Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC144010.15690/vramn1440ENDOCRINOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ЭНДОКРИНОЛОГИИReview ArticleParathyroid Hormone in the Regulation of Bone Growth and Resorption in Health and DiseaseПаратиреоидный гормон в регуляции процессов роста и резорбции кости в норме и патологииhttps://orcid.org/0000-0002-9124-294XY-8894-20184168-6851VorontsovaMaria V.ВоронцоваМария Владимировна
Russian Federation

MD, PhD

к.м.н.

maria.v.vorontsova@mail.ruhttps://orcid.org/0000-0001-6954-578754400164600B-4292-20127573-8527KulebyakinKonstantin Y.КулебякинКонстантин Юрьевич
Russian Federation

PhD in Biology

к.б.н.

konstantin-kuleb@mail.ruhttps://orcid.org/0000-0003-3832-63677156-6517MakazanNadezhda V.МаказанНадежда Викторовна
Russian Federation

MD, PhD

к.м.н.

nmakazan@yandex.ruhttps://orcid.org/0000-0002-5650-14409983-5662SozaevaLeila S.СозаеваЛейла Салиховна
Russian Federation

MD, PhD

к.м.н.

Leila.sozaeva@gmail.comhttps://orcid.org/0000-0002-1901-163736646806400A-8193-20142149-7839Tyurin-KuzminPyotr A.Тюрин-КузьминПетр Алексеевич
Russian Federation

PhD in Biology

к.б.н.

tyurinkuzmin.p@gmail.comLomonosov Moscow State UniversityМосковский государственный университет им. М.В. ЛомоносоваEnocrinology Research CentreНациональный медицинский исследовательский центр эндокринологии301120217655065172108202006102021Copyright ©; 2021, "Paediatrician" Publishers LLCCopyright ©; 2021, Издательство "Педиатръ"2021"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/1440

Parathyroid hormone (PTH) is a key hormone responsible for regulation of calcium homeostasis in the body. Since the main body calcium depot is bone tissue, PTH has a decisive effect on its homeostasis. In this case, the hormone can activate both bone formation and resorption. Thus, PTH can ensure the conjugation of anabolic and catabolic processes, which is necessary for the renewal of bone tissue, which is had to function under constant mechanical stress. At the same time, the use of PTH in medical practice is rather small, despite its high potential as a basis for the treatment of various pathologies associated with impaired bone homeostasis. Presented review, describes the intracellular signaling cascades and molecular mechanisms that underlie the action of PTH on bone tissue cells, and intracellular signaling cascades are described. A separate section examines the cellular mechanisms of the action of PTH on bone homeostasis, discusses how the effect of the hormone on different types of cells provides an interface between the processes of synthesis and resorption. In addition, the review examines diseases associated with impaired bone homeostasis, as well as the role of PTH and impaired signaling in their etiology.

Паратиреоидный гормон (ПТГ) — ключевой гормон, регулирующий гомеостаз кальция в организме. Поскольку основным депо кальция в организме является костная ткань, ПТГ оказывает определяющее влияние на ее гомеостаз. При этом гормон способен активировать как образование, так и резорбцию кости. Таким образом, ПТГ может обеспечивать сопряжение анаболических и катаболических процессов, что необходимо для обновления костной ткани, которая находится под постоянной механической нагрузкой. В то же время использование ПТГ в медицинской практике достаточно невелико, несмотря на его высокий потенциал в качестве основы для терапии различных патологий, связанных с нарушением обмена кости. В представленном обзоре рассмотрены молекулярные механизмы действия ПТГ на клетки костной ткани, описаны сигнальные внутриклеточные каскады. В отдельном разделе рассматриваются клеточные механизмы действия ПТГ на гомеостаз кости, обсуждается, как воздействие гормона на разные типы клеток обеспечивает сопряжение между процессами синтеза и резорбции. Кроме того, в обзоре рассматриваются заболевания, связанные с нарушением гомеостаза костной ткани, а также роль ПТГ и нарушения его сигналинга в их этиологии.

