ЗНАЧЕНИЕ ФАКТОРА РОСТА ФИБРОБЛАСТОВ 23 (FGF-23) В ОРГАНИЗМЕ ЧЕЛОВЕКА
DOI:
https://doi.org/10.31082/1728-452X-2020-217-218-7-8-37-43Ключевые слова:
фактор роста фибробластов, фосфор, паратгормон, гипертрофия левого желудочка, минерально-костные нарушенияАннотация
На сегодняшний день хроническая болезнь почек (ХБП) занимает одно из ведущих мест среди хронических неинфекционных заболеваний по показателям заболеваемости и смертности. Одним из грозных осложнений являются минерально-костные нарушения, ухудшающие клиническое течение и прогноз пациентов. Фактор роста фибробластов 23 типа (FGF-23) – это новый биомаркер, являющийся регулятором фосфатного метаболизма и играющий важную роль в патогенезе многих осложнений при ХБП.
Цель. Изучить физиологическую роль FGF-23, а также его потенциальное клиническое влияние в прогрессировании ХБП и её осложнений.
Материал и методы. Проведен поиск литературы глубиной в 20 лет в международных научных базах PubMed/Medline, Web of Science и Google Scholar по следующим ключевым словам: «Фактор роста фибробластов 23», «FGF-23», «фосфатный гомеостаз», «хроническая болезнь почек», «минерально-костные нарушения», «гипертрофия левого желудочка».
Результаты и обсуждение. FGF-23 – это белок, секретируемый костными клетками, основная физиологическая роль которого заключается в регулировании выведения фосфатов с мочой для поддержания их стабильного уровня в сыворотке крови. Более того, FGF-23 снижает уровень кальцитриола и ингибирует секрецию паратиреоидного гормона. При ХБП отмечается постепенное повышение уровня FGF-23 по мере снижения почечной функции, что может расцениваться как физиологическая компенсация для стабилизации уровня фосфора в сыворотке крови. По данным различных исследований FGF-23 может также ассоциироваться и с кардиоваскулярными осложнениями, такими как гипертрофия левого желудочка и сердечная недостаточность.
Выводы. Таким образом, FGF-23 – это не только маркер минерально-костных нарушений при ХБП, но и ключевое звено в патогенезе развития вторичного гиперпаратиреоза и кардиоваскулярных осложнений. Учитывая это, FGF-23 может представлять собой полифункциональную терапевтическую мишень, которая может улучшить прогноз жизни пациентов с ХБП.
Библиографические ссылки
Bikbov B, Purcell C, Levey A, et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709-733. DOI: 10.1016/S0140-6736(20)30045-3
Becherucci F, Roperto R, Materassi M, Romagnani P. Chronic kidney disease in children. Clin. Kidney J. 2016;9(4):583–591. DOI: 10.1093/ckj/sfw047
Tentori F, Blayney M, Albert J, et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the dialysis outcomes and practice patterns study (DOPPS). American Journal of Kidney Diseases. 2008;52(3):519–530. DOI: 10.1053/j.ajkd.2008.03.020
Wald R, Sarnak M, Tighiouart H, et al. Disordered mineral metabolism in hemodialysis patients: an analysis of cumulative effects in the hemodialysis (HEMO) study. American Journal of Kidney Diseases. 2008; 52(3):531–540. DOI: 10.1053/j.ajkd.2008.05.020
Consortium A. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26(3):345–348. https://doi.org/10.1038/81664
Goldsweig B, Carpenter T. Hypophosphatemic rickets: lessons from disrupted FGF23 control of phosphorus homeostasis. Curr Osteoporos Rep. 2015;13(2):88–97. https://doi.org/10.1007/s1191 4-015-0259-y.
Hasegawa Y, Kawai M, Bessho K, et.al. CYP7A1 expression in hepatocytes is retained with upregulated fibroblast growth factor 19 in pediatric biliary atresia. Hepatology Research. 2019;49(3):314-323. DOI:10.1111/hepr.13245.
Kharitonenkov A, Shiyanova T, Koester A, et al. FGF-21as a novel metabolic regulator. Journal of Clinical Investigation. 2005;115(6):1627–1635. DOI: 10.1172/JCI23606.
