Calcitonin
Encyclopedia
Calcitonin is a 32-amino acid linear polypeptide hormone
that is produced
in human
s primarily by the parafollicular
cells (also known as C-cells) of the thyroid
, and in many other animals in the ultimobranchial body
. It acts to reduce blood calcium
(Ca2+), opposing the effects of parathyroid hormone
(PTH). Calcitonin has been found in fish
, reptile
s, bird
s, and mammal
s. Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant in the regulation of normal calcium homeostasis.. It belongs to calcitonin-like protein family.
, and the precursor of adrenomedullin
.
Secretion of calcitonin is stimulated by:
(Ca2+) and phosphorus
metabolism
. In many ways, calcitonin counteracts parathyroid hormone
(PTH).
More specifically, calcitonin lowers blood Ca2+ levels in two ways:
In its skeleton-preserving actions, calcitonin protects against calcium loss from skeleton during periods of calcium mobilization, such as pregnancy
and, especially, lactation
While calcitonin is the antipode of parathyroid hormone (PTH) in those actions, it is not dissimilar from PTH in its effect on electrolyte reabsorption in the kidneys. Namely, calcitonin:
Other effects are in preventing postprandial hypercalcemia resulting from absorption of Ca2+. Also, calcitonin inhibits food intake in rats and monkeys, and may have CNS
action involving the regulation of feeding and appetite.
, found on osteoclasts, and in kidney and regions of the brain, is a G protein-coupled receptor
, which is coupled by Gs
to adenylate cyclase
and thereby to the generation of cAMP in target cells. It may also affect the ovaries in women and the testes in men.
s, it was later identified as the secretion of the C-cells
of the thyroid
gland.
It has been investigated as a possible non-operative treatment for spinal stenosis.
The following information is from the UK Electronic Medicines Compendium
Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidney following parenteral administration. The metabolites lack the specific biological activity of calcitonin. Bioavailability following subcutaneous and intramuscular injection in humans is high and similar for the two routes of administration (71% and 66%, respectively).
Calcitonin has short absorption and elimination half-lives of 10–15 minutes and 50–80 minutes, respectively. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically-inactive fragments of the molecule. Therefore, the metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevance of this finding is not known. Plasma protein binding is 30% to 40%.
An increased incidence of pituitary adenomas has been reported in rats given synthetic salmon calcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance. Salmon calcitonin does not cross the placental barrier.
In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin is secreted into the milk.
technology or by chemical peptide synthesis
. The pharmacological properties of the synthetic and recombinant peptides have been demonstrated to be qualitatively and quantitatively equivalent.
.
Oral calcitonin may have a chondroprotective role in osteoarthritis (OA), according to data in rats presented in December, 2005, at the 10th World Congress of the Osteoarthritis Research Society International (OARSI) in Boston, Massachusetts. Although calcitonin is a known antiresorptive agent, its disease-modifying effects on chondrocytes and cartilage metabolisms have not been well established until now.
This new study, however, may help to explain how calcitonin affects osteoarthritis. “Calcitonin acts both directly on osteoclasts, resulting in inhibition of bone resorption and following attenuation of subchondral bone turnover, and directly on chondrocytes, attenuating cartilage degradation and stimulating cartilage formation,” says researcher Morten Karsdal, MSC, PhD, of the department of pharmacology at Nordic Bioscience in Herlev, Denmark. “Therefore, calcitonin may be a future efficacious drug for OA.”
Subcutaneous injections of calcitonin in patients suffering from mania
resulted in significant decreases in irritability, euphoria and hyperactivity and hence calcitonin holds promise for treating bipolar disorder
. However no further work on this potential application of calcitonin has been reported.
for medullary thyroid cancer
, in which high calcitonin levels may be present and elevated levels after surgery may indicate recurrence. It may even be used on biopsy
samples from suspicious lesions (e.g., swollen lymph node
s) to establish whether they are metastasis
of the original cancer.
Cutoffs for calcitonin to distinguish cases with medullary thyroid cancer have been suggested to be as follows, with a higher value increasing the suspicion of medullary thyroid cancer:
When over 3 years of age, adult cutoffs may be used
(CGRP), beta type.
The following are the amino acid sequences of salmon and human calcitonin:
Compared to salmon calcitonin, human calcitonin differs at 16 residues.