parathyroid hormonebone tissuebone remodelingпаратиреоидный гормонкостная тканьремоделирование костиРоссийский научный фондRussian Science FundГрант № 19-75-30007Lupp A, Klenk C, Röcken C, et al. Immunohistochemical identification of the PTHR1 parathyroid hormone receptor in normal and neoplastic human tissues. Eur J Endocrinol. 2010;162(5):979–986. doi: https://doi.org/10.1530/eje-09-0821Brenza 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: https://doi.org/10.1073/pnas.95.4.1387Potts JT. Parathyroid hormone: past and present. J Endocrinol. 2005;187(3):311–325. doi: https://doi.org/10.1677/joe.1.06057Abou-Samra AB, Jüppner H, Force T, et al. Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: A single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. Proc Natl Acad Sci USA. 1992;89(7):2732–2736. doi: https://doi.org/10.1073/pnas.89.7.2732Usdin TB, Hoare SRJ, Wang T, et al. TIP39: a new neuropeptide and PTH2-receptor agonist from hypothalamus. Nat Neurosci. 1999;2(11):941–943. doi: https://doi.org/10.1038/14724Castro M, Nilolaev VO, Palm D, et al. Turn-on switch in parathyroid hormone receptor by a two-step parathyroid hormone binding mechanism. Proc Natl Acad Sci USA. 2005;102(44):16084–16089. doi: https://doi.org/10.1073/pnas.0503942102Shaywitz AJ, Greenberg ME. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu Rev Biochem. 1999;68:821–861. doi: https://doi.org/10.1146/annurev.biochem.68.1.821Ferrandon S, Feinstein TN, Castro M, et al. Sustained cyclic AMP production by parathyroid hormone receptor endocytosis. Nat Chem Biol. 2009;5(10):734–742. doi: https://doi.org/10.1038/nchembio.206Luttrell LM, Lefkowitz RJ. The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci. 2002;115(Pt 3):455–465.Wehbi VL, Stevenson HP, Feinstein TN, et al. Noncanonical GPCR signaling arising from a PTH receptor-arrestin-Gβγ complex. Proc Natl Acad Sci USA. 2013;110(4)–1530-1535. doi: https://doi.org/10.1073/pnas.1205756110Mahon MJ, Donowitz M, Yun CC, Segre GV. Na(+)/H(+ ) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. Nature. 2002;417(6891):858–861. doi: https://doi.org/10.1038/nature00816Cheloha RW, Gellman SH, Vilardaga JP, Gardella TJ, et al. PTH receptor-1 signalling-mechanistic insights and therapeutic prospects. Nat Rev Endocrinol. 2015;11(12):712–724. doi: https://doi.org/10.1038/nrendo.2015.139White AD, Fang F, Jean-Alphonse FG, et al. Ca(2+) allostery in PTH-receptor signaling. Proc Natl Acad Sci USA. 2019;116(8):3294–3299. doi: https://doi.org/10.1073/pnas.1814670116Kalinina NI, Sysoeva VYu, Rubina KA, et al. Mesenchymal stem cells in tissue growth and repair. Acta Naturae. 2011;3(4):30–37. doi: https://doi.org/10.32607/20758251-2011-3-4-30-37Méndez-Ferrer S, Michurina TV, Ferraro F, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466(7308):829–834. doi: https://doi.org/10.1038/nature09262Sinha P, Aarnisalo P, Chubb R, et al. Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy. J Biol Chem. 2016;291(4):1631–1642. doi: https://doi.org/10.1074/jbc.M115.679753Петрова Т.В., Свинарева Д.А., Нифонтова И.Н., и др. Стромальная регуляция стволовых кроветворных клеток в длительных культурах костного мозга человека под действием паратиреоидного гормона // Клеточные технологии в биологии и медицине. — 2006. — № 4. — С. 218–222. [Petrova TV, Svinareva DA, Nifontova IN, et al. Stromal’naja reguljacija stvolovyh krovetvornyh kletok v dlitel’nyh kul’turah kostnogo mozga cheloveka pod dejstviem paratireoidnogo gormona // Kletochnye tehnologii v biologii i medicine. 2006(4):218–222. (In Russ.)]Terauchi M, Li JY, Bedi B, et al. T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling. Cell Metab. 2009;10(3):229–240. doi: https://doi.org/10.1016/j.cmet.2009.07.010Свинарева Д.