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{{PBB_Controls<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox gene}}
| update_page = yes
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = no
| update_citations = yes
}}
{{GNF_Protein_box<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
| image = PBB_Protein_PTH_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1bwx.
| Name = Parathyroid hormone
| HGNCid = 9606
| Symbol = PTH
| AltSymbols =;
| OMIM = 168450
| ECnumber = 
| Homologene = 266
| MGIid = 97799
| GeneAtlas_image1 = PBB_GE_PTH_206977_at_tn.png
| Function = {{GNF_GO|id=GO:0005179 |text = hormone activity}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}}
| Process = {{GNF_GO|id=GO:0001501 |text = skeletal development}} {{GNF_GO|id=GO:0006874 |text = cellular calcium ion homeostasis}} {{GNF_GO|id=GO:0007186 |text = G-protein coupled receptor protein signaling pathway}} {{GNF_GO|id=GO:0007267 |text = cell-cell signaling}} {{GNF_GO|id=GO:0007595 |text = lactation}} {{GNF_GO|id=GO:0008628 |text = induction of apoptosis by hormones}} {{GNF_GO|id=GO:0045453 |text = bone resorption}} {{GNF_GO|id=GO:0046058 |text = cAMP metabolic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 5741
    | Hs_Ensembl = ENSG00000152266
    | Hs_RefseqProtein = NP_000306
    | Hs_RefseqmRNA = NM_000315
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 11
    | Hs_GenLoc_start = 13470178
    | Hs_GenLoc_end = 13474143
    | Hs_Uniprot = P01270
    | Mm_EntrezGene = 19226
    | Mm_Ensembl = ENSMUSG00000059077
    | Mm_RefseqmRNA = NM_020623
    | Mm_RefseqProtein = NP_065648
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 7
    | Mm_GenLoc_start = 113176759
    | Mm_GenLoc_end = 113179753
    | Mm_Uniprot = 
  }}
}}
{{SI}}
{{CMG}}


'''Parathyroid hormone '''('''PTH'''), also called '''parathormone''' or '''parathyrin''', is a [[hormone]] secreted by the [[parathyroid gland]]s that is important in [[bone remodeling]], which is an ongoing process in which [[bone tissue]] is alternately [[bone resorption|resorbed]] and [[ossification|rebuilt]] over time.  PTH is secreted in response to low blood serum [[calcium]] (Ca2+) levels.  PTH indirectly stimulates [[osteoclast]] activity within [[bone marrow]], in an effort to release more ionic calcium (Ca2+) into the blood to elevate serum [[calcium]] (Ca2+) levels.  The [[bone]]s act as a (metaphorical) "[[bank]] of [[calcium]]" from which the body can make "withdrawals" as needed to keep [[calcium in biology#Measurement|the amount of calcium in the blood]] at appropriate [[concentration|levels]] despite the ever-present challenges of [[metabolism]], [[stress (biology)|stress]], and [[nutrition]]al variations. PTH is "a key that unlocks the bank vault" to remove the calcium. In consequence, PTH is vital to [[health]], and health problems that yield too little or too much PTH (such as [[hypoparathyroidism]], [[hyperparathyroidism]], or [[paraneoplastic syndrome]]s) can wreak havoc in the form of [[bone disease]], [[hypocalcaemia]], and [[hypercalcaemia]].


PTH is secreted by the [[parathyroid chief cell|chief cells]] of the parathyroid glands as a [[polypeptide]] containing 84 [[amino acids]], which is a [[prohormone]]; effective hormone-receptor interaction requires solely the 34-N-terminal amino acids.  While PTH acts to increase the concentration of ionic [[calcium]] (Ca<sup>2+</sup>) in the [[blood]], [[calcitonin]], a hormone produced by the [[parafollicular cells]] (C cells) of the [[thyroid gland]], acts to decrease ionic calcium concentration. PTH essentially acts to increase the concentration of calcium in the blood by acting upon the [[parathyroid hormone 1 receptor]], which is present at high levels in bone and kidney, and the [[parathyroid hormone 2 receptor]], which is present at high levels in the central nervous system, pancreas, testis, and placenta.<ref>{{GeorgiaPhysiology|5/5ch6/s5ch6_11}}</ref> PTH half-life is approximately 4 minutes.<ref name="pmid12324490">{{cite journal | vauthors = Bieglmayer C, Prager G, Niederle B | title = Kinetic analyses of parathyroid hormone clearance as measured by three rapid immunoassays during parathyroidectomy | journal = Clinical Chemistry | volume = 48 | issue = 10 | pages = 1731–8 | date = Oct 2002 | pmid = 12324490 | doi =  | url = http://www.clinchem.org/cgi/content/abstract/48/10/1731 }}</ref> It has a molecular mass of approximately 9500 [[Dalton (unit)|Da]].<ref name="pmid4509319">{{cite journal | vauthors = Brewer HB, Fairwell T, Ronan R, Sizemore GW, Arnaud CD | title = Human parathyroid hormone: amino-acid sequence of the amino-terminal residues 1-34 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 69 | issue = 12 | pages = 3585–8 | year = 1972 | pmid = 4509319 | pmc = 389826 | doi = 10.1073/pnas.69.12.3585}}</ref>


'''Parathyroid hormone (PTH)''', or '''parathormone''', is secreted by the [[parathyroid gland]]s as a [[polypeptide]] containing 84 [[amino acids]]. It acts to increase the concentration of [[calcium]] (Ca<sup>2+</sup>) in the [[blood]], whereas [[calcitonin]] (a hormone produced by the [[parafollicular cells]] (C cells) of the [[thyroid gland]]) acts to decrease calcium concentration.
==Structure==
PTH acts to increase the concentration of calcium in the blood by acting upon [[parathyroid hormone receptor]] in three parts of the body:<ref>{{GeorgiaPhysiology|5/5ch6/s5ch6_11}}</ref>
hPTH-(1-34) crystallizes as a slightly bent, long helical dimer. Analysis reveals that the extended [[alpha helix|helical]] conformation of hPTH-(1-34) is the likely bioactive conformation.<ref name="pmid10837469">{{cite journal | vauthors = Jin L, Briggs SL, Chandrasekhar S, Chirgadze NY, Clawson DK, Schevitz RW, Smiley DL, Tashjian AH, Zhang F | title = Crystal structure of human parathyroid hormone 1-34 at 0.9-A resolution | journal = The Journal of Biological Chemistry | volume = 275 | issue = 35 | pages = 27238–44 | date = Sep 2000 | pmid = 10837469 | doi = 10.1074/jbc.M001134200 }}</ref> The [[N-terminus|N-terminal]] fragment 1-34 of parathyroid hormone (PTH) has been crystallized and the structure has been refined to 0.9 Å resolution.
{|
|[[File:the ribbon cartoon structure.png|150px|thumb|left|helical dimer structure of hPTH-(1-34)<ref name="pmid10881197">{{PDB|1ETE}}; {{cite journal | vauthors = Savvides SN, Boone T, Andrew Karplus P | title = Flt3 ligand structure and unexpected commonalities of helical bundles and cystine knots | journal = Nature Structural Biology | volume = 7 | issue = 6 | pages = 486–91 | date = Jun 2000 | pmid = 10881197 | doi = 10.1038/75896 }}</ref>]]
|}


