Calcitonin Peptides.

When the level of serum calcium is raised due to parafollicular cells present in the
thyroid gland, it results in the secretion of peptide calcitonin. Calcitonin is a peptide in nature.
Different types ofpeptide hormones respond differently towards signals and express in different
tissues. These hormones show structural analogy with calcitonin and transduce signals via
various receptors. Apart from having a similar structure, some of the peptides have few
overlapping biological activities, while others are unique.
Calcitonin in Homeostasis. The serum calcium level is maintained within a narrow range of 8.5 mg/dL
and 10.5 mg/ dL by the coordinated actions of the skeleton, the gut, and the kidneys. The regulation of
calcium level is necessary because it plays critical role in many essential physiological processes such
as coagulation, contraction of muscle, and glycogenolysis. Similarly, Ca++ controls cellular adhesions
[1]. Physicians have already recognized the significance of the regulation of calcium level and the
detrimental outcome of the disproportional level of calcium. In the late 19th century, the parathyroid
gland was discovered that lead to the empathy of calcium homeostasis and hormonal mech- anisms [2].
Later, in 1925, the researchers [3] described the physiological function of the parathyroid gland by
showing that tetany caused by parathyroidectomy was treated by the acid extracts of the parathyroid
gland. The researchers revealed that, at a low level of calcium, this gland secretes parathyroid hormone
(PTH) to restore the calcium level to its standard range. The investigations should be carried out to
explore the mechanism of action of PTH by the advanced improvement of PTH extraction methods [4,
5]. Another group of researchers investigated the regulation of calcium levels by thyroid-parathyroid
gland and calcium homeo- stasis in the perfusion system of anaesthetized dogs [6]. At high levels of
calcium, perfusion of thyroid-parathyroid glands causes a rapid decrease in blood calcium level within
fifteen minutes. According to a hypothesis, the permeation of high amount of calcium inhibits the
excretion of PTH that causes a rapid fall in systemic calcium levels, as PTH is the only hormone
released from the parathyroid gland. The investigators performed a test on dogs by removing their
thyroid-parathyroid glands to confirm the hypothesis as it was predicted that similar effects could be
seen on the calcium level in the body in PTH-free environment. Sur- prisingly, the systemic calcium
level was maintained at a high level. However, it was concluded that hypercalcemia causes the
production of a hormone which reduces the blood calcium level and does not inhibit the production of
PTH [6, 7]. The hormone was named as “calcitonin” since it controls the calcium tone. Many studies
are carried out that suggest another name of calcitonin as “thyrocalcitonin” since calcitonin is formed
by the thyroid gland [8]. The biological assay is used to study calcitonin by determining methodology
of parathyroid hormone by the regulation of calcium level in the body. A previous study [9] involved
the injection of 45Ca to pregnant rats and incorporated the embryonic bone in the tissue culture. This
bioassay was needed to evaluate the bone resorption and also the release of radioactivity-labeled
calcium. Bone resorption was in- duced under the effect of calcitonin that was purified mildly and
extracted from the thyroid gland of the rat. Thus, the bone resorption process was determined in
grouped format with PTH only in baseline conditions. These results iden- tified the hypocalcemic
mechanism of calcitonin and resulted in a decreased level of calcitonin at both PTH enthused and basal
bone resorption [9].
The clinical trial conducted in vivo estimated the
hydroxyproline calcitonin produced by collagen breakdown and showed further evidence of
calcitonin-based inhibition of bone resorption [10]. The result showed that calcitonin directly
suppressed the bone resorption and collagen breakdown as it rapidly reduced the excretion of urinary
hydroxyproline. Calcitonin was purified from various ani- mal species, including the mammals, the
fishes, and the birds [11]. In the human thyroid gland, calcitonin is produced in a large quantity that is
why purification of calcitonin was proved to be quiet challenging. Neher et al. [12] purified human
calcitonin (hCT) from the patients having tumors of the thyroid C cells, which forms calcitonin at
very elevated levels. This study showed the complete array of the amino acid sequence of hCT and
also determined that calcitonin present in a pig was different from hCT.

In contrast, both of them contained 32 amino acid peptides having a disulfide bridge near the
amino terminal and also had an amino carboxy terminal. During the as- sessment, the gene
sequence seemed to be a short arm of chromosome 11 connected directly with hCT gene
CALCA (calcitonin-related polypeptide alpha) [11, 13]. Thyroid C cells are considered as the
primary origin of circulating calcitonin in the human body; however, other organs such as
central nervous system (CNS), lungs, and thymus also showed some calcitonin like
immunoreactivity [14]. It is important to note that the patients who underwent thy-
roidectomy had come up with extrathyroidal excretion of calcitonin due to calcitonin-like
 immunoreactivity. As a result, the calcitonin was found to be present in blood and urine
samples.

