Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC110410.15690/vramn1104ENDOCRINOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ЭНДОКРИНОЛОГИИThe Parathyroid Hormone and Peptides Like It. Literature ReviewПаратиреоидный гормон и подобные ему пептиды. Обзор литературыhttps://orcid.org/0000-0002-9717-9742MokryshevaNatalia G.МокрышеваНаталья Георгиевна
Russian Federation

MD, Sc.D., prof.

11 Dm. Ulyanova street, 117036 Moscow.

SPIN-код: 5624-3875

Доктор медицинских наук, профессор.

117036, Москва, ул. Дмитрия Ульянова, д. 11.

SPIN-код: 5624-3875

parathyroid.enc@gmail.comhttps://orcid.org/0000-0001-7963-5022KrupinovaJulia A.КрупиноваЮлия Александровна
Russian Federation

MD.

11 Dm. Ulyanova street, 117036 Moscow.

SPIN-код: 6279-8247

117036, Москва, ул. Дмитрия Ульянова, д. 11.

SPIN-код: 6279-8247

j.krupinova@gmail.comhttps://orcid.org/0000-0002-9258-2591KovalevaElena V.КовалеваЕлена Владимировна
Russian Federation

Postgraduate student.

11 Dm. Ulyanova street, 117036 Moscow.

SPIN-код: 7387-6791

Аспирант.

117036, Москва, ул. Дмитрия Ульянова, д. 11; тел.: +7 (495) 500-00-63.

SPIN-код: 7387-6791

elen.v.kovaleva@gmail.comEndocrinology Research centreНациональный медицинский исследовательский центр эндокринологии310520197421361440402201916052019Copyright ©; 2019, "Paediatrician" Publishers LLCCopyright ©; 2019, Издательство "Педиатръ"2019"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/1104

Wide prevalence of the parathyroid glands pathology and the need for new methods of diagnosis and treatment are forcing researchers all over the world to go more deeply into the pathophysiological mechanisms. A parathyroid hormone (PTH) is main cause of mineral disorders. In addition, humans have a family with similar in structure molecules that contribute to the maintenance of calcium and phosphate homeostasis. The family includes PTH, parathyroid hormone-related protein (PTHrP) and tuberoinfundibular peptide 39 (TIP39, also known as PTH2). The genes encoding these peptides have highly homologous amino acid regions in the N-(amino) terminal receptor-binding sites of each family member, as well as the preserved structure of their organization, which seems to be due to the presence of one parent gene. The variety of classical and “non-classical” effects allows to expand the understanding of these substances and consider them as hormones that go beyond the regulation of phosphorus-calcium metabolism. The review provides information on the structure and biosynthesis of these peptides, as well as a wide range of their effects on the human body.

Широкая распространенность патологии околощитовидных желез и потребность в новых методах диагностики и лечения заставляет исследователей по всему миру все больше углубляться в патофизиологические механизмы. Ключевым гормоном, отвечающим за минеральные нарушения, является паратиреоидный гормон (ПТГ); кроме того, у человека имеется целое семейство сходных с ним по структуре молекул, привносящих свой вклад в поддержание фосфорно-кальциевого гомеостаза. К семейству относят ПТГ, паратгормонподобный пептид (ПТГпП) и тубероинфундибулярный пептид 39 (TIP39, также известный как PTH2). Гены, кодирующие данные пептиды, имеют участки высокогомологичных областей аминокислот в N(амино)-концевых рецепторсвязывающих участках каждого члена семейства, а также сохранную структуру их организации, что, по-видимому, связано с наличием одного родоначального гена. Многообразие классических и «неклассических» эффектов позволяет расширить представление о данных субстанциях и рассматривать их в качестве гормонов, выходящих за пределы регуляции фосфорно-кальциевого обмена. В обзоре представлена информация о структуре и биосинтезе этих пептидов, особенностях рецепторной передачи сигналов, а также о широком спектре их воздействия на организм человека.

