Transcript Calcium Homeostasis & Bone Metabolism

Calcium and Bones
Endocrine Controls
Calcium homeostasis is important because the ion is
needed to maintain nerve & muscle function & to control
many cellular activities in virtually all cells. It is also a
major structural component of the body in both the bone
& extracellular compartments.
The hormones involved in calcium metabolism in general
& in bone in particular include the protein parathyroid
hormone & the modified steroid calcitriol (1α,25 –
dihydroxy vitamin D3; 1α,25 – dihydroxycholecalciferol),
which both promote the movement of calcium ion into
circulation, & the counter-balancing protein hormone
calcitonin, which promotes a decrease in circulating
calcium.
Parathyroid
glands
Parathyroid hormone (PTH), an 84 amino acid-long
protein, is produced by processing of a longer
translation product by the parathyroid glands which are
embedded in the thyroid tissues in many vertebrate
species.
Calcitonin, a 32 amino acid-long peptide is produced by
the parafollicular or C cells of the thyroid interstitium;
these cells do not play a role in thyroid hormone
production.
Calcitriol is derived
from a metabolite of
cholesterol, 7-dehydrocholesterol formed in
the liver. Non-ezymatic
breakage of the B-ring
by ultraviolet light
exposure in the skin
form cholecalciferol
(vitamin D3) which may
also be obtained in the
diet, e.g., in vitamin D
fortified milk. Liver
hydroxylates cholecalciferol on the
sidechain to form 25hydroxycholecalciferol
which is carried by the
vitamin D carrier protein in serum to the kidney. In the kidney the molecule
can be hydroxylated once or twice more to form the active hormone calcitriol
or the inactive metabolites 24,25-dihydroxycholecalciferol or 1α, 24, 25trihydroxycholecalciferol. PTH promotes 1α hydroxylation & activation, CT
promotes 24 hydroxylation & inactivation.
Calcium (& phosphate)
balance is achieved by
actions on 3 central
tissues: kidney, intestine,
& bone. PTH & calcitriol
elevate Ca++ in serum by
stimulating kidney
tubules to reabsorb Ca++
from forming urine & by
stimulating osteoclasts
to mobilize calcium from
bone. Simultaneously,
calcitriol stimulates Ca++
absorption from foods in
the intestine. When
serum Ca++ is too high CT blocks PTH-stimulated formation of calcitriol in
the kidney & counters calcitriol & PTH actions on the kidney tubules. CT
also blocks PTH & calcitriol action in osteoclasts & calcitriol actions on
the intestine. CT’s actions in humans appear relatively minor with
changes of PTH level in response to serum Ca++ rises or falls playing a
larger role.
Bone is a complex tissue including inorganic, organic, & cellular
components. The major inorganic component is hydroxyapatite
a complex calcium salt including phosphate, carbonate,
magnesium, & other ions. This is sensitive to attack by acid &
forms about 2/3 of the weight of bone. It can serve as a reservoir
of problematic cations such as lead, radium, strontium, or
arsenic making effects of exposure more prolonged than if the
ions were always free in circulation.
Hydroxyapatie is interweaved with organic components such as
collagens & many minor protein contributors.
The cellular players are thought to be derived from blood-lineage
stem cells. They include: osteoblasts that cover the surface of
bone & help deposit bone mineral: osteocytes, also bone
builders, which occupy interior locations in bone that eventually
are walled off by mineral deposition; & osteoclasts, large
multinucleate cells, which are probably modified macrophages,
that act to break down & remodel bone. Other cells include
vascular endothelial cells in blood vessels & nerves.
A sketch of a cross section of long bone near the epiphyses, growth
plate, shows the various cells involved in bone remodeling in relation to
the bone matrix.
The major
hormonal
target for
calcium
homeostasis
in bone is the
osteoclast
which can
mobilize Ca++
by secreting
acid &
proteolytic
enzymes onto
the bone
matrix surface
in response to
stimulation by
PTH &
http://www.besthealth.com/besthealth/bodyguide/reftext/images/osteoclast.jpg
calcitriol.
CT blocks PTH (cAMP cascade) & calcitriol (nuclear receptor). Sex
steroids modulate bone cell activity; androgen stimulates bone
deposition, lack of estradiol causes bone loss.
Calcium ion
movement across
cells is shown. Note
that the cell forms are
more typical of
osteoblasts which
build bone and
usually transport
calcium toward the
matrix. An osteoclast,
as shown in the last
two slides, would
emphasize
degradation of bone
mineral & matrix &
would pump calcium
into the vasculature.
Don’t believe
everything you see in
books!