Calcitonin

Source: Wikipedia, the free encyclopedia.
CALCA
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl
UniProt
RefSeq (mRNA)

NM_001033952
NM_001033953
NM_001741
NM_001378949
NM_001378950

n/a

RefSeq (protein)

NP_001029125.1

n/a

Location (UCSC)Chr 11: 14.97 – 14.97 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Calcitonin is a 32

chordates[3] in the ultimopharyngeal body.[4] It acts to reduce blood calcium (Ca2+), opposing the effects of parathyroid hormone (PTH).[5]

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

calcitonin-like protein family
.

Historically calcitonin has also been called thyrocalcitonin.[7]

Biosynthesis and regulation

Calcitonin is formed by the

islet amyloid precursor protein, calcitonin gene-related peptide, and the precursor of adrenomedullin
.

Secretion of calcitonin is stimulated by:

Function

The hormone participates in calcium (Ca2+) metabolism. In many ways, calcitonin counteracts parathyroid hormone (PTH) and vitamin D.

More specifically, calcitonin lowers blood Ca2+ levels in two ways:

High concentrations of calcitonin may be able to increase urinary excretion of calcium and phosphate via the renal tubules.[13] leading to marked hypocalcemia. However, this is a minor effect with no physiological significance in humans. It is also a short-lived effect because the kidneys become resistant to calcitonin, as demonstrated by the kidney's unaffected excretion of calcium in patients with thyroid tumors that secrete excessive calcitonin.[14]

In its skeleton-preserving actions, calcitonin protects against calcium loss from the skeleton during periods of calcium mobilization, such as pregnancy and, especially, lactation. The protective mechanisms include the direct inhibition of bone resorption and the indirect effect through the inhibition of the release of prolactin from the pituitary gland. The reason provided is that prolactin induces the release of PTH related peptide which enhances bone resorption, but is still under investigation.[15][16][17]

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.

Calcitonin lowers blood calcium and phosphorus mainly through its inhibition of osteoclasts.

Osteoblasts do not have calcitonin receptors and are therefore not directly affected by calcitonin levels. However, since bone resorption and bone formation are coupled processes, eventually calcitonin's inhibition of osteoclastic activity leads to increased osteoblastic activity (as an indirect effect).[14]

Receptor

Structure of human calcitonin recptor-Gs complex. The transmembrane calcitonin receptor (blue) is bound to human calcitonin (red) and the Gs complex (yellow). PDB: 7TYO

The

adenylate cyclase in target cells. It may also affect the ovaries in women and the testes in men.[citation needed
]

Discovery

Calcitonin was first purified in 1962 by

Iain Macintyre and his team at the Royal Postgraduate Medical School, London, to be secreted by parafollicular cells of the thyroid gland.[20] Dr. Copp named the discovered hormone calcitonin because of its role in 'maintaining normal calcium tone'.[19]

Clinical significance

Calcitonin assay is used in identifying patients with nodular

thyroid diseases
. It is helpful in making an early diagnosis of medullary carcinoma of thyroid. A malignancy of the parafollicular cells, i.e. Medullary thyroid cancer (MTC), typically produces an elevated serum calcitonin level. Prognosis of MTC depends on early detection and treatment.

Calcitonin also has significantly impacted

alternatively spliced, now known to be a ubiquitous mechanism in eukaryotes.[21][22]

Pharmacology

Calcitonin has clinically been used for metabolic bone disorders for more than 50 years.[23] Salmon calcitonin is used for the treatment of:

It has been investigated as a possible non-operative treatment for spinal stenosis.[29]

The following information is from the UK Electronic Medicines Compendium[30]

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 kidney 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, vomiting, and secretory diarrhea.

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.[31] 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 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.[30]

Uses of calcitonin

Treatments

Calcitonin affecting the spine.

Calcitonin can be used therapeutically for the treatment of

hypercalcemia or osteoporosis.[32]
In a recent clinical study, subcutaneous injections of calcitonin have reduced the incidence of fractures and reduced the decrease in bone mass in women with type 2 diabetes complicated with osteoporosis.[33]

Subcutaneous injections of calcitonin in patients with mania resulted in significant decreases in irritability, euphoria and hyperactivity and hence calcitonin holds promise for treating bipolar disorder.[34] However no further work on this potential application of calcitonin has been reported.

