Calcitonin

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.^[1] It acts to reduce blood calcium (Ca²⁺), opposing the effects of parathyroid hormone (PTH).^[2] Calcitonin 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 in the regulation of normal calcium homeostasis.^[3]. 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 (CALCA). 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.

Secretion of calcitonin is stimulated by:

• an increase in serum [Ca²⁺]^[4]
• gastrin and pentagastrin.^[5]

Effects

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

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

• Inhibits Ca²⁺ absorption by the intestines^[6]
• Inhibits osteoclast activity in bones^[7]
• Inhibits renal tubular cell resorption of Ca²⁺ allowing it to be secreted in the urine^[8]

• Vitamin D regulation

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:

• Inhibits phosphate reabsorption by the kidney tubules^[9]
• Calcitonin decreases tubular reabsorption of Ca²⁺, leading to increased rates of its loss in urine.^[10]

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.

Receptor

The calcitonin receptor, found on osteoclasts,^[11] and in kidney and regions of the brain, is a G protein-coupled receptor, which is coupled by G_s 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.

Discovery

Calcitonin was purified in 1962 by Copp and Cheney.^[12] 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.^[13]

Pharmacology

Salmon calcitonin is used for the treatment of:

• Postmenopausal osteoporosis
• Hypercalcaemia
• Paget's disease
• Bone metastases
• Phantom limb pain^[14]

It has been investigated as a possible non-operative treatment for spinal stenosis.^[15]

The following information is from the UK Electronic Medicines Compendium^[16]

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.^{[citation needed]} 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.^[16]

Uses of calcitonin

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 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.”^[17]

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.^[18] However no further work on this potential application of calcitonin has been reported.

Diagnostics

It may be used diagnostically as a tumor marker 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 nodes) 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:^[19]

• 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.^[20] 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.^[21]

The following are the amino acid sequences of salmon and human calcitonin:^[22]

• 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.

