TM receptors, activating
several G-protein pathways – cAMP increase,
protein kinase C activation

osteoclast inactivation - decreased Ca++ level
in addition, decreased Ca++ reabsorption,
increased excretion in the kidney

Source: http://detari.web.elte.hu/ELUP/printable/calcium.pdf

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