Riminucci M, Collins M, Fedarko N, et al. FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting. Journal of Clinical Investigation. 2003;112(5):683–692. DOI: 10.1172/JCI18399
Yamashita T. Structural and biochemical properties of fibroblast growth factor 23. Therapeutic Apheresis and Dialysis. 2005;9(4):313–318. DOI: 10.1111/j.1744-9987.2005.00288.x.
Khosravi A, Cutler C, Kelly M, et al. Determination of the elimination half-life of fibroblast growth factor-23. Journal of Clinical Endocrinology and Metabolism. 2007;92(6):2374–2377. https://doi.org/10.1210/jc.2006-2865
Kurosu H, Ogawa Y, Miyoshi M, et al. Regulation of fibroblast growth factor-23 signaling by Klotho. The Journal of Biological Chemistry. 2006;281(10):6120–6123. DOI: 10.1074/jbc.C500457200.
Kuro-o M. Klotho as a regulator of oxidative stress and senescence. Biol Chem. 2008;389(3):233-241. PMID: 18177265, DOI: 10.1515/BC.2008.028
Farrow E, Davis S, Summers L, et al. Initial FGF23-mediated signaling occurs in the distal convoluted tubule. Journal of the American Society of Nephrology. 2009;20(5):955–960. DOI: 10.1681/ASN.2008070783
Miyamoto K, Segawa H, Ito M, et al. Physiological regulation of renal sodium-dependent phosphate cotransporters. Japanese Journal of Physiology. 2004;54(2):93–102. DOI: 10.2170/jjphysiol.54.93
Miyamoto K, Ito M, Kuwahata M, et al. Inhibition of intestinal sodium-dependent inorganic phosphate transport by fibroblast growth factor 23. Therapeutic Apheresis and Dialysis. 2005;9(4):331–335. DOI: 10.1111/j.1744-9987.2005.00292.x
Saito H, Kusano K, Kinosaki M, et al. Human fibroblast growth factor-23 mutants suppress Na-dependent phosphate co-transport activity and 1alpha,25-dihydroxyvitamin D3 production. J Biol Chem. 2003;278(4):2206–2211. DOI: 10.1074/jbc.M207872200
Shimada T, Hasegawa H, Yamazaki Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.
J Bone Miner Res. 2004;19(3):429–435. DOI: 10.1359/JBMR.0301264
Ben-Dov I, Galitzer H, Lavi-Moshayoff V, et al. The parathyroid is a target organ for FGF23 in rats. J Clin Invest. 2007;117(12):4003–4008. DOI: 10.1172/JCI32409
Kolek O, Hines E, Jones M, et al. 1α,25-dihydroxyvitamin D upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. American Journal of Physiology. 2005;289(6):G1036–G1042. DOI: 10.1152/ajpgi.00243.2005
Antoniucci D, Yamashita T, Portale A. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. Journal of Clinical Endocrinology and Metabolism. 2006;91(8):3144–3149. DOI: 10.1210/jc.2006-0021
Burnett S, Gunawardene S, Bringhurst F, et al. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. Journal of Bone and Mineral Research. 2006; 21(8):1187–1196. DOI: 10.1359/jbmr.060507
Ito N, Fukumoto S, Takeuchi Y, et al. Effect of acute changes of serum phosphate on fibroblast growth factor (FGF)23 levels in humans. Journal of Bone and Mineral Metabolism. 2007;25(6):419–422. DOI: 10.1007/s00774-007-0779-3
Marsell R, Grundberg E, Krajisnik T, et al. Fibroblast growth factor-23 is associated with parathyroid hormone and renal function in a population based cohort of elderly men. Eur J Endocrinol. 2008;158(1):125–129. DOI: 10.1530/EJE-07-0534
Roos M, Lutz J, Salmhofer H, et al. Relation between plasma fibroblast growth factor-23, serum fetuin-A levels and coronary artery calcification evaluated by multislice computed tomography in patients with normal kidney function. Clin Endocrinol (Oxf). 2008;68(4):660–665. DOI: 10.1111/j.1365-2265.2007.03074.x
Ferrari S, Bonjour J, Rizzoli R. Fibroblast growth factor-23 relationship to dietary phosphate and renal phosphate handling in healthy young men. J Clin Endocrinol Metab. 2005;90(3):1519–1524. DOI: 10.1210/jc.2004-1039