Diagnostics

It may be used diagnostically as a

metastases
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:[35]

  • 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

A Cochrane systematic review assessed the diagnostic accuracy of basal and stimulated calcitonin for Medullary Thyroid cancer.[36] Although both basal and combined basal and stimulated calcitonin testing presented high accuracy (sensitivity: between 82% and 100%; specificity: between 97.2% and 100%), these results had a high risk of bias due to design flaws of included studies.[36] Overall, the value of routine testing of calcitonin for diagnosis and prognosis of Medullary Thyroid Cancer remains uncertain and questionable.[36]

Increased levels of calcitonin have also been reported for various other conditions. They include:

pulmonary disease.[37]

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.[38] 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.[39]

The following are the amino acid sequences of salmon and human calcitonin:[citation needed][40]

  • 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.

Research

In addition to the injectable and nasal spray dosage forms of the salmon calcitonin, noninvasive oral formulations of the peptide are currently under clinical development. The short-half-life of this peptide in serum triggered several attempts to enhance plasma concentrations. The peptide is complexed with a macromolecule that acts as an absorption enhancer through the transcellular pathway and, additionally, protects the peptide from the harsh pH and enzymatic conditions of the GI tract. This complexation is weak, noncovalent and reversible and the drug remains chemically unmodified. After passage through the intestine, the delivery agent dissociates from the peptide. One of the extensively studied oral formulations is the disodium salts of 5-CNAC oral calcitonin. This novel oral platform in a number of clinical trials at different phases has demonstrated promising enhanced pharmacokinetic profile, high bioavailability, well-established safety and comparable efficacy to that of nasal calcitonin especially for treatment of postmenopausal bone loss.[23]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000110680 - Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. PMID 26644465
    .
  4. ^ Costoff A. "Sect. 5, Ch. 6: Anatomy, Structure, and Synthesis of Calcitonin (CT)". Endocrinology: hormonal control of calcium and phosphate. Medical College of Georgia. Archived from the original on September 5, 2008. Retrieved 2008-08-07.
  5. .
  6. ^ Costoff A. "Sect. 5, Ch. 6: Biological Actions of CT". Medical College of Georgia. Archived from the original on July 5, 2008. Retrieved 2008-08-07.
  7. PMID 25815174
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  10. ^ Costoff A. "Sect. 5, Ch. 6: Effects of CT on Bone". Medical College of Georgia. Archived from the original on June 22, 2008. Retrieved 2008-08-07.
  11. ^ Potts J, Jüppner H (2008). "Chapter 353. Disorders of the Parathyroid Gland and Calcium Homeostasis". In Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Loscalzo J (eds.). Harrison's Principles of Internal Medicine (18th ed.). McGraw-Hill. Archived from the original on 2017-05-08. Retrieved 2017-05-29.
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  14. ^ ]
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  24. NIAMS. August 2014. Archived
    from the original on 18 May 2015. Retrieved 16 May 2015.
  25. ^ "Hypercalcemia". The Lecturio Medical Concept Library. Retrieved 1 October 2021.
  26. ^ MedlinePlus Overview bonecancer
  27. ^ "Paget's Disease of Bone". The Lecturio Medical Concept Library. Retrieved 1 October 2021.
  28. S2CID 30651328
    .
  29. .
  30. ^ a b "Electronic Medicines Compendium". Archived from the original on 2005-11-08. Retrieved 2008-08-07.
  31. ^ "Injectable Salmon Calcitonin" (PDF). Archived from the original (PDF) on 2018-06-18. Retrieved 2017-02-07.
  32. S2CID 23551343
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  33. .
  34. .
  35. .
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  39. ^ "calcitonin domain annotation". SMART (a Simple Modular Architecture Research Tool). embl-heidelberg.de. Retrieved 2009-02-22.
  40. ^ "Salmon calicitonin". prospecbio.

Further reading

External links