Hormone
A hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
that is produced
in human
Human
Humans are the only living species in the Homo genus...
s primarily by the parafollicular
Parafollicular cell
Parafollicular cells are cells in the thyroid that produce and secrete calcitonin. They are located adjacent to the thyroid follicles and reside in the connective tissue. These cells are large and have a pale stain compared with the follicular cells or colloid...
cells (also known as C-cells) of the thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
, and in many other animals in the ultimobranchial body
Ultimobranchial body
The ultimopharyngeal body or ultimobranchial body or ultimobranchial gland is a small organ found in the neck region of many animals....
. It acts to reduce blood calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
(Ca2+), opposing the effects of parathyroid hormone
Parathyroid hormone
Parathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...
(PTH). Calcitonin has been found in fish
Fish
Fish are a paraphyletic group of organisms that consist of all gill-bearing aquatic vertebrate animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish, as well as various extinct related groups...
, reptile
Reptile
Reptiles are members of a class of air-breathing, ectothermic vertebrates which are characterized by laying shelled eggs , and having skin covered in scales and/or scutes. They are tetrapods, either having four limbs or being descended from four-limbed ancestors...
s, bird
Bird
Birds are feathered, winged, bipedal, endothermic , egg-laying, vertebrate animals. Around 10,000 living species and 188 families makes them the most speciose class of tetrapod vertebrates. They inhabit ecosystems across the globe, from the Arctic to the Antarctic. Extant birds range in size from...
s, and mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s. Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant in the regulation of normal calcium homeostasis.. It belongs to calcitonin-like protein family.
Biosynthesis and regulation
Calcitonin is formed by the proteolytic cleavage of a larger prepropeptide, which is the product of the CALC1 gene . The CALC1 gene belongs to a superfamily of related protein hormone precursors including islet amyloid precursor protein, calcitonin gene-related peptideCalcitonin gene-related peptide
Calcitonin gene related peptide is a member of the calcitonin family of peptides, which in humans exists in two forms, α-CGRP and β-CGRP. α-CGRP is a 37-amino acid peptide and is formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11...
, and the precursor of adrenomedullin
Adrenomedullin
Adrenomedullin is a peptide associated with pheochromocytoma- a tumour arising from adrenal medulla. It was discovered in 1993.Adrenomedullin is a ubiquitously expressed peptide initially isolated from phaechromyctoma in 1993...
.
Secretion of calcitonin is stimulated by:
- an increase in serum [Ca2+]
- gastrinGastrinIn humans, gastrin is a peptide hormone that stimulates secretion of gastric acid by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the antrum of the stomach, duodenum, and the pancreas...
and pentagastrinPentagastrinPentagastrin is a synthetic polypeptide that has effects like gastrin when given parenterally. It stimulates the secretion of gastric acid, pepsin, and intrinsic factor, and has been used as a diagnostic aid as the pentagastrin-stimulated calcitonin test.Pentagastrin binds to the cholecystokinin-B...
.
Effects
The hormone participates in calciumCalcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
(Ca2+) and phosphorus
Phosphorus
Phosphorus is the chemical element that has the symbol P and atomic number 15. A multivalent nonmetal of the nitrogen group, phosphorus as a mineral is almost always present in its maximally oxidized state, as inorganic phosphate rocks...
metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
. In many ways, calcitonin counteracts parathyroid hormone
Parathyroid hormone
Parathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...
(PTH).
More specifically, calcitonin lowers blood Ca2+ levels in two ways:
- Inhibits Ca2+ absorption by the intestines
- Inhibits osteoclastOsteoclastAn osteoclast is a type of bone cell that removes bone tissue by removing its mineralized matrix and breaking up the organic bone . This process is known as bone resorption. Osteoclasts were discovered by Kolliker in 1873...
activity in boneBoneBones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
s - Inhibits renal tubular cellNephronThe renal tubule is the portion of the nephron containing the tubular fluid filtered through the glomerulus. After passing through the renal tubule, the filtrate continues to the collecting duct system, which is not part of the nephron....
resorption of Ca2+ allowing it to be secreted in the urineUrineUrine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
- Vitamin DVitamin DVitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
regulation
In its skeleton-preserving actions, calcitonin protects against calcium loss from skeleton during periods of calcium mobilization, such as pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...
and, especially, lactation
Lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
While calcitonin is the antipode of parathyroid hormone (PTH) in those actions, it is not dissimilar from PTH in its effect on electrolyte reabsorption in the kidneys. Namely, calcitonin:
- Inhibits phosphate reabsorption by the kidneyKidneyThe kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
tubules - Calcitonin decreases tubular reabsorption of Ca2+, leading to increased rates of its loss in urine.