{| style="background:silver; color:black"
== Function ==
 
=== Regulation of serum calcium ===
 
[[File:Calcium balance 2.jpg|thumb|300px|right|A diagrammatic representation of the movements of calcium ions into and out of the blood plasma (the central square labeled  PLASMA Ca<sup>2+</sup>) in an adult in calcium balance.  The widths of the red arrows indicating movement into and out of the plasma are roughly in proportion to the daily amounts of calcium moved in the indicated directions. The size of the central square in not in proportion to the size of the diagrammatic bone, which represents the calcium present in the skeleton, and contains approximately 25,000&nbsp;mmol (or 1&nbsp;kg) of calcium compared to the 9&nbsp;mmol (360&nbsp;mg) dissolved in the blood plasma. The differently colored narrow arrows indicate where the specified hormones act, and their effects (“+” means stimulates; “-“ means inhibits) when their plasma levels are high. PTH is parathyroid hormone, 1,25&nbsp;OH&nbsp;VIT D<sub>3</sub> is [[calcitriol]] or 1,25&nbsp;dihydroxyvitamin D<sub>3</sub>, and [[Calcitonin|CALCITONIN]] is a hormone secreted by the [[thyroid gland]] when the plasma ionized calcium level is high or rising. The diagram does not show the extremely small amounts of calcium that move into and out of the cells of the body, nor does it indicate the calcium that is bound to the extracellular proteins (in particular the plasma proteins) or to plasma phosphate.<ref name="pmid25287933" /><ref name=Brini>{{cite book | first1 = Marisa | last1 = Brini | first2 = Denis | last2 = Ottolini | first3 = Tito | last3 = Calì | first4 = Ernesto | last4 = Carafoli | editor-first1 = Astrid | editor-last1 = Sigel  | editor-last2 = Helmut | editor-first2 = Roland K. O. | name-list-format = vanc | title = Interrelations between Essential Metal Ions and Human Diseases | series = Metal Ions in Life Sciences | volume = 13 | year = 2013 | publisher = Springer | pages = 81–137 | chapter = Chapter 4. Calcium in Health and Disease | doi = 10.1007/978-94-007-7500-8_4 }}</ref><ref name=Walter>{{cite book | vauthors= Walter F | title = Medical Physiology: A Cellular And Molecular Approach |publisher=Elsevier/Saunders |location= |year=2003| chapter = The Parathyroid Glands and Vitamin D |page=1094 |isbn=1-4160-2328-3 |oclc= |doi=}}</ref><ref name =guyton>Guyton A (1976). ‘’Medical Physiology’’. p.1062; New York, Saunders and Co.</ref><ref name=ganong>{{cite book | vauthors = Barrett KE, Barman SM, Boitano S, Brooks H | chapter = Chapter 23. Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone | veditors = Barrett KE, Barman SM, Boitano S, Brooks H | title = Ganong's Review of Medical Physiology | edition = 23e | chapter-url = http://www.accessmedicine.com/content.aspx?aID=5244785 }}</ref>]]
 
Parathyroid hormone regulates [[serum calcium]] through its effects on bone, kidney, and the intestine:<ref name="pmid15180028">{{cite journal | vauthors = Coetzee M, Kruger MC | title = Osteoprotegerin-receptor activator of nuclear factor-kappaB ligand ratio: a new approach to osteoporosis treatment? | journal = Southern Medical Journal | volume = 97 | issue = 5 | pages = 506–11 | date = May 2004 | pmid = 15180028 | doi = 10.1097/00007611-200405000-00018 }}</ref>
 
In bone, PTH enhances the release of calcium from the large reservoir contained in the bones.<ref>{{cite journal | vauthors = Poole KE, Reeve J | title = Parathyroid hormone - a bone anabolic and catabolic agent | journal = Current Opinion in Pharmacology | volume = 5 | issue = 6 | pages = 612–7 | date = Dec 2005 | pmid = 16181808 | doi = 10.1016/j.coph.2005.07.004 }}</ref> [[Bone resorption]] is the normal destruction of bone by [[osteoclast]]s, which are indirectly stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds to [[osteoblast]]s, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANKL and inhibits their secretion of [[Osteoprotegerin]] (OPG). Free OPG competitively binds to [[RANKL]] as a decoy receptor, preventing RANKL from interacting with RANK, a receptor for RANKL. The binding of RANKL to [[RANK]] (facilitated by the decreased amount of OPG available for binding the excess RANKL) stimulates these osteoclast precursors to fuse, forming new osteoclasts, which ultimately enhances [[bone resorption]]. Another mechanism to regulate this pathways as PTH does is by estrogen. Estrogen suppresses T cell TNF production by regulating T cell differentiation and activity in the bone marrow, thymus, and peripheral lymphoid organs. In the bone marrow, estrogen downregulates the proliferation of hematopoietic stem cells through an IL-7 dependent mechanism.<ref name="pmid12633785">{{cite journal | vauthors = Bord S, Ireland DC, Beavan SR, Compston JE | title = The effects of estrogen on osteoprotegerin, RANKL, and estrogen receptor expression in human osteoblasts | journal = Bone | volume = 32 | issue = 2 | pages = 136–41 | year = 2003 | pmid = 12633785 | doi = 10.1016/S8756-3282(02)00953-5 }}</ref>
 
In the kidney, approximately 250&nbsp;mmol of calcium ions are filtered into the [[glomerular filtrate]] per day. Most of this (245&nbsp;mmol/d) is reabsorbed from the tubular fluid, leaving about 5&nbsp;mmol/d to be excreted in the urine. This reabsorption occurs throughout the tubule (most, 60-70%, of it in the [[proximal tubule]]), except in the thin segment of the [[loop of Henle]].<ref name="pmid25287933">{{cite journal | vauthors = Blaine J, Chonchol M, Levi M | title = Renal control of calcium, phosphate, and magnesium homeostasis | journal = Clinical Journal of the American Society of Nephrology | volume = 10 | issue = 7 | pages = 1257–72 | year = 2015 | pmid = 25287933 | doi = 10.2215/CJN.09750913 }}</ref> Circulating parathyroid hormone only influences the reabsorption that occurs in the [[distal tubule]]s and the [[Collecting duct system|renal collecting ducts]]<ref name="pmid25287933" /> (but see Footnote{{#tag:ref |This reduction in the rate of calcium excretion via the urine is a minor effect of high parathyroid hormone levels in the blood. The main determinant of the amount of calcium excreted into the urine per day is the plasma ionized calcium concentration itself. The plasma parathyroid hormone (PTH) concentration only increases or decreases the amount of calcium excreted at any ''specified plasma ionized calcium concentration''. Thus, in primary [[hyperparathyroidism]] the quantity of calcium excreted in the urine per day is ''increased'' despite the high levels of PTH in the blood. This is because hyperparathyroidism results in [[hypercalcemia]], which increases the urinary calcium concentration ([[hypercalcuria]]) despite the moderately increased rate of calcium re-absorption from the renal tubular fluid caused by PTH's direct effect on those tubules. [[Renal stones]] are therefore often a first indication of hyperparathyroidism, especially since the hypercalcuria is accompanied by an increase in urinary phosphate excretion (a direct result of the high plasma PTH levels). Together the calcium and phosphate tend to precipitate out as water-insoluble salts, which readily  form solid “stones”.<ref name="pmid25287933" /><ref name=Harrison>{{cite book | last1 = Harrison | first1 = T.R. | last2 = Adams | first2 = R.D. | last3 = Bennett | first3 = I.L. | last4 = Resnick | first4 = W.H. | last5 = Thorn | first5 = G.W. | last6 = Wintrobe | first6 = M.M. | name-list-format = vanc | title = Principles of Internal Medicine | edition = Third | date = 1958 | publisher = McGraw-Hill Book Company | location = New York | pages = 575–578 | chapter = Metabolic and Endocrine Disorders }}</ref><ref>{{cite web | url = http://www.parathyroid.com/parathyroid-symptoms.htm | title = Symptoms of Hyperparathyroidism and Symptoms of Parathyroid Disease. | work = Parathyroid.com | publisher = Norman Parathyroid Center | access-date = 2015-12-30 }}</ref> |group=nb}}). A more important effect of PTH on the kidney is, however, its inhibition of the reabsorption of [[phosphate]] (HPO<sub>4</sub><sup>2−</sup>) from the tubular fluid, resulting in a decrease in the plasma phosphate concentration.  Phosphate ions form water-insoluble salts with calcium. Thus, a decrease in the phosphate concentration of the  blood plasma (for a given total calcium concentration) increases the amount of calcium that is ionized.<ref name="pmid6623048">{{cite journal | vauthors = Haldimann B, Vogt K | title = [Hyperphosphatemia and tetany following phosphate enema] | language = French | journal = Schweizerische Medizinische Wochenschrift | volume = 113 | issue = 35 | pages = 1231–3 | year = 1983 | pmid = 6623048 | doi = | url = }}</ref><ref name="pmid8915965">{{cite journal | vauthors = Sutters M, Gaboury CL, Bennett WM | title = Severe hyperphosphatemia and hypocalcemia: a dilemma in patient management | journal = Journal of the American Society of Nephrology : JASN | volume = 7 | issue = 10 | pages = 2056–61 | year = 1996 | pmid = 8915965 | doi = }}</ref> A third important effect of PTH on the kidney is its stimulation of the conversion of [[25-hydroxy vitamin D]] into [[1,25-dihydroxy vitamin D]] ([[calcitriol]]), which is released into the circulation. This latter form of vitamin D is the active hormone which stimulates calcium uptake from the intestine.<ref name=stryer>{{cite book | last1 = Stryer | first1 = Lubert | name-list-format = vanc | title = Biochemistry | edition = Fourth | location = New York | publisher = W.H. Freeman and Company | publication-date = 1995 | page = 707 | isbn = 978-0-7167-2009-6 }}</ref>
 
In the intestine, via kidney, PTH enhances the absorption of calcium in the [[intestine]] by increasing the production of activated [[vitamin D]]. Vitamin D activation occurs in the kidney. PTH up-regulates [[25-hydroxyvitamin D3 1-alpha-hydroxylase|25-hydroxyvitamin D<sub>3</sub> 1-alpha-hydroxylase]], the enzyme responsible for 1-alpha [[hydroxylation]] of [[25-hydroxy vitamin D]], converting vitamin D to its active form ([[1,25-dihydroxy vitamin D]]). This activated form of vitamin D increases the absorption of calcium (as Ca<sup>2+</sup> ions) by the intestine via [[calbindin]].
 
