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