Isakova T, Gutierrez O, Shah A, et al. Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. J Am Soc Nephrol. 2008;19(3):615-623. DOI: 10.1681/ASN.2007060673
Nishida Y, Taketani Y, Yamanaka-Okumura H, et al. Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men. Kidney Int. 2006;70(12):2141–2147. DOI: 10.1038/sj.ki.5002000
Krajisnik T, Björklund P, Marsell R, et al. Fibroblast growth factor-23 regulates parathyroid hormone and 1α-hydroxylase expression in cultured bovine parathyroid cells. Journal of Endocrinology. 2007;195(1):125–131. DOI: 10.1677/JOE-07-0267
Kawata T, Imanishi Y, Kobayashi K, et al. Parathyroid hormone regulates fibroblast growth factor-23 in a mouse model of primary hyperparathyroidism. Journal of the American Society of Nephrology. 2007;18(10):2683–2688. https://doi.org/10.1681/ASN.2006070783
Gutierrez O, Isakova T, Rhee E, et al. Fibroblast growth factor-23 mitigates hyperphosphatemia but accentuates calcitriol deficiency in chronic kidney disease. J Am Soc Nephrol. 2005;16(7):2205–2215. DOI: 10.1681/ASN.2005010052
Larsson T, Nisbeth U, Ljunggren O, et al. Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int. 2003; 64(6):2272–2279. DOI: 10.1046/j.1523-1755.2003.00328.x
Imanishi Y, Inaba M, Nakatsuka K, et al. FGF-23 in patients with end-stage renal disease on hemodialysis. Kidney Int. 2004;65(5):1943–1946. DOI: 10.1111/j.1523-1755.2004.00604.x
Koh N, Fujimori T, Nishiguchi S, et al. Severely reduced production of klotho in human chronic renal failure kidney. Biochemical and Biophysical Research Communications. 2001;280(4):1015–1020. DOI: 10.1006/bbrc.2000.4226
Levin A, Bakris G, Molitch M, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int. 2007;71(1):31–38. DOI: 10.1038/sj.ki.5002009
Moranne O, Froissart M, Rossert J, et al. Timing of onset of CKD-related metabolic complications. J Am Soc Nephrol. 2009;20(1):164–171. DOI: 10.1681/ASN.2008020159
Takemoto F, Shinki T, Yokoyama K, et al. Gene expression of vitamin D hydroxylase and megalin in the remnant kidney of nephrectomized rats. Kidney Int. 2003;64(2):414–420. DOI: 10.1046/j.1523-1755.2003.00114.x
Jones G. Expanding role for vitamin D in chronic kidney disease: importance of blood 25-OH-D levels and extra-renal 1alpha-hydroxylase in the classical and nonclassical actions of 1alpha,25-dihydroxyvitamin D(3). Semin Dial. 2007;20(4):316–324. DOI: 10.1111/j.1525-139X.2007.00302.x
Moe S, Chertow G, Parfrey P, et al. Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial Investigators*. Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Circulation. 2015;132(1):27–39. PMID: 26059012, DOI: 10.1161/CIRCULATIONAHA.114.013876
Kendrick J, Cheung A, Kaufman J, et al. FGF-23 associates with death, cardiovascular events, and initiation of chronic dialysis. J Am Soc Nephrol. 2011;22(10):1913–1922. DOI: 10.1681/ASN.2010121224. PMID: 21903574
Ix J, Katz R, Kestenbaum B, et al. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J Am Coll Cardiol. 2012;60(3):200–207
di Giuseppe R, Kuhn T, Hirche F, et al. Plasma fibroblast growth factor 23 and risk of cardiovascular disease: results from the EPIC-Germany case-cohort study. Eur J Epidemiol. 2015;30(2):131–141. https://doi.org/10.1007/s1065 4-014-9982-4
Hsu H, Wu M. Fibroblast growth factor 23: a possible cause of left ventricular hypertrophy in hemodialysis patients. Am J Med Sci. 2009;337(2):116–122. PMID: 19214027, DOI: 10.1097/MAJ.0b01 3e3181815498
Kirkpantur A, Balci M, Gurbuz O, et al. Serum fibroblast growth factor-23 (FGF23) levels are independently associated with left ventricular mass and myocardial performance index in maintenance haemodialysis patients. Nephrol Dial Transplant. 2011;26(4):1346–1354. PMID: 20813767, DOI: 10.1093/ndt/gfq539