PTH was one of the first hormones to be shown to use the G-protein, [[adenylyl cyclase]] second messenger system.
 
=== Regulation of serum phosphate ===
 
PTH reduces the reabsorption of [[phosphate]] from the [[proximal tubule]] of the [[kidney]],<ref>{{cite book | last1 = Gardner | first1 = David | first2 = Dolores | last2 = Shoback | name-list-format = vanc | page = 232 | title = Greenspan's Basic & Clinical Endocrinology | year=2011 | location = | publisher = McGraw Hill | isbn = 978-0-07-162243-1 | edition = 9th }}</ref> which means more phosphate is excreted through the urine.
 
However, PTH enhances the uptake of phosphate from the intestine and bones into the blood. In the bone, slightly more calcium than phosphate is released from the breakdown of bone. In the intestines, absorption of both calcium and phosphate is mediated by an increase in activated vitamin D. The absorption of phosphate is not as dependent on vitamin D as is that of calcium. The end result of PTH release is a small net drop in the serum concentration of phosphate.
 
=== Vitamin D synthesis ===
 
PTH increases the activity of [[1-α-hydroxylase]] enzyme, which converts 25-hydroxycholecalciferol, the major circulating form of inactive vitamin D, into 1,25-dihydroxycholecalciferol, the active form of [[vitamin D]], in the [[kidney]].
 
==== Interactive pathway map ====
 
{{VitaminDSynthesis WP1531|highlight=Parathyroid_hormone}}
 
== Regulation of PTH secretion ==
 
Secretion of parathyroid hormone is determined chiefly by [[blood plasma|serum]] ionized calcium concentration through [[feedback inhibition|negative feedback]]. Parathyroid cells express [[calcium-sensing receptor]]s on the cell surface. PTH is secreted when [Ca<sup>2+</sup>] is decreased (Calcitonin is secreted when serum calcium levels are elevated). The G-protein coupled calcium receptors bind extracellular calcium and may be found on the surface on a wide variety of cells distributed in the [[brain]], [[heart]], [[skin]], [[stomach]], C cells, and other tissues.  In the parathyroid gland, high concentrations of extracellular calcium result in activation of the Gq G-protein coupled cascade through the action of [[phospholipase C]].  This hydrolyzes [[phosphatidylinositol 4,5-bisphosphate]] (PIP2) to liberate intracellular messengers [[Inositol trisphosphate|IP3]] and [[diacylglycerol]] (DAG).  Ultimately, these two messengers result in a release of calcium from intracellular stores into the cytoplasmic space.  Hence a high extracellular calcium concentration leads to an increase in the cytoplasmic calcium concentration.  In contrast to the mechanism that most secretory cells use, this high cytoplasmic calcium concentration inhibits the fusion of vesicles containing granules of preformed PTH with the membrane of the parathyroid cell, and thus inhibits release of PTH.
 
In the parathyroids, magnesium serves this role in stimulus-secretion coupling. A mild decrease in serum magnesium levels stimulates the resorptive activity PTH has on the kidneys. Severe [[hypomagnesemia]] inhibits PTH secretion and also causes resistance to PTH, leading to a form of hypoparathyroidism that is reversible.<ref name="pmid10405219">{{cite journal | vauthors = Agus ZS | title = Hypomagnesemia | journal = Journal of the American Society of Nephrology | volume = 10 | issue = 7 | pages = 1616–22 | date = Jul 1999 | pmid = 10405219 | doi =  | url = http://jasn.asnjournals.org/content/10/7/1616.full }}</ref>
 
=== Stimulators ===
 
* Decreased serum [Ca<sup>2+</sup>].
* Mild decreases in serum [Mg<sup>2+</sup>].
* An increase in serum phosphate (increased phosphate causes it to complex with serum calcium,  forming calcium phosphate, which reduces stimulation of Ca-sensitive receptors (CaSr) that do not sense calcium phosphate, triggering an increase in PTH).
 
=== Inhibitors ===
 
* Increased serum [Ca<sup>2+</sup>].
* Severe decreases in serum [Mg<sup>2+</sup>], which also produces symptoms of [[hypoparathyroidism]] (such as [[hypocalcemia]]).<ref name=brs>{{cite book | last = Costanzo | first = Linda S. | authorlink =  | title = BRS Physiology | publisher = Lippincott, Williams, & Wilkins | year = 2007 | location =  | pages = 260 | url = https://www.amazon.com/Physiology-Board-Review-Linda-Costanzo/dp/0781773113/ | doi =  | id =  | isbn = 978-0-7817-7311-9 }}</ref>
* Calcitriol
 
== Clinical significance ==
 
[[Hyperparathyroidism]], the presence of excessive amounts of parathyroid hormone in the blood, occurs in two very distinct sets of circumstances. Primary hyperparathyroidism is due to autonomous, abnormal hypersecretion of PTH from the parathyroid gland, while [[secondary hyperparathyroidism]] is an appropriately high PTH level seen as a physiological response to [[hypocalcaemia]]. A low level of PTH in the blood is known as  [[hypoparathyroidism]] and is most commonly due to damage to or removal of parathyroid glands during thyroid surgery.
 
There are a number of rare but well-described genetic conditions affecting parathyroid hormone metabolism, including [[pseudohypoparathyroidism]], [[familial hypocalciuric hypercalcaemia]], and autosomal dominant hypercalciuric hypocalcemia. Of note, PTH is unchanged in [[pseudopseudohypoparathyroidism]]. In [[Osteoporosis|osteoporotic]] women, administration of an exogenous parathyroid hormone analogue ([[teriparatide]], by daily injection) superimposed on estrogen therapy produced increases in bone mass and reduced vertebral and nonvertebral fractures by 45 to 65%.<ref name="pmid11346808">{{cite journal | vauthors = Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH | title = Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis | journal = The New England Journal of Medicine | volume = 344 | issue = 19 | pages = 1434–41 | date = May 2001 | pmid = 11346808 | doi = 10.1056/NEJM200105103441904 }}</ref>
 
== Measurement ==
 
PTH can be measured in the blood in several different forms: intact PTH; N-terminal PTH; mid-molecule PTH, and C-terminal PTH, and different tests are used in different clinical situations.
 
The average PTH level is 8–51 pg/mL.<ref>{{cite book | last1 = Longo | first1 = Dan L. | last2 = Fauci | first2 = Anthony | last3 = Kasper | first3 = Dennis | last4 = Hauser | first4 = Stephen | last5 = Jameson | first5 = J. | last6 = Loscalzo | first6 = Joseph | name-list-format = vanc | title = Harrison's Principles of Internal Medicine | date = 2012 | publisher = McGraw-Hill | location = New York | isbn = 978-0-07-174889-6 | page = 3594 | edition = 18th }}</ref> Normal total plasma calcium level ranges from 8.5 to 10.2&nbsp;mg/dL (2.12&nbsp;mmol/L to 2.55&nbsp;mmol/L).<ref>{{cite web | url = http://www.nlm.nih.gov/medlineplus/ency/article/003477.htm | title = MedlinePlus Medical Encyclopedia: Serum calcium | publisher = National Library of Medicine, National Institutes of Health |accessdate=2009-02-01 | last = Zieve | first = David | name-list-format = vanc }}</ref>
 
