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Introduction

Homeostasis is the balance of
a consistent internal environment that is regulated by changes internally and
externally. It is controlled by the nervous system and the secretion of
hormones. Internal and external triggers send chemical messages throughout the
body that secrete hormones that are required for important overall regulation. For
example, the hypothalamus works together with other parts of the body to
regulate the body’s temperature, such as sweat glands and blood vessels. Water regulation is controlled by
homeostasis and is regulated by ingesting fluids when thirst is apparent. And
glucose regulation, hormones secreted from the pancreas help control blood
sugar levels, these hormones are called insulin and glucagon that are released
when glucose levels in the body are too high or too low (Scheuner et al., 2001). Stanniocalcin (STC; previously
named hypocalcin or teleocalcin) is a glycoprotein hormone that was thought to
be unique to teleostean and holostean fish (Ishibashi,
2002). Human STC shares 60% identity and 80% similarity with
fish STC (Zhang et al. 2000). The
role of stanniocalcin will be explained in detail including comparisons of the
hormone in bony fish and new studies including STC1 and STC2 in mammals and
humans.

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The
corpuscles of Stannius

The corpuscles of Stannius (CS) are small
endocrine glands that are generally located on the ventral surface of the
kidneys of bony fishes (see fig. 1). They
synthesize and secrete stanniocalcin (STC) (Yeung
et al. 2012) which is used primarily to protect against hypercalcemia. When
they were discovered they were mistaken to be the equivalent of a mammalian
adrenal gland because of their anatomy and association with the kidneys (Yeung et al., 2012). The theory is that
stanniocalcin in bony fish is exclusive to them, as humans and other mammals
don’t have the small endocrine glands. More recent studies comparing fish STC
and human STC suggest that certain human or mammalian STC actually has similar
function to the fish STC, and fish STC also has similar functions to mammals.

Due to their amino acid sequence similarity, many studies have been conducted
by administering fish STC or human/mammalian STC and focusing on how the
hormone reacts to controls in a laboratory setting.  

 

 

 

Stanniocalcin
in bony fish

The
main function of STC in fish is to prevent hypercalcemia, a rise in
extracellular serum levels is the primary stimulus for secreting STC (Madsen et al., 1998). The STC will act
on the gills and reduce further intake of Ca2+, the kidneys will
then initiate reabsorption of phosphate to chelate the extra Ca2+,
the gut can then slow down the intake of Ca2+ (Varghese et al., 1998). In bony fish, the main organs for
osmoregulation function are the gills or the intestines, their kidneys can’t
secrete hypertonic urine so they use the gills and intestines to help fluid
regulation by controlling Ca2+ and phosphate levels. Unlike
terrestrial mammals, fish face the challenging task of balancing the dramatic
ionic and osmotic gradients between the aquatic environment and their internal body
fluids (Guh, 2015). The
gills have a large epithelial surface area that act as a respiratory organ, the
same as the kidney would demonstrate in terrestrial animals. The gills aid ion
transportation, internal pH balance and secretions of nitrogenous waste and
maintenance. They have a similar function to the cells in a mammalian stomach
that secrete hydrochloric acid. Fish STC hormone compared to human STC hormone,
although similar in protein molecules, differ slightly in function. Fish STC is
known for its regulatory effect on calcium and phosphate transport by the
gills, gut and kidneys (Wagner, 2006).

The function and secretion of
STC in different species of bony fish has been researched in depth,
concentrating on how the hormone transports gill calcium around the body and
whether or not different species of fish have different internal strategies of
balancing and transporting gill calcium. Freshwater salmon hasn’t been studied
in as much depth compared to other fish species, although, it is now known that
freshwater salmon STC also plays a fundamental role in Ca2+ transport
and phosphate. The extracellular fluid has high levels of Ca2+ which
initiate STC secretion, this then enters the bloodstream and reduces the level
of the gut and gill Ca2+ including reneal phosphate excretion to
then restore normocalcemia (Wagner, 1998).

Freshwater salmon have displayed a rythmic homeostatic strategy, when
discussing STC, their bodies can regulate and maintain Ca2+ and
phosphate levels significantly well. Understanding the distribution of STC and
mRNA in the corpuscles of Stannius, and the effects of Ca2+ when the
STC hormone is secreted can determine the responsiveness of marine CS cells (see fig. 2). Increasing levels of Ca2+
in the extracellular fluid will increase the overall cell mRNA, boost
stability, stimulate the synthesis of mRNA and has an overall effect on STC
secretion. Therefore, Ca2+ can be classed as the main stimulus for
hormone secretion (Wagner 1997).

Stanniocalcin
in humans and mammals

Discovery of the mammalian STC gene

Suggesting
that there was a form of mammalian STC was based on conducting STC
immunoreactivity in the blood serum of the human kidney and many other species.

Evidence for existing human STC was discovered by Chang et al. (1995). When the
amino acid sequence was discovered it was found to share 60% identity and 73%
similarity to the fish STC, it was also named STC. When the second gene was
identified, the mammalian STC was renamed STC1 (Chang, 2003).