Faul C, Amaral A, Oskouei B. FGF23 induces left ventricular hypertrophy. Clin Invest. 2011;121(11):4393–4408. DOI: 10.1172/JCI46122
Scialla J, Xie H, Rahman M, et al. Fibroblast Growth Factor-23 and Cardiovascular Events in CKD. J Am Soc Nephrol. 2014;25(2):349–360. https://doi.org/10.1681/asn.20130 50465
Seiler S, Rogacev K, Roth H, et al. Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2-4. Clin J Am Soc Nephrol. 2014;9(6):1049–1058. https://doi.org/10.2215/CJN.07870 713
Bouma-de K, Bots M, Vervloet M, et al. Time-averaged level of fibroblast growth factor-23 and clinical events in chronic kidney disease. Nephrol Dial Transplant. 2014;29(1):88–97. https://doi.org/10.1093/ndt/gft45 6
Parker B, Schurgers L, Brandenburg V, et al. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann Intern Med. 2010;152(10):640–648. https://doi.org/10.7326/0003-4819-152-10-20100 5180-00004
Kestenbaum B, Sachs M, Hoofnagle A, et al. Fibroblast growth factor-23 and cardiovascular disease in the general population: the Multi-EthnicStudy of Atherosclerosis. Circ Heart Fail. 2014;7(3):409–417. DOI: 10.1161/CIRCHEARTFAILURE.113.000952
di Giuseppe R, Buijsse B, Hirche F, et al. Plasma fibroblast growth factor 23, parathyroid hormone, 25-hydroxyvitamin D3, and risk of heart failure: a prospective, case-cohort study. J Clin Endocrinol Metab. 2014; 99(3):947–955. https://doi.org/10.1210/jc.2013-2963
Marthi A, Donovan K, Haynes R, et al. Fibroblast growth factor-23 and risks of cardiovascular and noncardiovascular diseases: a meta-analysis. J Am Soc Nephrol. 2018;29(7):2015–2027. DOI: 10.1681/ASN.2017121334
Grabner A, Amaral A, Schramm K, et al. Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab. 2015;22(6):1020–1032. https ://doi.org/10.1016/j.cmet.2015.09.002
Grabner A, Schramm K, Silswal N, et al. FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Sci Rep. 2017;7(1):1993. https://doi.org/10.1038/s4159 8-017-02068 -6
Christov M, Clark A, Corbin B, et al. Inducible podocytespecific deletion of CTCF drives progressive kidney disease and bone abnormalities. JCI Insight. 2018;3(4):e95091. https://doi.org/10.1172/jci.insight.95091
Matsui I, Oka T, Kusunoki Y, et al. Cardiac hypertrophy elevates serum levels of fibroblast growth factor 23. Kidney Int. 2018;94(1):60–71. https://doi.org/10.1016/j.kint.2018.02.018
Andrukhova O, Slavic S, Odorfer K, et al. Experimental myocardial infarction upregulates circulating fibroblast growth factor-23. J Bone Miner Res. 2015;30(10):1831–1839. https://doi.org/10.1002/jbmr.2527
Richter M, Lautze H, Walther T, et al. The failing heart is a major source of circulating FGF23 via oncostatin M receptor activation. J Heart Lung Transplant. 2015;34(9):1211–1214. https://doi.org/10.1016/j.healu n.2015.06.007
Leifheit-Nestler M, Grabner A, Hermann L, et al. Vitamin D treatment attenuates cardiac FGF23/FGFR4 signaling and hypertrophy in uremic rats. Nephrol Dial Transplant. 2017;32(9):1493–1503. https://doi.org/10.1093/ndt/gfw454
Pastor-Arroyo E, Gehring N, Krudewig C, et al. The elevation of circulating fibroblast growth factor 23 without kidney disease does not increase cardiovascular disease risk. Kidney Int. 2018;94(1):49–59. PMID: 29735309, DOI: 10.1016/j.kint.2018.02.017
Liu E, Thoonen R, Petit E, et al. Increased circulating FGF23 does not lead to cardiac hypertrophy in the male hyp mouse model of XLH. Endocrinology. 2018;159(5):2165–2172. https://doi.org/10.1210/en.2018-00174
Takashi Y, Kinoshita Y, Hori M, et al. Patients with FGF23-related hypophosphatemic rickets/osteomalacia do not present with left ventricular hypertrophy. Endocr Res. 2017;42(2):132-137. PMID: 27754732, DOI: 10.1080/07435800.2016.1242604