== Model organisms ==
 
[[Model organism]]s have been used in the study of PTH function. A conditional [[knockout mouse]] line called ''Pth<sup>tm1a(EUCOMM)Wtsi</sup>'' was generated at the [[Wellcome Trust Sanger Institute]].<ref name="mgp_reference">{{cite journal |title=The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice |author=Gerdin AK |year=2010 |journal=Acta Ophthalmologica|volume=88 |pages=925–7|doi=10.1111/j.1755-3768.2010.4142.x }}</ref> Male and female animals underwent a standardized [[phenotypic screen]]<ref name="IMPCsearch_ref">{{cite web |url=http://www.mousephenotype.org/data/search?q=Pth#fq=*:*&facet=gene |title=International Mouse Phenotyping Consortium}}</ref> to determine the effects of deletion.<ref name="pmid21677750">{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = Jun 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}</ref><ref name="mouse_library">{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = Jun 2011 | pmid = 21677718 | doi = 10.1038/474262a }}</ref><ref name="mouse_for_all_reasons">{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = Jan 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}</ref><ref name="pmid23870131">{{cite journal | vauthors = White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A, Steel KP | display-authors = 6 | title = Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes | journal = Cell | volume = 154 | issue = 2 | pages = 452–64 | date = Jul 2013 | pmid = 23870131 | doi = 10.1016/j.cell.2013.06.022 | pmc=3717207}}</ref> Additional screens performed:  - In-depth immunological phenotyping<ref name="iii_ref">{{cite web |url= http://www.immunophenotyping.org/data/search?keys=Pth&field_gene_construct_tid=All |title=Infection and Immunity Immunophenotyping (3i) Consortium}}</ref>
{| class="wikitable sortable collapsible collapsed" border="1" cellpadding="2" |
|+ ''Pth'' knockout mouse phenotype
|-
! Characteristic!! Phenotype
|-
|-
| '''Reference Range'''
| colspan=2; style="text-align: center;" | All data available at.<ref name="IMPCsearch_ref"/><ref name="iii_ref" />
|-style="background:silver; color:black"
 
|-
|-
| '''PTH'''
| Insulin || bgcolor="#488ED3"|Normal
| 1-7 pmol/l
 
|}
|-
| Homozygous viability at P14 || bgcolor="#488ED3"|Normal
 
|-
| Homozygous Fertility || bgcolor="#488ED3"|Normal
 
|-
| Body weight || bgcolor="#488ED3"|Normal
 
|-
| Neurological assessment || bgcolor="#488ED3"|Normal
 
|-
| Grip strength || bgcolor="#488ED3"|Normal


==Functions==
|-
===Effects on serum calcium (raising)===
| [[Dysmorphology]] || bgcolor="#488ED3"|Normal


{| class="wikitable"
|-
| '''Region''' || '''Effect'''
| [[Indirect calorimetry]] || bgcolor="#488ED3"|Normal
|-
| [[bone]]s || It enhances the release of calcium from the large reservoir contained in the bones.<ref>{{cite journal | author = Poole K, Reeve J | title = Parathyroid hormone - a bone anabolic and catabolic agent. | journal = Curr Opin Pharmacol | volume = 5 | issue = 6 | pages = 612-7 | year = 2005 | pmid = 16181808 | doi = 10.1016/j.coph.2005.07.004}}</ref> [[Bone resorption]] is the normal destruction of bone by [[osteoclast]]s, which are indirectly stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds to [[osteoblast]]s, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of [[RANKL]], which can bind to osteoclast precursors containing [[RANK]], a receptor for RANKL. The binding of RANKL to RANK stimulates these precursors to fuse, forming new osteoclasts which ultimately enhances the resorption of bone.
|-  
| [[kidney]] || It enhances active reabsorption of calcium from [[distal tubule]]s<ref name="mcgill">http://sprojects.mmi.mcgill.ca/nephrology/presentation/presentation5.htm</ref> and the thick ascending limb.
|-
| [[intestine]] via kidney || It enhances the absorption of calcium in the [[intestine]] by increasing the production of activated [[vitamin D]]. Vitamin D activation occurs in the kidney. PTH up-regulates the enzyme responsible for 1-alpha [[hydroxylation]] of [[25-hydroxy vitamin D]], converting vitamin D to its active form ([[1,25-dihydroxy vitamin D]]). This actived form of vitamin D affects the absorption of calcium (as Ca<sup>2+</sup> ions) by the intestine via [[calbindin]].
|}


PTH was one of the first hormones to be shown to use the G-protein, adenylyl cyclase second messenger system.
|-
| [[Glucose tolerance test]] || bgcolor="#488ED3"|Normal


Normal total plasma calcium level is 9.4mg/dl(8-11) or 2.4mmol/L<ref>guyton</ref> <ref name="metabolism">http://books.google.com/books?id=BxLU6XhZsTAC&pg=RA1-PA281&lpg=RA1-PA281&dq=pth+second+messenger&source=web&ots=5awUECyZo-&sig=EhEGbV9WdI2Xp5Sv5eJQJ_63S3U#PRA1-PA281,M1</ref> .
|-
| [[Auditory brainstem response]] || bgcolor="#488ED3"|Normal


===Effects on serum phosphate (decrease, with compensation)===
|-
PTH reduces the reabsorption of [[phosphate]] from the [[proximal tubule]] of the [[kidney]]<ref name="mcgill"> </ref> which means more phosphate is excreted through the urine.
| [[Dual-energy X-ray absorptiometry|DEXA]] || bgcolor="#488ED3"|Normal


However, PTH enhances the uptake of phosphate from the intestine and bones into the blood. In the bone, slightly more calcium than phosphate is released from the breakdown of bone. In the intestines, which is mediated by an increase in activated vitamin D, the absorption of phosphate is not as dependent on vitamin D as is that of calcium. The end result is a small net drop in the serum concentration of phosphate.
|-
| [[Radiography]] || bgcolor="#488ED3"|Normal


==Feedback regulation==
|-
Increased calcium concentration in the blood acts (via feedback inhibition) to decrease PTH secretion by the parathyroid glands.
| Eye morphology || bgcolor="#488ED3"|Normal


This is achieved by the activation of calcium-sensing receptors located on parathyroid cells.<ref>{{GeorgiaPhysiology|5/5ch6/s5ch6_9}}</ref>
|-
| [[Clinical chemistry]] || bgcolor="#C40000"|Abnormal


== Differential Diagnosis ==
|-
'''Increased'''
| ''[[Haematology]]'' 16 Weeks || bgcolor="#488ED3"|Normal
*Age
*Primary hyperparathyroidism
:*Familial hypocalciuric hypercalcemia
:*Familial hyperparathyroidism
:*Gland hyperplasia
:*Lithium therapy
:*Parathyroid malignancy
*Osteomalacia
*Pseudohyperparathyroidism
*Ricketts
*Secondary hyperprathyroidism
*Vitamin D deficiency
'''Decreased'''
*Cancer
*Granulomatous
*PTH <2-20pg/ml and calcium <2.1mmol/l:Hypoparathyroidism
*PTH <2-20pg/ml and calcium >2.6mmol/l:hypercalcemia due to tumor


==Syndromes==
|-
* A high level of [[PTH]] in the blood is known as [[hyperparathyroidism]].
| Peripheral blood leukocytes 16 Weeks || bgcolor="#488ED3"|Normal
** If the cause is in the parathyroid gland it is called ''primary hyperparathyroidism''. The causes are parathyroid [[adenoma]], parathyroid [[hyperplasia]] and parathyroid cancer.
** If the cause is outside the gland, it is known as ''secondary hyperparathyroidism''. This can occur in [[chronic renal failure]].
* A low level of PTH in the blood is known as  [[hypoparathyroidism]]. Causes include surgical misadventure (''e.g.'' inadvertent removal during routine thyroid surgery), [[autoimmune disorder]], and [[inborn errors of metabolism]].


