“Parathyroid hormone”的意思、由来-开放百科全书

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 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. (Data indicate that PTH is also possibly secreted in small amounts from the brain and the thymus.^[1]) 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, testes, and placenta.^[2] PTH half-life is about 4 minutes.^[3] It has a molecular mass around 9500 Da.^[4]

Structure

hPTH-(1-34) crystallizes as a slightly bent, long, helical dimer. The extended helical conformation of hPTH-(1-34) is the likely bioactive conformation.^[5] The N-terminal fragment 1-34 of parathyroid hormone (PTH) has been crystallized and the structure has been refined to 0.9 Å resolution.

Function

Regulation of serum calcium

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, around 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.^[14] Circulating parathyroid hormone only influences the reabsorption that occurs in the distal tubules and the renal collecting ducts^[14] (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, because hyperparathyroidism results in hypercalcemia, which increases the urinary calcium concentration (hypercalcuria) despite the moderately increased rate of calcium reabsorption 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”.^[14]^[15]^[16] |group=nb}}). 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.^[17]^[18] 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.^[19]

Via the 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,^[20] 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 upregulates 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

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.^[21]

Stimulators

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%.^[23]

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.^[24] Normal total plasma calcium level ranges from 8.5 to 10.2 mg/dL (2.12 mmol/L to 2.55 mmol/L).^[25]

Model organisms

See also

Footnote

1. ^{{cite journal | vauthors =Gunther T, Chen ZF, Kim J, et al | title = Genetic ablation of parathyroid glands reveals another source of parathyroid hormone | journal = Nature | volume = 406 | pages =199-203 | date = July 2000 | pmid =10910362 | doi =10.1038/35018111 |url =https://www.nature.com/articles/35018111}}
2. ^{{GeorgiaPhysiology|5/5ch6/s5ch6_11}}
3. ^{{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 }}
4. ^{{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}}
5. ^{{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 }}
6. ^{{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 }}
7. ^{{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 }}
8. ^{{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=}}
9. ^Guyton A (1976). ‘’Medical Physiology’’. p.1062; New York, Saunders and Co.
10. ^{{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 }}
11. ^{{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 }}
12. ^{{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 }}
13. ^{{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 }}
14. ^¹²³{{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 | pmc = 4491294 }}
15. ^{{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 }}
16. ^{{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 }}
17. ^{{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 = }}
18. ^{{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 = }}
19. ^{{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 }}
20. ^{{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 }}
21. ^{{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 }}
22. ^{{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 }}
23. ^{{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 }}
24. ^{{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 }}
25. ^{{cite web | url = https://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 }}
26. ^{{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 }}
27. ^¹{{cite web |url=http://www.mousephenotype.org/data/search?q=Pth#fq=**&facet=gene |title=International Mouse Phenotyping Consortium}}
28. ^{{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 }}
29. ^{{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 }}
30. ^{{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 }}
31. ^{{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}}
32. ^¹{{cite web |url= http://www.immunophenotyping.org/data/search?keys=Pth&field_gene_construct_tid=All |title=Infection and Immunity Immunophenotyping (3i) Consortium}}