parathyroid hormoneparathyroid hormone-related proteincalciumcalcium and phosphate homeostasisparathyroid glandsпаратиреоидный гормонпаратгормонподобный пептидкальцийфосфорно-кальциевый гомеостазоколощитовидные железы1.Pinheiro PL, Cardoso JC, Power DM, Canário AV. Functional characterization and evolution of PTH/PTHrP receptors: insights from the chicken. BMC Evol Biol. 2012;12(1):110. doi: 10.1186/1471-2148-12-110.2.Guerreiro PM, Renfro JL, Power DM, Canario AV. The parathyroid hormone family of peptides: structure, tissue distribution, regulation, and potential functional roles in calcium and phosphate balance in fish. Am J Physiol Regul Integr Comp Physiol. 2007;292(2):R679−696. doi: 10.1152/ajpregu.00480.2006.3.Pinheiro PL, Cardoso JC, Gomes AS, et al. Gene structure, transcripts and calciotropic effects of the PTH family of peptides in Xenopus and chicken. BMC Evol Biol. 2010;10:373. doi: 10.1186/1471-2148-10-373.4.Asa SL, Henderson J, Goltzman D, Drucker DJ. Parathyroid hormone-like peptide in normal and neoplastic human endocrine tissues. J Clin Endocrinol Metab. 1990;71(5):1112–1118. doi: 10.1210/jcem-71-5-1112.5.John MR, Arai M, Rubin DA, et al. Identification and characterization of the murine and human gene encoding the tuberoinfundibular peptide of 39 residues. Endocrinology. 2002;143(3):1047–1057. doi: 10.1210/endo.143.3.8698.6.Gensure RC, Gardella TJ, Juppner H. Parathyroid hormone and parathyroid hormone-related peptide, and their receptors. Biochem Biophys Res Commun. 2005;328(3):666–678. doi: 10.1016/j.bbrc.2004.11.069.7.Papasani MR, Gensure RC, Yan Y-L, et al. Identification and characterization of the zebrafish and fugu genes encoding tuberoinfundibular peptide 39. Endocrinology. 2004;145(11):5294–5304. doi: 10.1210/en.2004-0159.8.Naveh-Many T. Molecular biology of the parathyroid [Internet]. Landes Bioscience; 2005. Available from: http://bookre.org/reader?file=679469.9.Toribio RE, Kohn CW, Capen CC, Rosol TJ. Parathyroid hormone (PTH) secretion, PTH mRNA and calcium-sensing receptor mRNA expression in equine parathyroid cells, and effects of interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha on equine parathyroid cell function. J Mol Endocrinol. 2003;31(3):609–620. doi: 10.1677/jme.0.0310609.10.Sakwe AM, Engstrom A, Larsson M, Rask L. Biosynthesis and secretion of parathyroid hormone are sensitive to proteasome inhibitors in dispersed bovine parathyroid cells. J Biol Chem. 2002;277(20):17687–1795. doi: 10.1074/jbc.M108576200.11.Brewer HB, Ronan R. Bovine parathyroid hormone: amino acid sequence. Proc Natl Acad Sci U S A. 1970;67(4):1862–1869. doi: 10.1073/pnas.67.4.1862.12.Cohn DV, Macgregor RR, Chu LL, et al. Calcemic fraction-A: biosynthetic peptide precursor of parathyroid hormone. Proc Natl Acad Sci U S A. 1972;69(6):1521–1525. doi: 10.1073/pnas.69.6.1521.13.Kemper B, Habener JF, Potts JT, Rich A. Proparathyroid hormone: identification of a biosynthetic precursor to parathyroid hormone. Proc Natl Acad Sci U S A. 1972;69(3):643–647. doi: 10.1073/pnas.69.3.643.14.Habener JF, Amherdt M, Ravazzola M, Orci L. Parathyroid hormone biosynthesis. Correlation of conversion of biosynthetic precursors with intracellular protein