==Measurements==
|-
PTH can be measured in the blood in several different forms: intact PTH; N-terminal PTH; mid-molecule PTH, and C-terminal PTH, and different tests are used in different clinical situations.
| ''[[Salmonella]]'' infection || bgcolor="#488ED3"|Normal


==References==
|-
{{Reflist|1}}
|}


==See also==
== See also ==
* [[Calcium metabolism]]  
* [[Calcium metabolism]]
* [[Disorders of calcium metabolism]]  
* [[Disorders of calcium metabolism]]
* [[Parathyroid hormone family]]
* [[Parathyroid hormone-related protein]]
* [[Parathyroid hormone-related protein]]


==Further reading==
==Footnote==
{{refbegin | 2}}
{{reflist|group=nb}}
{{PBB_Further_reading
 
| citations =  
== References ==
*{{cite journal  | author=Drüeke TB, Massy ZA |title=Advanced oxidation protein products, parathyroid hormone and vascular calcification in uremia. |journal=Blood Purif. |volume=20 |issue= 5 |pages= 494-7 |year= 2003 |pmid= 12207101 |doi= }}
{{Reflist|33em}}
*{{cite journal | author=Parfitt AM |title=Parathyroid hormone and periosteal bone expansion. |journal=J. Bone Miner. Res. |volume=17 |issue= 10 |pages= 1741-3 |year= 2003 |pmid= 12369776 |doi= }}
 
*{{cite journal | author=Martin TJ |title=Does bone resorption inhibition affect the anabolic response to parathyroid hormone? |journal=Trends Endocrinol. Metab. |volume=15 |issue= 2 |pages= 49-50 |year= 2004 |pmid= 15080150 |doi= }}
== Further reading ==
*{{cite journal | author=Keutmann HT, Sauer MM, Hendy GN, ''et al.'' |title=Complete amino acid sequence of human parathyroid hormone. |journal=Biochemistry |volume=17 |issue= 26 |pages= 5723-9 |year= 1979 |pmid= 728431 |doi= }}
{{refbegin|33em}}
*{{cite journal | author=Keutmann HT, Niall HD, O'Riordan JL, Potts JT |title=A reinvestigation of the amino-terminal sequence of human parathyroid hormone. |journal=Biochemistry |volume=14 |issue= 9 |pages= 1842-7 |year= 1975 |pmid= 1125201 |doi=    | doi=10.1021/bi00680a006}}
* {{cite journal | vauthors = Drüeke TB, Massy ZA | title = Advanced oxidation protein products, parathyroid hormone and vascular calcification in uremia | journal = Blood Purification | volume = 20 | issue = 5 | pages = 494–7 | year = 2003 | pmid = 12207101 | doi = 10.1159/000065203 }}
*{{cite journal | author=Parkinson DB, Thakker RV |title=A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism. |journal=Nat. Genet. |volume=1 |issue= 2 |pages= 149-52 |year= 1993 |pmid= 1302009 |doi= 10.1038/ng0592-149 }}
* {{cite journal | vauthors = Parfitt AM | title = Parathyroid hormone and periosteal bone expansion | journal = Journal of Bone and Mineral Research | volume = 17 | issue = 10 | pages = 1741–3 | date = Oct 2002 | pmid = 12369776 | doi = 10.1359/jbmr.2002.17.10.1741 }}
*{{cite journal | author=Handt O, Reis A, Schmidtke J |title=Ectopic transcription of the parathyroid hormone gene in lymphocytes, lymphoblastoid cells and tumour tissue. |journal=J. Endocrinol. |volume=135 |issue= 2 |pages= 249-56 |year= 1993 |pmid= 1474331 |doi= }}
* {{cite journal | vauthors = Martin TJ | title = Does bone resorption inhibition affect the anabolic response to parathyroid hormone? | journal = Trends in Endocrinology and Metabolism | volume = 15 | issue = 2 | pages = 49–50 | date = Mar 2004 | pmid = 15080150 | doi = 10.1016/j.tem.2004.01.002 }}
*{{cite journal | author=Tonoki H, Narahara K, Matsumoto T, Niikawa N |title=Regional mapping of the parathyroid hormone gene (PTH) by cytogenetic and molecular studies. |journal=Cytogenet. Cell Genet. |volume=56 |issue= 2 |pages= 103-4 |year= 1991 |pmid= 1672845 |doi= }}
* {{cite journal | vauthors = Keutmann HT, Sauer MM, Hendy GN, O'Riordan LH, Potts JT | title = Complete amino acid sequence of human parathyroid hormone | journal = Biochemistry | volume = 17 | issue = 26 | pages = 5723–9 | date = Dec 1978 | pmid = 728431 | doi = 10.1021/bi00619a019 }}
*{{cite journal | author=Klaus W, Dieckmann T, Wray V, ''et al.'' |title=Investigation of the solution structure of the human parathyroid hormone fragment (1-34) by 1H NMR spectroscopy, distance geometry, and molecular dynamics calculations. |journal=Biochemistry |volume=30 |issue= 28 |pages= 6936-42 |year= 1991 |pmid= 2069952 |doi=    | doi=10.1021/bi00242a018}}
* {{cite journal | vauthors = Keutmann HT, Niall HD, O'Riordan JL, Potts JT | title = A reinvestigation of the amino-terminal sequence of human parathyroid hormone | journal = Biochemistry | volume = 14 | issue = 9 | pages = 1842–7 | date = May 1975 | pmid = 1125201 | doi = 10.1021/bi00680a006 }}
*{{cite journal | author=Arnold A, Horst SA, Gardella TJ, ''et al.'' |title=Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism. |journal=J. Clin. Invest. |volume=86 |issue= 4 |pages= 1084-7 |year= 1990 |pmid= 2212001 |doi=   | doi=10.1172/JCI114811}}
* {{cite journal | vauthors = Parkinson DB, Thakker RV | title = A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism | journal = Nature Genetics | volume = 1 | issue = 2 | pages = 149–52 | date = May 1992 | pmid = 1302009 | doi = 10.1038/ng0592-149 }}
*{{cite journal | author=Nussbaum SR, Gaz RD, Arnold A |title=Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone. |journal=N. Engl. J. Med. |volume=323 |issue= 19 |pages= 1324-8 |year= 1990 |pmid= 2215618 |doi= }}
* {{cite journal | vauthors = Handt O, Reis A, Schmidtke J | title = Ectopic transcription of the parathyroid hormone gene in lymphocytes, lymphoblastoid cells and tumour tissue | journal = The Journal of Endocrinology | volume = 135 | issue = 2 | pages = 249–56 | date = Nov 1992 | pmid = 1474331 | doi = 10.1677/joe.0.1350249 }}
*{{cite journal | author=Ahn TG, Antonarakis SE, Kronenberg HM, ''et al.'' |title=Familial isolated hypoparathyroidism: a molecular genetic analysis of 8 families with 23 affected persons. |journal=Medicine (Baltimore) |volume=65 |issue= 2 |pages= 73-81 |year= 1986 |pmid= 3005800 |doi= }}
* {{cite journal | vauthors = Tonoki H, Narahara K, Matsumoto T, Niikawa N | title = Regional mapping of the parathyroid hormone gene (PTH) by cytogenetic and molecular studies | journal = Cytogenetics and Cell Genetics | volume = 56 | issue = 2 | pages = 103–4 | year = 1991 | pmid = 1672845 | doi = 10.1159/000133059 }}
*{{cite journal | author=Tregear GW, van Rietschoten J, Greene E, ''et al.'' |title=Solid-phase synthesis of the biologically active N-terminal 1 - 34 peptide of human parathyroid hormone. |journal=Hoppe-Seyler's Z. Physiol. Chem. |volume=355 |issue= 4 |pages= 415-21 |year= 1975 |pmid= 4474131 |doi= }}
* {{cite journal | vauthors = Marx UC, Adermann K, Bayer P, Meyer M, Forssmann WG, Rösch P | title = Structure-activity relation of NH2-terminal human parathyroid hormone fragments | journal = The Journal of Biological Chemistry | volume = 273 | issue = 8 | pages = 4308–16 | date = Feb 1998 | pmid = 9468478 | doi = 10.1074/jbc.273.8.4308 }}
*{{cite journal | author=Niall HD, Sauer RT, Jacobs JW, ''et al.'' |title=The amino-acid sequence of the amino-terminal 37 residues of human parathyroid hormone. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=71 |issue= 2 |pages= 384-8 |year= 1974 |pmid= 4521809 |doi=   | doi=10.1073/pnas.71.2.384}}
* {{cite journal | vauthors = Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, Kronenberg HM | title = Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism | journal = The Journal of Clinical Investigation | volume = 86 | issue = 4 | pages = 1084–7 | date = Oct 1990 | pmid = 2212001 | pmc = 296835 | doi = 10.1172/JCI114811 }}
*{{cite journal | author=Andreatta RH, Hartmann A, Jöhl A, ''et al.'' |title=[Synthesis of sequence 1-34 of human parathyroid hormone] |journal=Helv. Chim. Acta |volume=56 |issue= 1 |pages= 470-3 |year= 1973 |pmid= 4721748 |doi= 10.1002/hlca.19730560139 }}
* {{cite journal | vauthors = Nussbaum SR, Gaz RD, Arnold A | title = Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone | journal = The New England Journal of Medicine | volume = 323 | issue = 19 | pages = 1324–8 | date = Nov 1990 | pmid = 2215618 | doi = 10.1056/NEJM199011083231907 }}
*{{cite journal | author=Jacobs JW, Kemper B, Niall HD, ''et al.'' |title=Structural analysis of human proparathyroid hormone by a new microsequencing approach. |journal=Nature |volume=249 |issue= 453 |pages= 155-7 |year= 1974 |pmid= 4833516 |doi=    | doi=10.1038/249155a0}}
* {{cite journal | vauthors = Ahn TG, Antonarakis SE, Kronenberg HM, Igarashi T, Levine MA | title = Familial isolated hypoparathyroidism: a molecular genetic analysis of 8 families with 23 affected persons | journal = Medicine | volume = 65 | issue = 2 | pages = 73–81 | date = Mar 1986 | pmid = 3005800 | doi = 10.1097/00005792-198603000-00001 }}
*{{cite journal | author=Vasicek TJ, McDevitt BE, Freeman MW, ''et al.'' |title=Nucleotide sequence of the human parathyroid hormone gene. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=80 |issue= 8 |pages= 2127-31 |year= 1983 |pmid= 6220408 |doi=   | doi=10.1073/pnas.80.8.2127}}
* {{cite journal | vauthors = Tregear GW, van Rietschoten J, Greene E, Niall HD, Keutmann HT, Parsons JA, O'Riordan JL, Potts JT | title = Solid-phase synthesis of the biologically active N-terminal 1 - 34 peptide of human parathyroid hormone | journal = Hoppe-Seyler's Zeitschrift für Physiologische Chemie | volume = 355 | issue = 4 | pages = 415–21 | date = Apr 1974 | pmid = 4474131 | doi = 10.1515/bchm2.1974.355.1.415 }}
*{{cite journal | author=Mayer H, Breyel E, Bostock C, Schmidtke J |title=Assignment of the human parathyroid hormone gene to chromosome 11. |journal=Hum. Genet. |volume=64 |issue= 3 |pages= 283-5 |year= 1983 |pmid= 6885073 |doi=    | doi=10.1007/BF00279412}}
* {{cite journal | vauthors = Niall HD, Sauer RT, Jacobs JW, Keutmann HT, Segre GV, O'Riordan JL, Aurbach GD, Potts JT | title = The amino-acid sequence of the amino-terminal 37 residues of human parathyroid hormone | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 71 | issue = 2 | pages = 384–8 | date = Feb 1974 | pmid = 4521809 | pmc = 388010 | doi = 10.1073/pnas.71.2.384 }}
*{{cite journal | author=Hendy GN, Kronenberg HM, Potts JT, Rich A |title=Nucleotide sequence of cloned cDNAs encoding human preproparathyroid hormone. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=78 |issue= 12 |pages= 7365-9 |year= 1982 |pmid= 6950381 |doi= }}
* {{cite journal | vauthors = Andreatta RH, Hartmann A, Jöhl A, Kamber B, Maier R, Riniker B, Rittel W, Sieber P | title = [Synthesis of sequence 1-34 of human parathyroid hormone] | journal = Helvetica Chimica Acta | volume = 56 | issue = 1 | pages = 470–3 | year = 1973 | pmid = 4721748 | doi = 10.1002/hlca.19730560139 }}
*{{cite journal  | author=Hendy GN, Bennett HP, Gibbs BF, ''et al.'' |title=Proparathyroid hormone is preferentially cleaved to parathyroid hormone by the prohormone convertase furin. A mass spectrometric study. |journal=J. Biol. Chem. |volume=270 |issue= 16 |pages= 9517-25 |year= 1995 |pmid= 7721880 |doi= }}
* {{cite journal | vauthors = Jacobs JW, Kemper B, Niall HD, Habener JF, Potts JT | title = Structural analysis of human proparathyroid hormone by a new microsequencing approach | journal = Nature | volume = 249 | issue = 453 | pages = 155–7 | date = May 1974 | pmid = 4833516 | doi = 10.1038/249155a0 }}
}}
* {{cite journal | vauthors = Vasicek TJ, McDevitt BE, Freeman MW, Fennick BJ, Hendy GN, Potts JT, Rich A, Kronenberg HM | title = Nucleotide sequence of the human parathyroid hormone gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 80 | issue = 8 | pages = 2127–31 | date = Apr 1983 | pmid = 6220408 | pmc = 393770 | doi = 10.1073/pnas.80.8.2127 }}
* {{cite journal | vauthors = Mayer H, Breyel E, Bostock C, Schmidtke J | title = Assignment of the human parathyroid hormone gene to chromosome 11 | journal = Human Genetics | volume = 64 | issue = 3 | pages = 283–5 | year = 1983 | pmid = 6885073 | doi = 10.1007/BF00279412 }}
* {{cite journal | vauthors = Hendy GN, Kronenberg HM, Potts JT, Rich A | title = Nucleotide sequence of cloned cDNAs encoding human preproparathyroid hormone | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 78 | issue = 12 | pages = 7365–9 | date = Dec 1981 | pmid = 6950381 | pmc = 349267 | doi = 10.1073/pnas.78.12.7365 }}
* {{cite journal | vauthors = Hendy GN, Bennett HP, Gibbs BF, Lazure C, Day R, Seidah NG | title = Proparathyroid hormone is preferentially cleaved to parathyroid hormone by the prohormone convertase furin. A mass spectrometric study | journal = The Journal of Biological Chemistry | volume = 270 | issue = 16 | pages = 9517–25 | date = Apr 1995 | pmid = 7721880 | doi = 10.1074/jbc.270.16.9517 }}
{{refend}}
{{refend}}
<br>


