Second year undergraduate essay written for the Cell Pathology module of the Biomedical Sciences course at the University of Oxford.
//Essay title: Describe the mechanisms by which extracellular calcium concentration is regulated. Discuss the disease processes that may occur when this regulator...
Describe the mechanisms by which extracellular calcium concentrati on is regulated.
Discuss the disease processes that may occur when this regulatory system
malfuncti ons.
Calcium in the extracellular fluid (ECF) is tightly regulated by a complex homeostatic
mechanism, involving three major hormones – parathyroid hormone, 1,25-dihydroxyvitamin
D (1,25(OH)2 D), and calcitonin. It is important to maintain calcium homeostasis because
calcium plays a critical role in many cellular processes such as muscle contraction, nerve
conduction and exocytosis, dysregulation of the regulatory system can therefore cause
various diseases. In this essay, we describe how ECF [Ca 2+] is controlled, along with how
diseases can arise when these regulatory processes malfunction.
To begin with, calcium homeostasis involves calcium fluxes between the ECF and the
kidneys, gut and bones, ECF concentration of the physiologically active form of calcium i.e.
free ionised Ca2+ is tightly regulated at around 1.2mM. 99% of total body calcium is stored in
bone with phosphate as hydroxyapatite crystals, calcium constantly recycles between bone
and ECF through resorption and deposition but these processes usually balance out to
maintain a steady ECF Ca2+ pool. A small fraction of dietary Ca2+ is absorbed in the gut and
the remainder is lost as faeces. Absorbed Ca 2+ is filtered and reabsorbed by the kidneys, with
a small amount being excreted in urine. By matching urinary excretion to net absorption of
Ca2+, total body calcium is kept constant. Fluctuations in ECF [Ca 2+], such as due to an altered
calcium intake, is buffered through altering Ca 2+ balance between the ECF and the three
aforementioned organs through hormonal mechanisms, malfunctions of the system alter
ECF [Ca2+], causing hypo- or hypercalcaemia. For instance, low ECF [Ca 2+] in hypocalcaemia
increases activity of a voltage-gated sodium channel which is calcium-sensitive, causing
nerve hyperexcitability and muscle tetany due to decrease in threshold potential, this can
be recognised by carpopedal spasms. In contrast, hypercalcaemia with high ECF [Ca 2+]
reduces excitability of nerves and may lead to formation of kidney stones, eventually
resulting in renal or cardiac failure. We now discuss how hypo/hypercalcaemia arise from
malfunctions of Ca2+ regulatory pathways, the interactions between pathways can be
summarised as:
Parathyroid hormone (PTH) from chief cells of the parathyroid gland raises ECF [Ca 2+] while
promoting phosphate loss by binding to the PTH 1R receptor (PTH1R) in bones and the
kidneys. In bones, intermittent release of PTH has predominately bone-synthetic effects by
enhancing osteoblast proliferation, but chronic increase in PTH raises ECF [Ca 2+] by indirectly
favouring bone resorption. To illustrate, PTH exert a range of actions on osteoblasts
including upregulating its RANKL expression which binds to RANK on osteoclast progenitor
cells, increase cytokine (M-CSF, IL-12) production and reduced osteoprotegerin (OPG)
synthesis to disinhibit RANKL/RANK signalling, these effects indirectly activate osteoclasts.
, Meanwhile, PTH enhances calcium efflux from bone matrix by promoting protease synthesis
in rearranged osteoblasts, this supports reabsorption of the digested matrix by osteoclasts.
Indirect effects of PTH was tested by Chambers et al. (1986), they showed that PTH had not
effect on osteoclasts disaggregated from neonatal rat long bones and incubated alone, but
caused a 2- to 4- fold increase in reabsorption activity in osteoclasts that are co-cultured
with osteoblasts.
On the other hand, PTH has direct and indirect effects on the kidneys to raise ECF [Ca 2+]
while lowering phosphate level. PTH acts directly on basolateral membranes of proximal
(PT) and distal convoluted tubule (DCT) to modify transepithelial transport of phosphate and
Ca2+ respectively. Along with enhancing Ca2+ reabsorption, PTH redistributes Na/phosphate
cotransporters away from PT apical membrane to reabsorb less phosphate so precipitation
of calcium phosphate salts is diminished and more Ca 2+ is mobilised. PTH also upregulates
synthesis of 1,25(OH)2 D in kidneys by upregulating transcription of the enzyme 1 α -
hydroxylase (CYP27B1) which mediates the conversion of 25-hydroxyvitamin D into
1,25(OH)2 D. As described later, PTH indirectly increases ECF [Ca 2+] through the action of net
action of 1,25(OH)2 D.
Excess PTH release in hyperparathyroidism causes hypercalcaemia. Primary
hyperparathyroidism can be caused by a rare genetic disorder called multiple endocrine
neoplasia (MEN), MEN1 involves development of tumours that usually first appear in the
parathyroid glands whereas patients with MEN2 develop medullary thyroid carcinoma.
Secondary hyperparathyroidism arises as a maladaptive process in response to declining
kidney function, failure to activate vitamin D and impaired phosphate excretion, causing a
sustained elevation of PTH that contributes to a viscous cycle. In contrary, abnormally low
PTH in hypoparathyroidism causes hypocalcaemia, with its origin ranging from surgical or
autoimmune to familial or idiopathic.
PTH synthesis is stimulated by low ECF [Ca 2+], sensed by Ca2+- sensing receptor (CaSR), a
GPCR that is simultaneously coupled to Gα q and Gα i. Binding of Ca2+ to CaSR inhibits adenylyl
cyclase and stimulates phospholipase C, resulting in low cAMP and high intracellular Ca 2+
levels that inhibit PTH secretion. In contrary, low ECF [Ca 2+] leads to opposite downstream
events that increases PTH secretion. CaSR was first identified in bovine parathyroid in 1993
by Hebert and Brown through expression cloning of the bovine CaSR in Xenopus laevis
oocyte, the group also hypothesised the presence of renal CaSR. Further work of the group
identified a cDNA encoding a rat kidney CaSR which share 92% of the identity of the bovine
CaSR, their later use of immunofluorescence microscopy to localise renal CaSR with
polyclonal antibodies confirmed that the receptor mRNA is present throughout the kidneys.
Recent studies support the idea that renal CaSR are capable of regulating renal handling of
ions according to ECF [Ca2+], independent of changes in PTH levels. For example, Loupy et al.
(2012) used an allosteric inhibiter to investigate the role of renal CaSR in
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