А., Нифонтова И.Н., Дризе Н.И. Влияние паратиреоидного гормона ПТГ (1-34) на кроветворные и стромальные стволовые клетки // Бюллетень экспериментальной биологии и медицины. — 2004. — № 138. — С. 645–648. [Svinareva DA, Nifontova IN, Drize NI. Vlijanie paratireoidnogo gormona PTG (1-34) na krovetvornye i stromal’nye stvolovye kletki // Bjulleten’ jeksperimental’noj biologii i mediciny. 2004(138):645–648. (In Russ.)]Захаров Ю.М., Макарова Э.Б. Регуляция остеогенной дифференциации мезенхимальных стволовых клеток костного мозга // Российский физиологический журнал им. И.М. Сеченова. — 2013. – № 99. — С. 417–432. [Zaharov YM, Makarova EB. Reguljacija osteogennoj differenciacii mezenhimal’nyh stvolovyh kletok kostnogo mozga // Rossijskij fiziologicheskij zhurnal im. I.M. Sechenova. 2013(99):417–432. (In Russ.)]Prisby R, Guignandon A, Vanden-Bossche A, et al. Intermittent PTH(1-84) is osteoanabolic but not osteoangiogenic and relocates bone marrow blood vessels closer to bone-forming sites. J Bone Miner Res. 2011;26(11):2583–2596. doi: https://doi.org/10.1002/jbmr.459Selvamurugan N, Chou WY, Pearman AT, et al. Parathyroid hormone regulates the rat collagenase-3 promoter in osteoblastic cells through the cooperative interaction of the activator protein-1 site and the runt domain binding sequence. J Biol Chem. 1998;273(17):10647–10657. doi: https://doi.org/10.1074/jbc.273.17.10647Pellicelli M, Miller JA, Arabian A, et al. The PTH-Galphas-protein kinase A cascade controls alphaNAC localization to regulate bone mass. Mol Cell Biol. 2014;34(9):1622–1633. doi: https://doi.org/10.1128/mcb.01434-13Thouverey C, Caverzasio J. Suppression of p38alpha MAPK Signaling in Osteoblast Lineage Cells Impairs Bone Anabolic Action of Parathyroid Hormone. J Bone Miner Res. 2016;31(5):985–993. doi: https://doi.org/10.1002/jbmr.2762Guo J, Liu M, Yang D, et al. Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation. Cell Metab. 2010;11(2):161–171. doi: https://doi.org/10.1016/j.cmet.2009.12.007Suzuki A, Ozono K, Kubota T, et al. PTH/cAMP/PKA signaling facilitates canonical Wnt signaling via inactivation of glycogen synthase kinase-3beta in osteoblastic Saos-2 cells. J Cell Biochem. 2008;104(1):304–317. doi: https://doi.org/10.1002/jcb.21626Klein-Nulend J, Nijweide PJ, Burger EH. Osteocyte and bone structure. Curr Osteoporos Rep. 2003;1(1):5–10. doi: https://doi.org/10.1007/s11914-003-0002-yFermor B, Skerry TM. PTH/PTHrP receptor expression on osteoblasts and osteocytes but not resorbing bone surfaces in growing rats. J Bone Miner Res. 1995;10(12):1935–1943. doi: https://doi.org/10.1002/jbmr.5650101213Takeda N, Tsuboyama T, Kasai R, et al. Expression of the c-fos gene induced by parathyroid hormone in the bones of SAMP6 mice, a murine model for senile osteoporosis. Mech Ageing Dev. 1999;108(1):87–97. doi: https://doi.org/10.1016/s0047-6374(99)00002-0Chow JW, Fox S, Jagger CJ, Chambers TJ. Role for parathyroid hormone in mechanical responsiveness of rat bone. Am J Physiol. 1998;274(1):E146–E154. doi: https://doi.org/10.1152/ajpendo.1998.274.1.E146Fukumoto S. Physiological regulation and disorders of phosphate metabolism--pivotal role of fibroblast growth factor 23. Intern Med. 2008;47(5):337–343. doi: https://doi.org/10.2169/internalmedicine.47.0730Fukumoto S. The role of bone in phosphate metabolism. Mol Cell Endocrinol. 2009;310(1–2):63–70. doi: https://doi.org/10.1016/j.mce.2008.08.031Lavi-Moshayoff V, Wasserman G, Meir T, et al. PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. Am J Physiol Renal Physiol. 2010;299(4):F882–E889. doi: https://doi.org/10.1152/ajprenal.00360.2010Nagy V, Penninger JM. The RANKL-RANK Story. Gerontology. 