Calcium
and phosphate balance
Soluble Ca2+,
hydroxyapatite and calcitonin
As
calcium (Ca2+) is one of the main components of our bones, large
amounts are present
in our body. At the same time, comparatively low
extracellular concentrations of Ca2+ are fine-tuned to regulate important
functions, not to speak of even far lower intracellular concentrations. This
dichotomy is possible due to the low solubility product of Ca2+ and
phosphate (PO43-): if one ion is added to a
solution of the other, most of it precipitates as calcium phosphate.
In the
bone, the two ions combine with hydroxide (OH-) to form hydroxyapatite Ca10(PO4)6(OH)2 a hard mineral forming hexagonal crystals. Up to 70% of the
weight of bone is due to hydroxyapatite. Dental enamel consists almost
exclusively of the mineral, accounting for its mechanical resistance. The
disadvantage to this solution is that hydroxyapatite is sensitive to acidity.
Low pH attacks enamel via the same mechanism that osteoclasts use to resorb
bone. Citric acid from an orange, or lactic acid produced by bacteria
metabolizing sugar in dental plaque make protons come into contact with the enamel
surface. A proton H+ pulls out the hydroxide ion OH- from Ca5(PO4)3(OH)
to form a H2O water molecule, with the rest disintegrating into 5 Ca2+
und 3 PO43- ions. The hydroxyapatite complex dissolves, ultimately
leading to caries.
Plasma Ca2+
concentration is physiologically maintained in a small window between 2.2 and
2.7 mM. This measured Ca2+ is the sum of three forms: Ca2+
bound to plasma proteins (about 45%), Ca2+ complexed with small
organic anions (10%) and free ionized Ca2+ (about 45%). Hence, total Ca2+
depends on plasma protein concentration. The biologically relevant, regulated
parameter is free Ca2+.
Ca2+
balance is basically maintained by two hormones: parathyroid hormone (PTH) and
calcitriol (1,25-dihydroxyvitamin D). PTH regulates short-term plasma Ca2+
concentrations by dipping into bone reserves. Vitamin D strategically maintains
the total Ca2+ pool of the body.
A third Ca2+
regulating hormone, calcitonin, is of minor importance in humans. It is
secreted by parafollicular C cells in the thyroid gland and lowers plasma Ca2+
levels for a short time by directly inhibiting osteoclast activity, with the
system quickly swinging back to a neutral position. Neither a total loss of
calcitonin-producing cells (e. g., by thyroidectomy), nor massive
overproduction by rare tumors lastingly interfere with Ca2+ balance.
Probably, calcitonin is a remnant from evolution. Animals such as salmon, which
switch from fresh water to calcium-rich sea water, seem to rely on calcitonin
to cope with massive differences in Ca2+ intake.
Parathyroid
hormone
Parathyroid
hormone (PTH) is named for the four parathyroid glands producing it, tiny
epitheloid bodies located right behind the thyroid. An increase in the
concentration of free Ca2+ activates the calcium-sensing receptor (CaSR)
located at the membrane of their chief cells. The cells react by decreasing PTH
production. A second means to lower PTH secretion is a high concentration of
1,25 dihydroxyvitamin D. The message of Vitamin D seems to be: "Stop
cannibalizing our bones, I'll organize more Ca2+ from outside in a
minute!" PTH is a small protein of 84 amino acids and has an extremely
short half-life of about four minutes. PTH increases Ca2+ concentration
via two main mechanisms: by liberating it from bone and by influencing the
kidneys.
PTH's
net effect in bone is an increase in resorption by activation of osteoclasts.
This is achieved via a detour, as osteoclasts do not express PTH receptors. PTH
is sensed by osteoblasts, which react by producing IL-1, IL-6 and other
cytokines to activate osteoclasts. In addition, PTH increases osteoblast
production of the two molecules that induce differentiation and proliferation
of more osteoclasts: M-CSF (macrophage colony-stimulating factor) and RANKL.
RANK-ligand
(RANKL) is a molecule from the TNF-superfamily. It acts as a trimer,
either on the surface of osteoblasts, or, "cut off", as a soluble
signaling molecule. In the bone marrow, M-CSF and RANKL encounter precursor
cells of the hematopoietic lineage leading to macrophages and neutrophil granulocytes.