See also

• Procalcitonin

References

1. ^ Costoff A. "Sect. 5, Ch. 6: Anatomy, Structure, and Synthesis of Calcitonin (CT)". Endocrinology: hormonal control of calcium and phosphate. Medical College of Georgia. http://www.lib.mcg.edu/edu/eshuphysio/program/section5/5ch6/s5ch6_21.htm. Retrieved 2008-08-07. 
2. ^ Boron WF, Boulpaep EL (2004). "Endocrine system chapter". Medical Physiology: A Cellular And Molecular Approach. Elsevier/Saunders. ISBN 1-4160-2328-3. 
3. ^ Costoff A. "Sect. 5, Ch. 6: Biological Actions of CT". Medical College of Georgia. http://www.lib.mcg.edu/edu/eshuphysio/program/section5/5ch6/s5ch6_23.htm. Retrieved 2008-08-07. 
4. ^ Costanzo, Linda S. (2007). BRS Physiology. Lippincott, Williams, & Wilkins. pp. 263. ISBN 978-0781773119. http://www.amazon.com/Physiology-Board-Review-Linda-Costanzo/dp/0781773113/. 
5. ^ 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. http://www.kurtis.it/abs/index.cfm?id_articolo_numero=3037. 
6. ^ Costoff A. "Sect. 5, Ch. 6: Effects of CT on the Small Intestine". Medical College of Georgia. http://www.lib.mcg.edu/edu/eshuphysio/program/section5/5ch6/s5ch6_26.htm. Retrieved 2008-08-07. 
7. ^ Costoff A. "Sect. 5, Ch. 6: Effects of CT on Bone". Medical College of Georgia. http://www.lib.mcg.edu/edu/eshuphysio/program/section5/5ch6/s5ch6_24.htm. Retrieved 2008-08-07. 
8. ^ Potts, John; Jüppner, Harald (2008). "Chapter 353. Disorders of the Parathyroid Gland and Calcium Homeostasis". In Dan L. Longo, Dennis L. Kasper, J. Larry Jameson, Anthony S. Fauci, Stephen L. Hauser, and Joseph Loscalzo. Harrison's Principles of Internal Medicine (18 ed.). McGraw-Hill. 
9. ^ Carney SL (1997). "Calcitonin and human renal calcium and electrolyte transport". Miner Electrolyte Metab 23 (1): 43–7. PMID 9058369. 
10. ^ Rhoades, Rodney (2009). Medical Physiology: Principles for Clinical Medicine. Philadelphia: Lippincott Williams & Wilkins. ISBN isbn-13: 978-0-7817-6852-8. 
11. ^ Nicholson GC, Moseley JM, Sexton PM, et al (1986). "Abundant calcitonin receptors in isolated rat osteoclasts. Biochemical and autoradiographic characterization". J Clin Invest 78 (2): 355–60. doi:10.1172/JCI112584. PMC 423551. PMID 3016026. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=423551. 
12. ^ Copp DH, Cheney B (January 1962). "Calcitonin-a hormone from the parathyroid which lowers the calcium-level of the blood". Nature 193 (4813): 381–2. doi:10.1038/193381a0. PMID 13881213. 
13. ^ 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 (2): 244–252. doi:10.1210/endo-73-2-244. PMID 14076205. 
14. ^ Wall GC, Heyneman CA (April 1999). "Calcitonin in phantom limb pain". Ann Pharmacother 33 (4): 499–501. doi:10.1345/aph.18204. PMID 10332543. 
15. ^ Tran de QH, Duong S, Finlayson RJ (July 2010). "Lumbar spinal stenosis: a brief review of the nonsurgical management". Can J Anaesth 57 (7): 694–703. doi:10.1007/s12630-010-9315-3. PMID 20428988. 
16. ^ ^{a b} "Electronic Medicines Compendium". http://emc.medicines.org.uk/. Retrieved 2008-08-07. 
17. ^ Kleinman DM (2006-01-04). "Oral Calcitonin May Delay Onset of Joint Disease and Relieve Pain of OA". Musculoskeletal Report. Musculoskeletal Report, LLC. http://www.mskreport.com/articles.cfm?ArticleID=515. Retrieved 2008-08-07. 
18. ^ Vik A, Yatham LN (March 1998). "Calcitonin and bipolar disorder: a hypothesis revisited". J Psychiatry Neurosci 23 (2): 109–17. PMC 1188909. PMID 9549251. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1188909. 
19. ^ Basuyau, J. -P.; Mallet, E.; Leroy, M.; Brunelle, P. (2004). "Reference Intervals for Serum Calcitonin in Men, Women, and Children". Clinical Chemistry 50 (10): 1828–1830. doi:10.1373/clinchem.2003.026963. PMID 15388660.  edit
20. ^ PDB 2GLH 2GLH; Andreotti G, Méndez BL, Amodeo P, Morelli MA, Nakamuta H, Motta A (August 2006). "Structural determinants of salmon calcitonin bioactivity: the role of the Leu-based amphipathic alpha-helix". J. Biol. Chem. 281 (34): 24193–203. doi:10.1074/jbc.M603528200. PMID 16766525. 
21. ^ "calcitonin domain annotation". SMART (a Simple Modular Architecture Research Tool). embl-heidelberg.de. http://smart.embl-heidelberg.de/smart/do_annotation.pl?BLAST=DUMMY&DOMAIN=SM00113. Retrieved 2009-02-22. 
22. ^ http://www.newworldencyclopedia.org/entry/Calcitonin

Further reading

• MacIntyre I, Alevizaki M, Bevis PJ, Zaidi M (1987). "Calcitonin and the peptides from the calcitonin gene". Clin. Orthop. Relat. Res. &na; (217): 45–55. doi:10.1097/00003086-198704000-00007. PMID 3549095. 
• Di Angelantonio S, Giniatullin R, Costa V, et al. (2004). "Modulation of neuronal nicotinic receptor function by the neuropeptides CGRP and substance P on autonomic nerve cells". Br. J. Pharmacol. 139 (6): 1061–73. doi:10.1038/sj.bjp.0705337. PMC 1573932. PMID 12871824. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1573932. 
• Findlay DM, Sexton PM (2005). "Calcitonin". Growth Factors 22 (4): 217–24. doi:10.1080/08977190410001728033. PMID 15621724. 
• Sponholz C, Sakr Y, Reinhart K, Brunkhorst F (2007). "Diagnostic value and prognostic implications of serum procalcitonin after cardiac surgery: a systematic review of the literature". Critical care (London, England) 10 (5): R145. doi:10.1186/cc5067. PMC 1751067. PMID 17038199. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1751067. 
• Schneider HG, Lam QT (2007). "Procalcitonin for the clinical laboratory: a review". Pathology 39 (4): 383–90. doi:10.1080/00313020701444564. PMID 17676478. 

External links

• The Calcitonin Protein
• MeSH Calcitonin