migration as determined by electron microscope autoradiography. J Cell Biol. 1979;80(3):715–731. doi: 10.1083/jcb.80.3.715.15.Kemper B, Habener JF, Mulligan RC, et al. Pre-proparathyroid hormone: a direct translation product of parathyroid messenger RNA. Proc Natl Acad Sci U S A. 1974;71(9):3731–3735. doi: 10.1073/pnas.71.9.3731.16.Yasuda T, Banville D, Hendy GN, Goltzman D. Characterization of the human parathyroid hormone-like peptide gene. Functional and evolutionary aspects. J Biol Chem. 1989;264(13):7720–7725.17.Liu Y, Ibrahim AS, Tay B-H, et al. Parathyroid hormone gene family in a cartilaginous fish, the elephant shark (Callorhinchus milii). J Bone Miner Res. 2010;25(12):2613–2623. doi: 10.1002/jbmr.178.18.Kremer R, Li J, Camirand A, Karaplis AC. Parathyroid hormone related protein (PTHrP) in tumor progression. Adv Exp Med Biol. 2011;720:145–160. doi: 10.1007/978-1-4614-0254-1_12.19.Gardella TJ, Vilardaga J-P. International Union of Basic and Clinical Pharmacology. XCIII. The parathyroid hormone receptors ― family B G protein-coupled receptors. Pharmacol Rev. 2015 г.;67(2):310–337. doi: 10.1124/pr.114.009464.20.Wysolmerski JJ. Parathyroid hormone-related protein: an update. J Clin Endocrinol Metab. 2012;97(9):2947–2956. doi: 10.1210/jc.2012-2142.21.Vilardaga J-P, Romero G, Friedman PA, Gardella TJ. Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm. Cell Mol Life Sci CMLS. 2011;68(1):1–13. doi: 10.1007/s00018-010-0465-9.22.Zuscik MJ, O’Keefe RJ, Gunter TE, et al. Parathyroid hormone-related peptide regulation of chick tibial growth plate chondrocyte maturation requires protein kinase A. J Orthop Res. 2002;20(5):1079–1090. doi: 10.1016/S0736-0266(02)00027-X.23.Boras-Granic K, VanHouten J, Hiremath M, Wysolmerski J. Parathyroid hormone-related protein is not required for normal ductal or alveolar development in the post-natal mammary gland. PloS One. 2011;6(11):e27278–e27278. doi: 10.1371/journal.pone.0027278.24.Burtis WJ, Wu T, Bunch C, et al. Identification of a novel 17,000-dalton parathyroid hormone-like adenylate cyclase-stimulating protein from a tumor associated with humoral hypercalcemia of malignancy. J Biol Chem.1987;262(15):7151–7156.25.Cabrera-Vera TM, Vanhauwe J, Thomas TO, et al. Insights into G protein structure, function, and regulation. Endocr Rev. 2003; 24(6):765–781. doi: 10.1210/er.2000-0026.26.El Abdaimi K, Papavasiliou V, Goltzman D, Kremer R. Expression and regulation of parathyroid hormone-related peptide in normal and malignant melanocytes. Am J Physiol Cell Physiol. 2000;279(4):C1230−1238. doi: 10.1152/ajpcell.2000.279.4.C1230.27.Kakonen S-M, Selander KS, Chirgwin JM, et al. Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways. J Biol Chem. 2002;277(27):24571–24578. doi: 10.1074/jbc.M202561200.28.Pizzi H, Gladu J, Carpio L, et al. Androgen regulation of parathyroid hormone-related peptide production in human prostate cancer cells. Endocrinology. 2003;144(3):858–867. doi: 10.1210/en.2002-220754.29.Jans DA, Thomas RJ, Gillespie MT. Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles. Vitam Horm. 2003;66:345–384. doi: 10.1016/s0083-6729(03)01010-0.30.de Miguel F, Fiaschi-Taesch N, Lopez-Talavera JC, et al. The C-terminal region of PTHrP, in addition to the nuclear localization signal, is essential for the intracrine stimulation of proliferation in vascular smooth muscle cells. Endocrinology. 