 

Humans and mouse
STC1 protein share 98% amino acid similarity, and about 80% amino acid
similarity with fish. For this reason, human and mouse studies comparing STC1
are popular when it comes to scientific studies (Jiang et al. 2000) In mammalian form, STC is expressed in
different parts of the body including the kidney, lungs and the liver (James et al. 2005). In the kidney and
gut, it regulates serum calcium levels by increasing phosphate reabsorption (Radman et al., 2001). The corpuscles of
Stannius do not exist in mammals, and it was long assumed that STC and the
effects it has on bony fish were exclusive to bony fish only. It was also
assumed that calcium and phosphate regulation and secretion were unique to fish
(Madsen et al., 1997). STC in mammals
has only recently been discovered, discussing the overall role and function of
mammalian STC is yet to be concluded, although, new research can give an insight
into explaining mammalian STC and how it differs compared to fish STC. the
level of similarity in regard to sequence in human STC1 and salmon STC is 92%,
over the first 204 amino acids, 118 are identical to each other and the
remainder 43 at the C-terminus are dissimilar (Chang, 2003). In a recent study conducted by the Department of
Growth and Development, Hiroshima University, scientists tested mammalian STC
focusing on bones, skeletal tissues and other tissues. Mouse and rat models
were cloned using human STC and the results shown high levels of human STC in
the liver, heart, adipose tissue, mammary glands and testis. They concluded
that physiological and pathological processes are regulated by human STC levels
and that calcium and phosphate levels may be the reason why STC is synthesized
and secreted. Only further evidence of human STC tested on other mammals can
help determine exactly what the hormone can manipulate (Yoshiko, 2004). An interesting fact about newly discovered STC1 is
that it only circulates in the serum of pregnant and lactating females. STC1 is
undetectable by radioimmunoassay. Pregnant and lactating rats and mice STC is
easily detectable due to the STC hormone corresponding naturally with ovarian
STC gene expression (James et al., 2005).

Human STC is also known to also be a biomarker of colon cancer in humans (Arabzadeh et al., 2014), a novel target molecule for aggressive prostate cancers (Tamura et al., 2009), and association
with colorectal cancer progression (Yokoi
et al., 2017).

Previous studies have used
fish STC in certain mammals and have found that it caused hypercalcemia and hypocalcaemia
when given to rats. The kidney in the mammalian body is one of many tissues
that produce the protein in mammals, so it is unknown yet if STC is targeted
there renally.

Comparison
Case Studies – human STC (hSTC) and fish STC

The mammalian homolog to fish STC was discovered in
1995 and has resulted in progressively growing interest ever since as to its
possible role in humans (Wagner, 2006). Human
STC was found to be 247 amino acids long and to share 73% amino acid sequence similarity
with fish STC (Olsen et al., 2006). Scientists
have discovered that the STC hormone isn’t only produced by the corpuscles of
Stannius in fish, but the kidneys in a human body prove to be a possible source
for secreting a similar functioning hormone. Human STC is known to have been
found in different regions of the body, suggesting that it may be an inhibitor
for mineral metabolism (Hulova, 1999).

In a recent study, goldfish were injected with human STC and Salmon STC,
another group was injected with saline. The results shown that gill calcium
transport was significantly reduced in comparison to saline-injected controls,
although, gill calcium transport was still noticeable in goldfish that had been
given human STC and salmon STC, proving that the antibodies of recombinant STC
had an effect (see fig. 3). Scientists
will also try and manipulate STC by administering other hormones that may have
an effect on STC secretion. For example, calcitriol was recently used in a
study to show the effects of fish STC (STC1) and human STC (STC2). The hormone
was given to rats over the course of 6 days, the study focused on the changes
of STC levels in the ovaries and kidneys, these organs were chosen due to have
demonstrated high levels of STC1. Changes were measured by plasma and Ca2+
levels. The results shown that the level of STC1 increased in the kidneys and STC2
decreased (see fig. 4). This supports
the theory that STC1 and STC2 are part of the same stanniocalcin family, and
that anti-hypercalcaemic and anti-hypocalcaemic reactions were restoring
normocalcemia. When analysing STC1 and STC2 levels in the ovaries, both hormone
was highly expressed although no changes occurred, this may suggest an ovary
related STC hormone working independently of the calcium levels.

 

 

 

 

 

 

 

 

 

 

 

Conclusion

When Stanniocalcin was discovered in the human genome, it
was unsure as to whether the hormone displayed the same properties as
stanniocalcin found in fish. It has always been thought that stanniocalcin in
fish is used as an anti-hypercalcaemic glycoprotein (Guh, 2017). Whether it had similar effects on humans or mammals was
a question many scientists found themselves asking, and with not that much
information to go by, found themselves carrying out studies to determine the
function of STC1 and STC2. When researching the topic, fish STC has clearly
been studied for some time and the information available is widely spread.

Although, human STC is more difficult to uncover, due to the nature of the
topic. However, mammalian STC studies including mice and rats were easier to
find. I found that recent studies replicated in terms methods and materials
used to carry out a scientific study on human or mammalian STC, although, most
individual studies tested for different results, and some studies found
evidence of new information regarding human STC and fish STC, such as STC1 and
STC2 found in the ovaries of rats over the course of calcitriol treatment
remaining unchanged, suggesting the ovaries are capable of controlling STC
levels independently. As mentioned, research and studies surrounding human and
mammalian STC are of a minority compared to fish STC, although, I believe
continuous studies will unravel information about STC1 and STC2.

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