Calcium Homeostasis: Endocrine Regulation of (Ca)

Calcium Homeostasis
Calcium homeostasis refers to the regulation of the concentration of calcium

ions in the extracellular fluid [Ca++]ECF. This parameter is tightly controlled
because the calcium ions have a stabilizing effect on voltage-gated ion
channels. For instance, when [Ca++]ECF is too low (hypocalcemia), voltage-
gated ion channels start opening spontaneously, causing nerve and muscle
cells to become hyperactive. The syndrome of involuntary muscle spasms due
to low [Ca++]ECF is called hypocalcemic tetany. Conversely, when [Ca++]ECFis
too high (hypercalcemia), voltage-gated ion channels don't open as easily,
and there is depressed nervous system function. Another problem of
hypercalcemia is that calcium can combine with phosphate ions,
forming deposits of calcium phosphate (calcification and stones) in blood
vessels and in the kidneys.
The figure above illustrates the physiological influences on [Ca++]ECF.

[Ca++]ECF is influenced by dietary intake, Ca++ absorption in the small intestine,
and by excretion of Ca++ in the urine. Importantly, the bones contain 99% of
the Ca++ in the body, so bones provide a reservoir of Ca++ that can be used to
maintain [Ca++]ECF.
Endocrine Regulation of [Ca++]ECF

The two most
important
hormones for
maintaining
calcium levels in
the body
are parathyroid
hormone
(PTH) and 1,25(O
H)2D (the active
form of vitamin
D). The major
regulator is PTH,
which is part of a
negative feedback
loop to maintain
[Ca++]ECF (see Hum
oral regulation).
PTH secretion is
stimulated by
hypocalcemia, and
it works through
three mechanisms
to increase
Ca levels:
++
 PTH stimulates the release of Ca++ from bone, in part by stimulating bone
resorption.
 PTH decreases urinary loss of Ca++ by stimulating Ca++ reabsorption.
 PTH indirectly stimulates Ca++ absorption in the small intestine by stimulating

synthesis of 1,25(OH)2D in the kidney.
PTH Effects on Bone
PTH has a rapid effect (occurring within minutes), whereby it stimulates
osteoblasts to pump Ca++ ions out of the fluid surrounding the bone (which
has a higher Ca++ concentration) and into the ECF. Over a longer time course,
PTH stimulates bone resorption by stimulating osteoclastogenesis.
Although PTH stimulates bone resorption, it is actually the osteoblasts that
express PTH receptors. PTH stimulation of osteoblasts causes them to express
the signaling molecule RANKL that activates the RANK receptor on osteoclast
precursors. For more details, see the page on Bone remodeling.
PTH Effects on Kidney

PTH has two important effects on the kidney that work to increase [Ca++]ECF.
First, it decreases the loss of Ca++ ions in the urine by
stimulating Ca++ reabsorption. "Reabsorption" is the term used to describe
the transfer of substances from the forming urine back into the
ECF. Filtration, the first step in urine formation, is a nonspecific process,
whereby water and low molecular weight substances move by bulk flow from
the plasma and into the forming urine. Reabsorption, which is performed by
the cells of the kidney tubules, allows the recovery of those useful small
molecules such as glucose, amino acids, and Ca++ ions. As well as stimulating
Ca++ reabsorption, PTH also inhibits phosphate reabsorption in the kidney.
The other key effect of PTH on the kidney is

to stimulate production of 1,25(OH)2D, the
active form of vitamin D. A precursor (known
specifically as vitamin D3 or cholecalciferol) is
synthesized in a photochemical reaction in the
skin, in response to sunlight. Cholecalciferol is
then chemically modified in the liver to form
25-(OH)D (this also happens to a similar
compound that is present in foods) . The
enzyme in the liver is constitutively active,
meaning it is always working. By contrast, the
kidney enzyme is regulated. The role of PTH
is to stimulate the regulated kidney enzyme,
resulting in the production of 1,25(OH)2D.
This is extremely important for bone health
and Ca++ homeostasis because 1,25(OH)2D
works in the small intestine to
promote Ca absorption.
++ 1,25(OH)2D is
a nonpolar hormone that causes its effects
by binding to a nuclear receptor to change gene expression.
In kidney disease, inadequate amounts of 1,25(OH)2D are made. What

happens is that Ca++ homeostasis is maintained at the expense of bone.
[Ca++]ECF drops because of a lack of Ca++ absorption from the diet.
Hypocalcemia stimulates high levels of PTH secretion; this is
termed secondary hyperparathyroidismbecause the problem that causes
the hyperparathyroidism is in the kidney, not at the parathyroid gland.
Secondary hyperparathyroidism is treated by administering vitamin D and
Ca++ supplements. The drug cinacalcet is approved for the treatment of
secondary hyperparathyroidism. Cinacalcet is a calcimimetic drug that binds
to the Ca++ receptor on cells in the parathyroid gland, inhibiting the secretion
of PTH.

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Calcium Homeostasis

Calcium homeostasis refers to the regulation of the concentration of calcium

The figure above illustrates the physiological influences on [Ca++]ECF.

Endocrine Regulation of [Ca++]ECF

 PTH decreases urinary loss of Ca++ by stimulating Ca++ reabsorption.

 PTH indirectly stimulates Ca++ absorption in the small intestine by stimulating

PTH Effects on Kidney

The other key effect of PTH on the kidney is

In kidney disease, inadequate amounts of 1,25(OH)2D are made. What

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