These precursor cells express RANK (receptor-activator of NFκB), a
transmembrane protein of the TNF receptor superfamily. RANK functions as
receptor for RANKL. As precursor cell RANK is trimerized by osteoblast-emitted
RANKL, the precursor cells are activated to differentiate first to
mononucleated osteoclast precursors that subsequently fuse to mature
polynucleated osteoclasts. Osteoblasts secrete a further protein,
osteoprotegerin (OPG), that looks like a soluble receptor for RANKL. This is called
a decoy receptor; by neutralizing RANKL, it acts as its inhibitor. Thus, the
formation rate of osteoclasts depends on the relative amounts of RANKL and OPG
produced by osteoblasts. While PTH induces expression of M-CSF and RANKL, it
inhibits production of OPG, cranking up the generation of osteoclasts.
If PTH
just mobilized Ca2+, not much would be gained: due to the low
solubility product with phosphate, it would soon reprecipitate. Therefore, PTH
simultaneously lowers phosphate levels by inhibiting renal reabsorption in both
the proximal and distal tubule. This is achieved by removing the Na/phosphate
cotransporter from the luminal membrane and parking it in vesicles below. Apart
from inducing phosphaturia, PTH increases reabsorption of Ca2+ in
the distal tubule, further reducing the already minimal loss of Ca2+ in
the urine. The third renal function of PTH is to stimulate hydroxylation of
carbon atom 1 of vitamin D: this is the last and rate-limiting step in its
activation. From there, 1,25 dihydroxyvitamin D sets out to refill the Ca2+
pool.
Vitamin
D
Lipid-soluble
vitamin D3 can be taken up with animal foods, especially fatty fish species
(cod liver oil, mackerel, salmon), or can be produced in our own skin from
7-dehydrocholesterol. This requires sunlight to open the second ring of the
cholesterol backbone. This UV B-dependent synthesis is probably the cause of
Caucasians' pale complexion. Until the first wave of homo sapiens left
Africa about 60,000 years ago, all modern humans probably had dark skin. The
further north the people migrated, the less ultraviolet light they absorbed.
Those with lighter complexions obtained a selective advantage, as they were
better able to synthesize vitamin D. Ethnic groups using the sea as their primary
food source, like the Inuit, took up enough vitamin D3 with their food and were
thus able to retain a higher level of pigmentation than people living off the
land. The causal relationship between a lack of sunlight and rickets was only
recognized in the late 19th century.
Two
successive hydroxylation steps are required to metabolize D3 and D2, which
already contain one hydroxyl group, to their active form, calcitriol. The first
hydroxyl group is added at position 25, the end of the side chain, in the
liver. The second hydroxylation occurs in the kidney, at position 1 of the
first ring of the erstwhile cholesterol structure. This decisive, last
activation step is performed in the proximal tubule under tightly regulated conditions.
PTH stimulates hydroxylation, while the end product calcitriol as well as
increased levels of phosphate act inhibitory. 1,25-dihydroxyvitamin D
(calcitriol) equilibrates over the entire body and binds to the vitamin D
receptor (VDR), a member of the nuclear receptor superfamily. As a
ligand-dependent transcription factor, one of its functions is the induction of
genes that are necessary to maintain Ca2+ reserves.
The
central target organ in this respect is the duodenum. Here, calcitriol induces
several proteins that in concert enhance absorption of Ca2+ from
food. While Ca2+ concentrations in the lumen of the gut and in blood
are in the nanomolar range, they are much lower inside the cell; too much free Ca2+
in the cytosol would be dangerous. At the luminal side of the duodenal
epithelial cell, vitamin D induces a channel, allowing Ca2+ to
trickle in passively. In the cytosol, the Ca2+-affine protein
calbindin is increased to neutralize passaging Ca2+. At the
basolateral membrane, an ATP-driven Ca2+-H+-antiporter as
well as a Na+-driven Ca2+-Na+-antiporter are induced to
pump Ca2+ into the blood against a steep concentration gradient. Calcitriol
also enhances phosphate absorption in the small intestine.
In the
kidney, the action of vitamin D parallels that of PTH by increasing
reabsorption of Ca2+ in the distal tubule, although its effect is
much weaker. Contrary to PTH, vitamin D also enhances reabsorption of
phosphate: both ions are required to promote bone mineralization.
Together, these
effects of vitamin D raise Ca2+ and phosphate concentrations above
their solubility product, inducing their precipitation in osteoid, an effect
that is enhanced by vitamin D-stimulated transcription of the osteocalcin gene
in osteoblasts. This predominant, indirect effect outweighs an opposite direct,
receptor-mediated activation of osteoblast and osteoclast precursors that
enhances bone turnover and Ca2+ mobilization.
(Credit:
Arno Helmberg)
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