Other effects are in preventing postprandial hypercalcemia resulting from absorption of Ca2+. Also, calcitonin inhibits food intake in rats and monkeys, and may have CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
action involving the regulation of feeding and appetite.
Receptor
The calcitonin receptorCalcitonin receptor
The calcitonin receptor is a G protein-coupled receptor that binds the peptide hormone calcitonin and is involved in maintenance of calcium homeostasis, particularly with respect to bone formation and metabolism ....
, found on osteoclasts, and in kidney and regions of the brain, is a G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
, which is coupled by Gs
Gs alpha subunit
The Gs alpha subunit is a heterotrimeric G protein subunit that activates the cAMP-dependent pathway by activating adenylate cyclase.-Receptors:The G protein-coupled receptors that couple to this kind of G-protein include:...
to adenylate cyclase
Adenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
and thereby to the generation of cAMP in target cells. It may also affect the ovaries in women and the testes in men.
Discovery
Calcitonin was purified in 1962 by Copp and Cheney. While it was initially considered a secretion of the parathyroid glandParathyroid gland
The parathyroid glands are small endocrine glands in the neck that produce parathyroid hormone. Humans usually have four parathyroid glands, which are usually located on the rear surface of the thyroid gland, or, in rare cases, within the thyroid gland itself or in the chest...
s, it was later identified as the secretion of the C-cells
Parafollicular cell
Parafollicular cells are cells in the thyroid that produce and secrete calcitonin. They are located adjacent to the thyroid follicles and reside in the connective tissue. These cells are large and have a pale stain compared with the follicular cells or colloid...
of the thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...
gland.
Pharmacology
Salmon calcitonin is used for the treatment of:- Postmenopausal osteoporosisOsteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
- HypercalcaemiaHypercalcaemiaHypercalcaemia is an elevated calcium level in the blood. . It can be an asymptomatic laboratory finding, but because an elevated calcium level is often indicative of other diseases, a workup should be undertaken if it persists...
- Paget's diseasePaget's diseaseSir James Paget, a surgeon and pathologist, described several diseases, including:* Paget's disease of bone * Paget's disease of the breast* Paget-Schroetter disease* Extramammary Paget's disease...
- Bone metastasesBone MetastasesBone metastases, or metastatic bone disease, is a class of cancer metastases that results from primary tumor invasion to bone. Bone-originating cancers like osteosarcoma, chondrosarcoma, and Ewing's sarcoma are rare...
- Phantom limb pain
It has been investigated as a possible non-operative treatment for spinal stenosis.
The following information is from the UK Electronic Medicines Compendium
General characteristics of the active substance
Salmon calcitonin is rapidly absorbed and eliminated. Peak plasma concentrations are attained within the first hour of administration.Animal studies have shown that calcitonin is primarily metabolised via proteolysis in the kidney following parenteral administration. The metabolites lack the specific biological activity of calcitonin. Bioavailability following subcutaneous and intramuscular injection in humans is high and similar for the two routes of administration (71% and 66%, respectively).
Calcitonin has short absorption and elimination half-lives of 10–15 minutes and 50–80 minutes, respectively. Salmon calcitonin is primarily and almost exclusively degraded in the kidneys, forming pharmacologically-inactive fragments of the molecule. Therefore, the metabolic clearance is much lower in patients with end-stage renal failure than in healthy subjects. However, the clinical relevance of this finding is not known. Plasma protein binding is 30% to 40%.
Characteristics in patients
There is a relationship between the subcutaneous dose of calcitonin and peak plasma concentrations. Following parenteral administration of 100 IU calcitonin, peak plasma concentration lies between about 200 and 400 pg/ml. Higher blood levels may be associated with increased incidence of nausea and vomiting.Preclinical safety data
Conventional long-term toxicity, reproduction, mutagenicity, and carcinogenicity studies have been performed in laboratory animals. Salmon calcitonin is devoid of embryotoxic, teratogenic, and mutagenic potential.An increased incidence of pituitary adenomas has been reported in rats given synthetic salmon calcitonin for 1 year. This is considered a species-specific effect and of no clinical relevance. Salmon calcitonin does not cross the placental barrier.