== External links ==
* PTH at [http://labtestsonline.org/understanding/analytes/pth/tab/test Lab Tests Online]
* [http://www.acb.org.uk/docs/NHLM/Parathyroid%20hormone.pdf Parathyroid hormone: analyte monograph] - the Association for Clinical Biochemistry and Laboratory Medicine
* [http://www.personalabs.com/panels.aspx?CatName=Thyroid%20/%20Parathyroid&Visible=True Parathyroid Function Test Online]
{{PDB Gallery|geneid=5741}}
{{Hormones}}
{{Hormones}}
{{Signaling peptide/protein receptor modulators}}
[[Category:Parathyroid hormone receptor agonists]]
[[Category:Peptide hormones]]
[[Category:Peptide hormones]]
[[Category:Hormones of the parathyroid glands]]
[[Category:Hormones of the parathyroid glands]]
[[Category:Endocrinology]]
[[Category:Hormones of calcium metabolism]]
 
[[bg:Паратироиден хормон]]
[[cs:Parathormon]]
[[da:Parathyroideahormon]]
[[de:Parathormon]]
[[dv:ޕަރަތައިރޮއިޑް ހޯރމޯން]]
[[es:Parathormona]]
[[fr:Parathormone]]
[[it:Paratormone]]
[[nl:Parathormoon]]
[[ja:パラトルモン]]
[[no:PTH]]
[[pl:Parathormon]]
[[pt:Hormônio da paratireóide]]
[[ru:Паратиреоидный гормон]]
[[sk:Paratyroid]]
[[sl:Parathormon]]
[[fi:Parathormoni]]
[[sv:Parathormon]]
[[tr:Parathormon]]
 
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Parathyroid hormone (PTH), also called parathormone or parathyrin, is a hormone secreted by the parathyroid glands that is important in bone remodeling, which is an ongoing process in which bone tissue is alternately resorbed and rebuilt over time. PTH is secreted in response to low blood serum calcium (Ca2+) levels. PTH indirectly stimulates osteoclast activity within bone marrow, in an effort to release more ionic calcium (Ca2+) into the blood to elevate serum calcium (Ca2+) levels. The bones act as a (metaphorical) "bank of calcium" from which the body can make "withdrawals" as needed to keep the amount of calcium in the blood at appropriate levels despite the ever-present challenges of metabolism, stress, and nutritional variations. PTH is "a key that unlocks the bank vault" to remove the calcium. In consequence, PTH is vital to health, and health problems that yield too little or too much PTH (such as hypoparathyroidism, hyperparathyroidism, or paraneoplastic syndromes) can wreak havoc in the form of bone disease, hypocalcaemia, and hypercalcaemia.