2001;142(9):4096–4105. doi: 10.1210/endo.142.9.8388.31.Henderson JE, Amizuka N, Warshawsky H, et al. Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death. Mol Cell Biol. 1995;15(8):4064–4075. doi: 10.1128/mcb.15.8.4064.32.Gardella TJ, Juppner H. Interaction of PTH and PTHrP with their receptors. Rev Endocr Metab Disord. 2000;1(4):317–329.33.Reid IR, Civitelli R, Avioli LV, Hruska KA. Parathyroid hormone depresses cytosolic pH and DNA synthesis in osteoblast-like cells. Am J Physiol. 1988;255(1 Pt 1):E9−15. doi: 10.1152/ajpendo.1988.255.1.E9.34.Castro M, Nikolaev VO, Palm D, et al. Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism. Proc Natl Acad Sci U S A. 2005;102(44):16084–16089. doi: 10.1073/pnas.0503942102.35.Dean T, Vilardaga J-P, Potts JT, Gardella TJ. Altered selectivity of parathyroid hormone (PTH) and PTH-related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor. Mol Endocrinol Baltim Md. 2008;22(1):156–166. doi: 10.1210/me.2007-0274.36.Hoare SR, Sullivan SK, Schwarz DA, et al. Ligand affinity for amino-terminal and juxtamembrane domains of the corticotropin releasing factor type I receptor: regulation by G-protein and nonpeptide antagonists. Biochemistry (Mosc). 2004;43(13):3996–4011. doi: 10.1021/bi036110a.37.Vilardaga J-P, Bunemann M, Krasel C, et al. Measurement of the millisecond activation switch of G protein-coupled receptors in living cells. Nat Biotechnol. 2003;21(7):807–812. doi: 10.1038/nbt838.38.Jilka RL, Weinstein RS, Parfitt AM, Manolagas SC. Quantifying osteoblast and osteocyte apoptosis: challenges and rewards. J Bone Miner Res. 2007;22(10):1492–1501. doi: 10.1359/jbmr.070518.39.Miyakoshi N, Kasukawa Y, Linkhart TA, et al. Evidence that anabolic effects of PTH on bone require IGF-I in growing mice. Endocrinology. 2001;142(10):4349–4356. doi: 10.1210/endo.142.10.8436.40.Li X, Qin L, Bergenstock M, et al. Parathyroid hormone stimulates osteoblastic expression of MCP-1 to recruit and increase the fusion of pre/osteoclasts. J Biol Chem. 2007;282(45):33098–33106. doi: 10.1074/jbc.M611781200.41.Kim MS, Day CJ, Morrison NA. MCP-1 is induced by receptor activator of nuclear factor-{kappa}B ligand, promotes human osteoclast fusion, and rescues granulocyte macrophage colony-stimulating factor suppression of osteoclast formation. J Biol Chem. 2005;280(16):16163–16169. doi: 10.1074/jbc.M412713200.42.Bellido T, Saini V, Pajevic PD. Effects of PTH on osteocyte function. Bone. 2013;54(2):250–257. doi: 10.1016/j.bone.2012.09.016.43.Brenza HL, Kimmel-Jehan C, Jehan F, et al. Parathyroid hormone activation of the 25-hydroxyvitamin D3-1alpha-hydroxylase gene promoter. Proc Natl Acad Sci USA. 1998;95(4):1387–1391. doi: 10.1073/pnas.95.4.1387.44.Halapas A, Diamanti-Kandarakis E, Kremastinos D, Koutsilieris M. The PTHrP/PTH.1-R bioregulation system in cardiac hypertrophy: possible therapeutic implications. Vivo Athens Greece. 