2015;61(6):534–542. doi: https://doi.org/10.1159/000371845Park JH, Lee NK, Lee SY. Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation. Molecules and cells. 2017;40(10):706–713. doi: https://doi.org/10.14348/molcells.2017.0225Park-Min K-H. Mechanisms involved in normal and pathological osteoclastogenesis. Cellular and molecular life sciences : CMLS. 2018;75(14):2519–2528. doi: https://doi.org/10.1007/s00018-018-2817-9Ikebuchi Y, Aoki S, Honma M, et al. Coupling of bone resorption and formation by RANKL reverse signalling. Nature. 2018;561(7722):195–200. doi: https://doi.org/10.1038/s41586-018-0482-7Бруцкая-Стемпковская Е.В., Шепелькевич А.П., Васильева Н.А., и др. Костные проявления первичного гиперпаратиреоза у женщин в постменопаузальном периоде // Хирургия. Восточная Европа. — 2018. — Т. 7. — № 3. — С. 383–396. [Brutskaya-Stempkovskaya E.1, Shepelkevich A.1, Vasilieva N, et al. Bone disorders in postmenopausal women with primary hyperparathyroidism. Surgery. Eastern Europe. 2018;7(3):383-396. In Russ.)]Zanocco KA, Yeh MW. Primary Hyperparathyroidism: Effects on Bone Health. Endocrinol Metab Clin North Am. 2017;46(1):87–104. doi: https://doi.org/10.1016/j.ecl.2016.09.012Vu TD, et al. New insights into the effects of primary hyperparathyroidism on the cortical and trabecular compartments of bone. Bone. 2013;55(1):57–63. doi: https://doi.org/10.1016/j.bone.2013.03.009Cusano NE, Nishiyama KK, Zhang C, et al. Noninvasive Assessment of Skeletal Microstructure and Estimated Bone Strength in Hypoparathyroidism. J Bone Miner Res. 2016;31(2):308–316. doi: https://doi.org/10.1002/jbmr.2609Rubin MR, Dempster DW, Zhou H, et al. Dynamic and structural properties of the skeleton in hypoparathyroidism. J Bone Miner Res. 2008;23(12):2018–2024. doi: https://doi.org/10.1359/jbmr.080803Rubin MR, Dempster DW, Sliney Jr J, et al. PTH(1-84) administration reverses abnormal bone-remodeling dynamics and structure in hypoparathyroidism. J Bone Miner Res. 2011;26(11):2727–2736. doi: https://doi.org/10.1002/jbmr.452Blomstrand S, Claësson I, Säve-Söderbergh J. A case of lethal congenital dwarfism with accelerated skeletal maturation. Pediatr Radiol. 1985;15(2):141–143. doi: https://doi.org/10.1007/bf02388725Galera MF, de Silva Patrício FR, Lederman HM, et al. Blomstrand chondrodysplasia: a lethal sclerosing skeletal dysplasia. Case report and review. Pediatr Radiol. 1999;29(11):842–845. doi: https://doi.org/10.1007/s002470050709Duchatelet S, Ostergaard E, Cortes D, et al. Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes. Hum Mol Genet. 2005;14(1):1–5. doi: https://doi.org/10.1093/hmg/ddi001Shapiro MS, Bernheim J, Gutman A, et al. Multiple abnormalities of anterior pituitary hormone secretion in association with pseudohypoparathyroidism. J Clin Endocrinol Metab. 1980;51(3):483–487. doi: https://doi.org/10.1210/jcem-51-3-483Дзеранова Л.К., Маказан Н.В., Пигарова Е.А., и др. Множественная гормональная резистентность и метаболические нарушения при псевдогипопаратиреозе // Ожирение и метаболизм. — 2018.— Т. 15. — № 2. — С. 51–56. [Dzeranova LK, Makazan NV, Pigarova EA, et al. Multiple hormonal resistance and metabolic disorders in pseudogypoparatiosis. Obesity and metabolism. 2018;15(2):51–55. (In Russ.)] doi: https://doi.org/10.14341/OMET20182Hanna P, Grybek V, Peres de Nanclares G, et al. Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity. J Bone Miner Res. 2018;33(8):1480–1488. doi: https://doi.org/10.1002/jbmr.3450Kaplan FS, Craver R, MacEwen GD, et al. Progressive osseous heteroplasia: a distinct developmental disorder of heterotopic ossification. Two new case reports and follow-up of three previously reported cases. J Bone Joint Surg Am. 1994;76(3):425–436.Dumitrescu CE, Collins MT. McCune-Albright syndrome. Orphanet Journal of Rare Diseases. 