PTH is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids, which is a prohormone; effective hormone-receptor interaction requires solely the 34-N-terminal amino acids. While PTH acts to increase the concentration of ionic calcium (Ca2+) in the blood, calcitonin, a hormone produced by the parafollicular cells (C cells) of the thyroid gland, acts to decrease ionic calcium concentration. PTH essentially acts to increase the concentration of calcium in the blood by acting upon the parathyroid hormone 1 receptor, which is present at high levels in bone and kidney, and the parathyroid hormone 2 receptor, which is present at high levels in the central nervous system, pancreas, testis, and placenta.[1] PTH half-life is approximately 4 minutes.[2] It has a molecular mass of approximately 9500 Da.[3]

Structure

hPTH-(1-34) crystallizes as a slightly bent, long helical dimer. Analysis reveals that the extended helical conformation of hPTH-(1-34) is the likely bioactive conformation.[4] The N-terminal fragment 1-34 of parathyroid hormone (PTH) has been crystallized and the structure has been refined to 0.9 Å resolution.

File:The ribbon cartoon structure.png
helical dimer structure of hPTH-(1-34)[5]

Function

Regulation of serum calcium

File:Calcium balance 2.jpg
A diagrammatic representation of the movements of calcium ions into and out of the blood plasma (the central square labeled PLASMA Ca2+) in an adult in calcium balance. The widths of the red arrows indicating movement into and out of the plasma are roughly in proportion to the daily amounts of calcium moved in the indicated directions. The size of the central square in not in proportion to the size of the diagrammatic bone, which represents the calcium present in the skeleton, and contains approximately 25,000 mmol (or 1 kg) of calcium compared to the 9 mmol (360 mg) dissolved in the blood plasma. The differently colored narrow arrows indicate where the specified hormones act, and their effects (“+” means stimulates; “-“ means inhibits) when their plasma levels are high. PTH is parathyroid hormone, 1,25 OH VIT D3 is calcitriol or 1,25 dihydroxyvitamin D3, and CALCITONIN is a hormone secreted by the thyroid gland when the plasma ionized calcium level is high or rising. The diagram does not show the extremely small amounts of calcium that move into and out of the cells of the body, nor does it indicate the calcium that is bound to the extracellular proteins (in particular the plasma proteins) or to plasma phosphate.[6][7][8][9][10]

Parathyroid hormone regulates serum calcium through its effects on bone, kidney, and the intestine:[11]

In bone, PTH enhances the release of calcium from the large reservoir contained in the bones.[12] Bone resorption is the normal destruction of bone by osteoclasts, which are indirectly stimulated by PTH. Stimulation is indirect since osteoclasts do not have a receptor for PTH; rather, PTH binds to osteoblasts, the cells responsible for creating bone. Binding stimulates osteoblasts to increase their expression of RANKL and inhibits their secretion of Osteoprotegerin (OPG). Free OPG competitively binds to RANKL as a decoy receptor, preventing RANKL from interacting with RANK, a receptor for RANKL. The binding of RANKL to RANK (facilitated by the decreased amount of OPG available for binding the excess RANKL) stimulates these osteoclast precursors to fuse, forming new osteoclasts, which ultimately enhances bone resorption. Another mechanism to regulate this pathways as PTH does is by estrogen. Estrogen suppresses T cell TNF production by regulating T cell differentiation and activity in the bone marrow, thymus, and peripheral lymphoid organs. In the bone marrow, estrogen downregulates the proliferation of hematopoietic stem cells through an IL-7 dependent mechanism.[13]

In the kidney, approximately 250 mmol of calcium ions are filtered into the glomerular filtrate per day. Most of this (245 mmol/d) is reabsorbed from the tubular fluid, leaving about 5 mmol/d to be excreted in the urine. This reabsorption occurs throughout the tubule (most, 60-70%, of it in the proximal tubule), except in the thin segment of the loop of Henle.[6] Circulating parathyroid hormone only influences the reabsorption that occurs in the distal tubules and the renal collecting ducts[6] (but see Footnote[nb 1]). A more important effect of PTH on the kidney is, however, its inhibition of the reabsorption of phosphate (HPO42−) from the tubular fluid, resulting in a decrease in the plasma phosphate concentration. Phosphate ions form water-insoluble salts with calcium. Thus, a decrease in the phosphate concentration of the blood plasma (for a given total calcium concentration) increases the amount of calcium that is ionized.[16][17] A third important effect of PTH on the kidney is its stimulation of the conversion of 25-hydroxy vitamin D into 1,25-dihydroxy vitamin D (calcitriol), which is released into the circulation. This latter form of vitamin D is the active hormone which stimulates calcium uptake from the intestine.[18]

In the intestine, via kidney, PTH enhances the absorption of calcium in the intestine by increasing the production of activated vitamin D. Vitamin D activation occurs in the kidney. PTH up-regulates 25-hydroxyvitamin D3 1-alpha-hydroxylase, the enzyme responsible for 1-alpha hydroxylation of 25-hydroxy vitamin D, converting vitamin D to its active form (1,25-dihydroxy vitamin D). This activated form of vitamin D increases the absorption of calcium (as Ca2+ ions) by the intestine via calbindin.

PTH was one of the first hormones to be shown to use the G-protein, adenylyl cyclase second messenger system.

Regulation of serum phosphate

PTH reduces the reabsorption of phosphate from the proximal tubule of the kidney,[19] which means more phosphate is excreted through the urine.

However, PTH enhances the uptake of phosphate from the intestine and bones into the blood. In the bone, slightly more calcium than phosphate is released from the breakdown of bone. In the intestines, absorption of both calcium and phosphate is mediated by an increase in activated vitamin D. The absorption of phosphate is not as dependent on vitamin D as is that of calcium. The end result of PTH release is a small net drop in the serum concentration of phosphate.

Vitamin D synthesis

PTH increases the activity of 1-α-hydroxylase enzyme, which converts 25-hydroxycholecalciferol, the major circulating form of inactive vitamin D, into 1,25-dihydroxycholecalciferol, the active form of vitamin D, in the kidney.

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

[[File:
<imagemap> Image:VitaminDSynthesis WP1531.png
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Vitamin D Synthesis Pathway (view / edit)
  1. ↑ The interactive pathway map can be edited at WikiPathways: "VitaminDSynthesis_WP1531".

Regulation of PTH secretion

Secretion of parathyroid hormone is determined chiefly by serum ionized calcium concentration through negative feedback. Parathyroid cells express calcium-sensing receptors on the cell surface. PTH is secreted when [Ca2+] is decreased (Calcitonin is secreted when serum calcium levels are elevated). The G-protein coupled calcium receptors bind extracellular calcium and may be found on the surface on a wide variety of cells distributed in the brain, heart, skin, stomach, C cells, and other tissues. In the parathyroid gland, high concentrations of extracellular calcium result in activation of the Gq G-protein coupled cascade through the action of phospholipase C. This hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to liberate intracellular messengers IP3 and diacylglycerol (DAG). Ultimately, these two messengers result in a release of calcium from intracellular stores into the cytoplasmic space. Hence a high extracellular calcium concentration leads to an increase in the cytoplasmic calcium concentration. In contrast to the mechanism that most secretory cells use, this high cytoplasmic calcium concentration inhibits the fusion of vesicles containing granules of preformed PTH with the membrane of the parathyroid cell, and thus inhibits release of PTH.

In the parathyroids, magnesium serves this role in stimulus-secretion coupling. A mild decrease in serum magnesium levels stimulates the resorptive activity PTH has on the kidneys. Severe hypomagnesemia inhibits PTH secretion and also causes resistance to PTH, leading to a form of hypoparathyroidism that is reversible.[20]

Stimulators

  • Decreased serum [Ca2+].
  • Mild decreases in serum [Mg2+].
  • An increase in serum phosphate (increased phosphate causes it to complex with serum calcium, forming calcium phosphate, which reduces stimulation of Ca-sensitive receptors (CaSr) that do not sense calcium phosphate, triggering an increase in PTH).

Inhibitors

Clinical significance

Hyperparathyroidism, the presence of excessive amounts of parathyroid hormone in the blood, occurs in two very distinct sets of circumstances. Primary hyperparathyroidism is due to autonomous, abnormal hypersecretion of PTH from the parathyroid gland, while secondary hyperparathyroidism is an appropriately high PTH level seen as a physiological response to hypocalcaemia. A low level of PTH in the blood is known as hypoparathyroidism and is most commonly due to damage to or removal of parathyroid glands during thyroid surgery.

