Calcitonin
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[edit] Description
Calcitonin is a 32-amino acid linear polypeptide hormone that is produced in humans primarily by the parafollicular cells (also known as C-cells) of the thyroid, and in many other animals in the ultimobranchial body.<ref name="Costoff_Calcitonin_Structure">Template:Cite web</ref> It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH).<ref name="isbn1-4160-2328-3">Template:Cite book</ref> It has been found in fish, reptiles, birds, and mammals. Its importance in humans has not been as well established as its importance in other animals, as its function is usually not significant to regulation of normal calcium homeostasis.<ref name="Costoff_Calcitonin_Biological_Actions">Template:Cite web</ref>
[edit] Biosynthesis
Calcitonin is formed by the proteolytic cleavage of a larger prepropeptide, which is the product of the CALC1 gene (Template:Gene). The CALC1 gene belongs to a superfamily of related protein hormone precursors including islet amyloid precursor protein, calcitonin gene-related peptide, and the precursor of adrenomedullin.
[edit] Physiology
The hormone participates in calcium (Ca2+) and phosphorus metabolism. In many ways, calcitonin counteracts parathyroid hormone (PTH).
To be specific, calcitonin affects blood Ca2+ levels in three ways:
- Inhibits Ca2+ absorption by the intestines<ref name="Costoff_Calcitonin_Small_Intestine">Template:Cite web</ref>
- Inhibits osteoclast activity in bones<ref name="Costoff_Calcitonin_Bone">Template:Cite web</ref>
- Inhibits Ca2+ and phosphate reabsorption by the kidney tubules<ref name="pmid9058369">Carney SL (1997). "Calcitonin and human renal calcium and electrolyte transport". Miner Electrolyte Metab 23 (1): 43–7. PMID 9058369.</ref>
Secretion of calcitonin is stimulated by:
- an increase in serum [Ca2+]<ref>Template:Cite book</ref>
- gastrin and pentagastrin.<ref>Erdogan MF, Gursoy A, Kulaksizoglu M (October 2006). "Long-term effects of elevated gastrin levels on calcitonin secretion". J Endocrinol Invest. 29 (9): 771-775. PMID 17114906.</ref>
[edit] Actions
Its actions, in a broad sense, are:
- Bone mineral metabolism:
- - Protect against Ca2+ loss from skeleton during periods of Ca2+ stress such as pregnancy and lactation
- Serum calcium level regulation
- - Prevent postprandial hypercalcemia resulting from absorption of Ca2+ from foods during a meal
- - Vitamin D regulation
- A satiety hormone:
- - Inhibit food intake in rats and monkeys
- - May have CNS action involving the regulation of feeding and appetite
[edit] Receptor
The calcitonin receptor, found primarily on osteoclasts, is a G protein-coupled receptor, which is coupled by Gs to adenylyl cyclase and thereby to the generation of cAMP in target cells.
[edit] Discovery
Calcitonin was purified in 1962 by Copp and Cheney.<ref name="pmid13881213">Copp DH, Cheney B (January 1962). "Calcitonin-a hormone from the parathyroid which lowers the calcium-level of the blood". Nature 193: 381–2. doi: . PMID 13881213.</ref> While it was initially considered a secretion of the parathyroid glands, it was later identified as the secretion of the C-cells of the thyroid gland.<ref name="pmid14076205">Hirsch PF, Gauthier GF, Munson PL (august 1963). "Thyroid hypocalcemic principle and recurrent laryngeal nerve injury as factors affecting the response to parathyroidectomy in rats". Endocrinology 73: 244–252. PMID 14076205.</ref>
[edit] Pharmacology
Salmon calcitonin is used for the treatment of:
- Postmenopausal osteoporosis
- Hypercalcaemia
- Paget's disease
- Bone metastases
- Phantom limb pain<ref name="pmid10332543">Wall GC, Heyneman CA (April 1999). "Calcitonin in phantom limb pain". Ann Pharmacother 33 (4): 499–501. doi: . PMID 10332543.</ref>
The following information is from the UK Electronic Medicines Compendium<ref name="UKEMC">Template:Cite web</ref>
[edit] 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%.
[edit] 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.
[edit] 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.
[edit] 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 DNA technology or by chemical peptide synthesis. The pharmacological properties of the synthetic and recombinant peptides have been demonstrated to be qualitatively and quantitatively equivalent.<ref name="UKEMC"/>
[edit] Uses of calcitonin
[edit] Treatments
Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis.
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 an established 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.”<ref name="url:Oral Calcitonin May Delay Onset of Joint Disease and Relieve Pain of OA">Template:Cite web</ref>
[edit] Diagnostics
It may be used diagnostically as a tumor marker for a form of thyroid cancer (medullary thyroid adenocarcinoma), 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 nodes) to establish whether they are metastasis of the original cancer.
[edit] 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.<ref>http://www.rcsb.org/pdb/explore.do?structureId=2GLH: Structure summary from PDB</ref>. Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP), beta type. <ref>http://smart.embl-heidelberg.de/smart/do_annotation.pl?BLAST=DUMMY&DOMAIN=SM00113</ref> The following is the amino acid sequence of calcitonin in 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. Compared to salmon calcitonin, human calcitonin differs at 16 residues: 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. <ref>http://www.newworldencyclopedia.org/entry/Calcitonin</ref>
[edit] Source Organism
Equus caballus (Horse).
[edit] Taxomomy
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;Mammalia; Eutheria; Laurasiatheria; Perissodactyla; Equidae; Equus.
[edit] Subcellular Localization
Secreted.
[edit] Developmental Stage
[edit] Similarity
Belongs to the calcitonin family.
[edit] Post translational Modification
[edit] Function
Causes a rapid but short-lived drop in the level of calcium and phosphate in blood by promoting the incorporation of those ions in the bones
[edit] GeneID
100033906