2008;3(1):12. doi: https://doi.org/10.1186/1750-1172-3-12Майлян Э.А., Игнатенко Г.А., Резниченко Н.А. Уровни гормонов и маркеров костного обмена при постменопаузальном остеопорозе // Медико-социальные проблемы семьи. — 2018. — Т. 23. — № 1. — C. 41–48. [Maylyan EA, Ignatenko GA, Reznichenko NA. Hormone levels and markers of bone metabolismin postmenopausal osteoporosis. Medical and Social Problems Of Family. 2018;23(1):41–48. (In Russ.)]Jilka RL. Biology of the basic multicellular unit and the pathophysiology of osteoporosis. Med Pediatr Oncol. 2003;41(3):182–185. doi: https://doi.org/10.1002/mpo.10334Мамедова Е.О., Гребенникова Т.А., Белая Ж.Е., Рожинская Л.Я. Антитела к склеростину как новая анаболическая терапия остеопороза // Остеопороз и остеопатии. — 2019. — Т. 21. — № 3. — C. 21–29. [Mamedova EO, Grebennikova TA, Belaya ZhE, Rozhinskaya LYa. Sclerostin antibodies as novel anabolic therapy for osteoporosis. Osteoporosis and Bone Diseases. 2018;21(3):21-29. (In Russ.)] doi: https://doi.org/10.14341/osteo10127Ishtiaq S, Fogelman I, Hampson G. Treatment of post-menopausal osteoporosis: beyond bisphosphonates. J Endocrinol Invest. 2015;38(1):13–29. doi: https://doi.org/10.1007/s40618-014-0152-zРожинская Л.Я., Гранская С.А., Мамедова Е.О., и др. Применение Деносумаба для лечения остеопороза различного генеза в реальной клинической практике // Остеопороз и остеопатии. — 2020. — Т. 23. — № 1. — C. 4–13. [Rozhinskaya LYa, Gronskaia SA, Mamedova EO, et al. The comparative efficiency of denosumab treatment in patients with postmenopausal osteoporosis, primary hyperparathyroidism and glucocorticoid-induced osteoporosis in real clinical practice. Osteoporosis and Bone Diseases. 2020;23(1):4–13. (In Russ.)] doi: https://doi.org/10.14341/osteo12415Anastasilakis AD, Polyzos SA, Makras P, et al. Clinical Features of 24 Patients With Rebound-Associated Vertebral Fractures After Denosumab Discontinuation: Systematic Review and Additional Cases. J Bone Miner Res. 2017;32(6):1291–1296. doi: https://doi.org/10.1002/jbmr.3110Kates SL, Ackert-Bicknell CL. How do bisphosphonates affect fracture healing? Injury. 2016;47(Suppl 1):S65–S68. doi: https://doi.org/10.1016/s0020-1383(16)30015-8Wojda SJ, Donahue SW. Parathyroid hormone for bone regeneration. J Orthop Res. 2018;36(10):2586–2594. doi: https://doi.org/10.1002/jor.24075Fu R, Selph S, McDonagh M, et al. Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion: a systematic review and meta-analysis. Ann Intern Med. 2013;158(12):890–902. doi: https://doi.org/10.7326/0003-4819-158-12-201306180-00006Raggio BS, Winters R. Modern management of osteoradionecrosis. Curr Opin Otolaryngol Head Neck Surg. 2018;26(4):254–259. doi: https://doi.org/10.1097/moo.0000000000000459Mannstadt M, Clarke BL, Vokes T, et al. Efficacy and safety of recombinant human parathyroid hormone (1-84) in hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, randomised, phase 3 study. Lancet Diabetes Endocrinol. 2013;1(4):275–283. doi: https://doi.org/10.1016/s2213-8587(13)70106-2Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med. 2007;146(5):326–339. doi: https://doi.org/10.7326/0003-4819-146-5-200703060-00005Piemonte S, Romagnoli E, Cipriani C, et al. The effect of recombinant PTH(1-34) and PTH(1-84) on serum ionized calcium, 1,25-dihydroxyvitamin D, and urinary calcium excretion: a pilot study. Calcif Tissue Int. 2009;85(4):287–292. doi: https://doi.org/10.1007/s00223-009-9280-4Cipriani C, Irani D, Bilezikian JP. Safety of osteoanabolic therapy: a decade of experience. J Bone Miner Res. 2012;27(12):2419–2428. doi: https://doi.org/10.1002/jbmr.1800