2006;20(6B):837–844.45.Schlüter KD, Weber M, Piper HM. Parathyroid hormone induces protein kinase C but not adenylate cyclase in adult cardiomyocytes and regulates cyclic AMP levels via protein kinase C-dependent phosphodiesterase activity. Biochem J. 1995;310(Pt 2):439–444. doi: 10.1042/bj3100439.46.Brown SJ, Ruppe MD, Tabatabai LS. The parathyroid gland and heart disease. Methodist Debakey Cardiovasc J. 2017;13(2):49–54. doi: 10.14797/mdcj-13-2-49.47.Ogino K, Burkhoff D, Bilezikian JP. The hemodynamic basis for the cardiac effects of parathyroid hormone (PTH) and PTH-related protein. Endocrinology. 1995;136(7):3024–3030. doi: 10.1210/endo.136.7.7789328.48.Fischer E, Hannemann A, Rettig R, et al. A high aldosterone to renin ratio is associated with high serum parathyroid hormone concentrations in the general population. J Clin Endocrinol Metab. 2014;99(3):965–971. doi: 10.1210/jc.2013-3214.49.Tomaschitz A, Ritz E, Pieske B, et al. Aldosterone and parathyroid hormone interactions as mediators of metabolic and cardiovascular disease. Metabolism. 2014;63(1):20–31. doi: 10.1016/j.metabol.2013.08.016.50.Thomas SS, Mitch WE. Parathyroid hormone stimulates adipose tissue browning: a pathway to muscle wasting. Curr Opin Clin Nutr Metab Care. 2017;20(3):153–157. doi: 10.1097/MCO.0000000000000357.51.Van Houten J, Dann P, McGeoch G, et al. The calcium-sensing receptor regulates mammary gland parathyroid hormone-related protein production and calcium transport. J Clin Invest. 2004;113(4):598–608. doi: 10.1172/JCI18776.52.Wysolmerski JJ, Cormier S, Philbrick WM, et al. Absence of functional type 1 parathyroid hormone (PTH)/PTH-related protein receptors in humans is associated with abnormal breast development and tooth impaction. J Clin Endocrinol Metab. 2001;86(4):1788–1794. doi: 10.1210/jc.86.4.1788.53.Calvi LM, Schipani E. The PTH/PTHrP receptor in Jansen’s metaphyseal chondrodysplasia. J Endocrinol Invest. 2000;23(8):545–554. doi: 10.1007/BF03343773.54.Nissenson RA. Parathyroid hormone (PTH)/PTHrP receptor mutations in human chondrodysplasia. Endocrinology. 1998;139(12):4753–4755. doi: 10.1210/endo.139.12.6454.55.Kronenberg HM. PTHrP and skeletal development. Ann N Y Acad Sci. 2006;1068:1–13. doi: 10.1196/annals.1346.002.56.Marino R. Growth plate biology: new insights. Curr Opin Endocrinol Diabetes Obes. 2011;18(1):9–13. doi: 10.1097/MED.0b013e3283423df9.57.Ono W, Sakagami N, Nishimori S, et al. Parathyroid hormone receptor signalling in osterix-expressing mesenchymal progenitors is essential for tooth root formation. Nat Commun. 2016;7:11277. doi: 10.1038/ncomms11277.58.Song GJ, Fiaschi-Taesch N, Bisello A. Endogenous parathyroid hormone-related protein regulates the expression of PTH type 1 receptor and proliferation of vascular smooth muscle cells. Mol Endocrinol. 2009;23(10):1681–1690. doi: 10.1210/me.2009-0098.59.Stuart WD, Maeda S, Khera P, et al. Parathyroid hormone-related protein induces G1 phase growth arrest of vascular smooth muscle cells. Am J Physiol Endocrinol Metab. 2000;279(1):E60−67. doi: 10.1152/ajpendo.2000.279.1.E60.60.Mozar A, Lin H, Williams K, et al. Parathyroid hormone-related peptide (1-36) Enhances beta-cell regeneration and increases beta cell mass in a mouse model of partial pancreatectomy. PloS One. 2016;11(7):e0158414. doi: 10.1371/journal.pone.0158414.