1.. Effect of Calcitonin on an Elevated Level of Blood Calcium. The observation that calcitonin lowers
the amount of cir- culating calcium resulted in the hypothesis that its physi- ological function in
hypercalcemia might be involved in restoring ordinary concentrations of serum calcium. In several in
vitro studies, this hypothesis was tested in rats, many of which were parathyroidectomized (PTX)
without PTH-secreting cells or thyroparathyroidectomized (TPTX) without C-cells, which secrete both
PTH and calcitonin. When calcium injection or infusion directly caused hy- percalcemia, the existence
of thyroid gland was essential to reduce the calcium concentrations in the circulation [83, 84]. Same
conclusions were observed with the IV administration of parathyroid or partially purified PTH-induced
hyper- calcemia, conforming its advantages in hypercalcemia [85]. A general finding in renal failure is
the resistance produced due to the calcemic mechanism present in PTH and sec- ondary
hyperthyroidism. Rodriguez et al. documented the fact that the presence of thyroid gland is mandatory
in suppressing the calcemic action to PTH in rats. This re- duction can be seen in the PTH-induced
hypercalcemia in both cases of PTH-induced hypercalcemia associated with kidney failure or diet-
provoked hyperparathyroidism [86]. It was also suggested that the biological characteristics of
calcitonin in bone loss protection was affected by other hormones.
The TPTX rats with decreased calcitonin were treated
with PTH to produce an increased level of calcitonin, which resulted in bone damage from the
proximal part of the tibia side. On the contrary, the PTX rats that had sufficient calcitonin came up
with no damage to the bone, thus rendering the protective function of calcitonin, under these
circumstances [87]. Based on the findings that osteopenia caused by ovariectomy (OVX) rats is
involved with a re- duction in the circulation of calcitonin, it was suggested that calcitonin stimulated
the degradation process of bone caused by estrogen deficiency. However, this hypothesis has not been
supported by experimental proof. For example, in rats, with and without thyroid gland showed a
nonsignificantly different decline in femur density and calcium content [88]. The key strength of the
research mentioned above is the usage of animal models that enable careful manipulation of hormone
level by removing thyroids, parathyroid, and ovaries. These results confirm that the key origin of calci-
tonin is thyroid and shows the potential to cope up with an increased level of calcitonin due to various
reasons. These studies did not illustrate response to the fundamental issue of the biological and
functional role of CT; despite these apparent improvements in scientific understanding, it de- fines its
function in a pathology. The growth of those mice that are genetically altered in subsequent years has
given the potential objective for further research towards the con- tribution of calcitonin in stressed
conditions.

Bone Resorption by Osteoclasts. Mature osteoclasts are created by merging of precursor hematopoietic cells
and play a vital role in bone resorption. A high number of local and systemic variables regulate the
differentiation and activity of osteoclasts. The interaction of macrophage colony-stimu- lating factor to its
receptor c-FMS induces the osteoclast differentiation, which results in stimulation of expression of nuclear
factor-kappa-β (RANK). The RANK-RANK ligand (RANKL) interaction stimulates the differentiation and
activation of osteoclasts. Osteoprotegerin (OPG) is an os- teoblast lineage cell-secreted decoy receptor,
which interacts with RANKL and competitively inhibits RANK/RANKL interaction. Thus, the main factor
in controlling osteoclast activation and bone resorption is the ratio between OPG and RANKL levels [89].
Mature osteoclasts degrade the extra- cellular matrix of the bone, utilizing a specific methodology that is
already documented in previous studies. When mineralized bone matrix interacts with fully differentiated
osteoclasts, a “sealing region” is produced that covers the resorption lacuna’s enclosed area. The osteoclast
membrane present in the sealing arena undergoes twisting and forms a tangled border. These borders are
meant to be used for the transportation; i.e., protons, and matrix-degrading enzymes are released during the
bone resorption method. Shortly after the discovery of calcitonin, it was found that the bone resorption is
the vital factor for the fast decrease in calcium concentration of the circulation under the effect of calcitonin
[11]. After some years, the complete detail about calcitonin family was described [90]. Furthermore, the
osteoclasts exhibit the expression of CTR, RAMP1-3, and CRLR, re- vealing the interaction potential of the
calcitonin family with these cells [91].

Calcitonin. Calcitonin binding to osteoclasts receptor results in the loss of the ruffled boundary within
minutes, which results in cell removal along with its restriction of movement and bone dissociation [92,
93]. Several different mechanisms can stimulate calcitonin activity in the osteo- clasts, such as cAMP
affects motility restriction and qui- escent state induction. At the same time, intracellular calcium signaling
mediates the removal along with dis- ruption of the resorption process in the sealed area [94, 95]. Various
studies on the mechanistic aspects of sealing area unbinding revealed about calcitonin-based modulation of
Src and tyrosine kinase Pyk2 that is strongly expressed in osteoclasts and located primarily in the sealing
area [96, 97]. When mature osteoclasts of the mouse were administered with sCT, it did not affect the
amount of osteoclast cells in culture; however, the ability of bone resorption by the pretreated cells was
reduced [98–101]. The sCT-treated cells exhibited pits of smaller size as compared to control cells,
indicating a prolonged suppressive impact of sCT on the motility of osteoclast.