There are a number of rare but well-described genetic conditions affecting parathyroid hormone metabolism, including pseudohypoparathyroidism, familial hypocalciuric hypercalcaemia, and autosomal dominant hypercalciuric hypocalcemia. Of note, PTH is unchanged in pseudopseudohypoparathyroidism. In osteoporotic women, administration of an exogenous parathyroid hormone analogue (teriparatide, by daily injection) superimposed on estrogen therapy produced increases in bone mass and reduced vertebral and nonvertebral fractures by 45 to 65%.[22]

Measurement

PTH can be measured in the blood in several different forms: intact PTH; N-terminal PTH; mid-molecule PTH, and C-terminal PTH, and different tests are used in different clinical situations.

The average PTH level is 8–51 pg/mL.[23] Normal total plasma calcium level ranges from 8.5 to 10.2 mg/dL (2.12 mmol/L to 2.55 mmol/L).[24]

Model organisms

Model organisms have been used in the study of PTH function. A conditional knockout mouse line called Pthtm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[25] Male and female animals underwent a standardized phenotypic screen[26] to determine the effects of deletion.[27][28][29][30] Additional screens performed: - In-depth immunological phenotyping[31]

See also

Footnote

  1. ↑ This reduction in the rate of calcium excretion via the urine is a minor effect of high parathyroid hormone levels in the blood. The main determinant of the amount of calcium excreted into the urine per day is the plasma ionized calcium concentration itself. The plasma parathyroid hormone (PTH) concentration only increases or decreases the amount of calcium excreted at any specified plasma ionized calcium concentration. Thus, in primary hyperparathyroidism the quantity of calcium excreted in the urine per day is increased despite the high levels of PTH in the blood. This is because hyperparathyroidism results in hypercalcemia, which increases the urinary calcium concentration (hypercalcuria) despite the moderately increased rate of calcium re-absorption from the renal tubular fluid caused by PTH's direct effect on those tubules. Renal stones are therefore often a first indication of hyperparathyroidism, especially since the hypercalcuria is accompanied by an increase in urinary phosphate excretion (a direct result of the high plasma PTH levels). Together the calcium and phosphate tend to precipitate out as water-insoluble salts, which readily form solid “stones”.[6][14][15]

References

  1. ↑ Essentials of Human Physiology by Thomas M. Nosek. Section 5/5ch6/s5ch6_11.
  2. ↑ Bieglmayer C, Prager G, Niederle B (Oct 2002). "Kinetic analyses of parathyroid hormone clearance as measured by three rapid immunoassays during parathyroidectomy". Clinical Chemistry. 48 (10): 1731–8. PMID 12324490.
  3. ↑ Brewer HB, Fairwell T, Ronan R, Sizemore GW, Arnaud CD (1972). "Human parathyroid hormone: amino-acid sequence of the amino-terminal residues 1-34". Proceedings of the National Academy of Sciences of the United States of America. 69 (12): 3585–8. doi:10.1073/pnas.69.12.3585. PMC 389826. PMID 4509319.
  4. ↑ Jin L, Briggs SL, Chandrasekhar S, Chirgadze NY, Clawson DK, Schevitz RW, Smiley DL, Tashjian AH, Zhang F (Sep 2000). "Crystal structure of human parathyroid hormone 1-34 at 0.9-A resolution". The Journal of Biological Chemistry. 275 (35): 27238–44. doi:10.1074/jbc.M001134200. PMID 10837469.
  5. ↑ PDB: 1ETE​; Savvides SN, Boone T, Andrew Karplus P (Jun 2000). "Flt3 ligand structure and unexpected commonalities of helical bundles and cystine knots". Nature Structural Biology. 7 (6): 486–91. doi:10.1038/75896. PMID 10881197.
  6. ↑ 6.0 6.1 6.2 6.3 Blaine J, Chonchol M, Levi M (2015). "Renal control of calcium, phosphate, and magnesium homeostasis". Clinical Journal of the American Society of Nephrology. 10 (7): 1257–72. doi:10.2215/CJN.09750913. PMID 25287933.
  7. ↑ Brini M, Ottolini D, Calì T, Carafoli E (2013). "Chapter 4. Calcium in Health and Disease". In Sigel A, Helmut RK. Interrelations between Essential Metal Ions and Human Diseases. Metal Ions in Life Sciences. 13. Springer. pp. 81–137. doi:10.1007/978-94-007-7500-8_4.
  8. ↑ Walter F (2003). "The Parathyroid Glands and Vitamin D". Medical Physiology: A Cellular And Molecular Approach. Elsevier/Saunders. p. 1094. ISBN 1-4160-2328-3.
  9. ↑ Guyton A (1976). ‘’Medical Physiology’’. p.1062; New York, Saunders and Co.
  10. ↑ Barrett KE, Barman SM, Boitano S, Brooks H. "Chapter 23. Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone". In Barrett KE, Barman SM, Boitano S, Brooks H. Ganong's Review of Medical Physiology (23e ed.).
  11. ↑ Coetzee M, Kruger MC (May 2004). "Osteoprotegerin-receptor activator of nuclear factor-kappaB ligand ratio: a new approach to osteoporosis treatment?". Southern Medical Journal. 97 (5): 506–11. doi:10.1097/00007611-200405000-00018. PMID 15180028.
  12. ↑ Poole KE, Reeve J (Dec 2005). "Parathyroid hormone - a bone anabolic and catabolic agent". Current Opinion in Pharmacology. 5 (6): 612–7. doi:10.1016/j.coph.2005.07.004. PMID 16181808.
  13. ↑ Bord S, Ireland DC, Beavan SR, Compston JE (2003). "The effects of estrogen on osteoprotegerin, RANKL, and estrogen receptor expression in human osteoblasts". Bone. 32 (2): 136–41. doi:10.1016/S8756-3282(02)00953-5. PMID 12633785.
  14. ↑ Harrison T, Adams R, Bennett I, Resnick W, Thorn G, Wintrobe M (1958). "Metabolic and Endocrine Disorders". Principles of Internal Medicine (Third ed.). New York: McGraw-Hill Book Company. pp. 575–578.
  15. ↑ "Symptoms of Hyperparathyroidism and Symptoms of Parathyroid Disease". Parathyroid.com. Norman Parathyroid Center. Retrieved 2015-12-30.
  16. ↑ Haldimann B, Vogt K (1983). "[Hyperphosphatemia and tetany following phosphate enema]". Schweizerische Medizinische Wochenschrift (in French). 113 (35): 1231–3. PMID 6623048.
  17. ↑ Sutters M, Gaboury CL, Bennett WM (1996). "Severe hyperphosphatemia and hypocalcemia: a dilemma in patient management". Journal of the American Society of Nephrology : JASN. 7 (10): 2056–61. PMID 8915965.
  18. ↑ Stryer L (1995). Biochemistry (Fourth ed.). New York: W.H. Freeman and Company. p. 707. ISBN 978-0-7167-2009-6.
  19. ↑ Gardner D, Shoback D (2011). Greenspan's Basic & Clinical Endocrinology (9th ed.). McGraw Hill. p. 232. ISBN 978-0-07-162243-1.
  20. ↑ Agus ZS (Jul 1999). "Hypomagnesemia". Journal of the American Society of Nephrology. 10 (7): 1616–22. PMID 10405219.
  21. ↑ Costanzo, Linda S. (2007). BRS Physiology. Lippincott, Williams, & Wilkins. p. 260. ISBN 978-0-7817-7311-9.
  22. ↑ Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH (May 2001). "Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis". The New England Journal of Medicine. 344 (19): 1434–41. doi:10.1056/NEJM200105103441904. PMID 11346808.
  23. ↑ Longo DL, Fauci A, Kasper D, Hauser S, Jameson J, Loscalzo J (2012). Harrison's Principles of Internal Medicine (18th ed.). New York: McGraw-Hill. p. 3594. ISBN 978-0-07-174889-6.
  24. ↑ Zieve D. "MedlinePlus Medical Encyclopedia: Serum calcium". National Library of Medicine, National Institutes of Health. Retrieved 2009-02-01.
  25. ↑ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica. 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
  26. ↑ 26.0 26.1 "International Mouse Phenotyping Consortium".
  27. ↑ Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  28. ↑ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  29. ↑ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  30. ↑ White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, et al. (Jul 2013). "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell. 154 (2): 452–64. doi:10.1016/j.cell.2013.06.022. PMC 3717207. PMID 23870131.
  31. ↑ 31.0 31.1 "Infection and Immunity Immunophenotyping (3i) Consortium".

Further reading

External links

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