In lactating animals given calcitonin, suppression of milk production has been observed. Calcitonin is secreted into the milk.
Pharmaceutical manufacture
Calcitonin was extracted from the Ultimobranchial glands (thyroid-like glands) of fish, particularly salmon. Salmon calcitonin resembles human calcitonin, but is more active. At present, it is produced either by recombinant DNARecombinant DNA
Recombinant DNA molecules are DNA sequences that result from the use of laboratory methods to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms...
technology or by chemical peptide synthesis
Peptide synthesis
In organic chemistry, peptide synthesis is the production of peptides, which are organic compounds in which multiple amino acids are linked via amide bonds which are also known as peptide bonds...
. The pharmacological properties of the synthetic and recombinant peptides have been demonstrated to be qualitatively and quantitatively equivalent.
Treatments
Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosisOsteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
.
Oral calcitonin may have a chondroprotective role in osteoarthritis (OA), according to data in rats presented in December, 2005, at the 10th World Congress of the Osteoarthritis Research Society International (OARSI) in Boston, Massachusetts. Although calcitonin is a known antiresorptive agent, its disease-modifying effects on chondrocytes and cartilage metabolisms have not been well established until now.
This new study, however, may help to explain how calcitonin affects osteoarthritis. “Calcitonin acts both directly on osteoclasts, resulting in inhibition of bone resorption and following attenuation of subchondral bone turnover, and directly on chondrocytes, attenuating cartilage degradation and stimulating cartilage formation,” says researcher Morten Karsdal, MSC, PhD, of the department of pharmacology at Nordic Bioscience in Herlev, Denmark. “Therefore, calcitonin may be a future efficacious drug for OA.”
Subcutaneous injections of calcitonin in patients suffering from mania
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
resulted in significant decreases in irritability, euphoria and hyperactivity and hence calcitonin holds promise for treating bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
. However no further work on this potential application of calcitonin has been reported.
Diagnostics
It may be used diagnostically as a tumor markerTumor marker
A tumor marker is a substance found in the blood, urine, or body tissues that can be elevated in cancer, among other tissue types. There are many different tumor markers, each indicative of a particular disease process, and they are used in oncology to help detect the presence of cancer...
for medullary thyroid cancer
Medullary thyroid cancer
Medullary thyroid cancer is a form of thyroid carcinoma which originates from the parafollicular cells , which produce the hormone calcitonin....
, in which high calcitonin levels may be present and elevated levels after surgery may indicate recurrence. It may even be used on biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
samples from suspicious lesions (e.g., swollen lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
s) to establish whether they are metastasis
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
of the original cancer.
Cutoffs for calcitonin to distinguish cases with medullary thyroid cancer have been suggested to be as follows, with a higher value increasing the suspicion of medullary thyroid cancer:
- females: 5 ng/L or pg/mL
- males: 12 ng/L or pg/mL
- children under 6 months of age: 40 ng/L or pg/mL
- children between 6 months and 3 years of age: 15 ng/L or pg/mL
When over 3 years of age, adult cutoffs may be used
Structure
Calcitonin is a polypeptide hormone of 32 amino acids, with a molecular weight of 3454.93 daltons. Its structure comprises a single alpha helix. Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptideCalcitonin gene-related peptide
Calcitonin gene related peptide is a member of the calcitonin family of peptides, which in humans exists in two forms, α-CGRP and β-CGRP. α-CGRP is a 37-amino acid peptide and is formed from the alternative splicing of the calcitonin/CGRP gene located on chromosome 11...
(CGRP), beta type.
The following are the amino acid sequences of salmon and human calcitonin:
- salmon: Cys-Ser-Asn-Leu-Ser-Thr-Cys-Val-Leu-Gly-Lys-Leu-Ser-Gln-Glu-Leu-His-Lys-Leu-Gln-Thr-Tyr-Pro-Arg-Thr-Asn-Thr-Gly-Ser-Gly-Thr-Pro
- human: Cys-Gly-Asn-Leu-Ser-Thr-Cys-Met-Leu-Gly-Thr-Tyr-Thr-Gln-Asp-Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro
Compared to salmon calcitonin, human calcitonin differs at 16 residues.