Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2012, vol. 21, nr 3, May-June, p. 391–401

Publication type: review article

Language: English

Fibroblast Growth Factor 23 – Structure, Function and Role in Kidney Diseases

Czynnik wzrostu fibroblastów 23 – budowa, czynność i znaczenie w patogenezie chorób nerek

Piotr Kocełak1,, Magdalena Olszanecka-Glinianowicz1,, Jerzy Chudek1,

1 Department of Pathophysiology, Medical University of Silesia, Katowice, Poland

Abstract

The fibroblast growth factor (FGF) family comprises a number of polypeptides which share a common homology core region. FGF-23, produced by osteoblasts and osteocytes, belongs to the FGF-19 subfamily and serves as the main phosphatonine. Two forms of circulating FGF-23 are detectable in serum: full-length FGF-23 – intact FGF-23 (iFGF-23), which is biologically active, and the inactive C-terminal FGF-23 (cFGF-23). FGF-23 with a coreceptor (Klotho protein) inhibits renal phosphate reabsorption and synthesis of calcitriol by reducing 1α-hydroxylase (CYP27B1) activity, reducing vitamin D-dependent phosphate intestinal absorption. High phosphorus intake, 1,25-dihydroxyvitamin D3 and PTH are the main stimuli for FGF-23 secretion. Impaired FGF-23 metabolism is involved in phosphate disturbances manifesting as rickets or osteomalacia or increased tissue calcinosis. FGF-23 may be also produced by some tumors leading to hypophosphatemia. Both cFGF-23 and iFGF-23 concentrations start to increase with mild impairment of the glomerular filtration rate in stage 2 or 3 of chronic kidney disease (CKD) as a consequence of the increased FGF-23 production. It seems that enhanced FGF-23 secretion may constitute a protective mechanism against enhanced phosphate accumulation in the early stages of CKD. However, it may lead to calcitriol deficiency and escalation of secondary hyperparathyroidism. Increased FGF-23 level is supposed to be an independent factor increasing mortality of CKD patients. There is ambiguous data if FGF-23 only reflects disturbances in calcium-phosphate metabolism or if it exerts a detrimental effect itself by diminishing calcitriol synthesis, inducing cell proliferation or acting through low-affinity, Klotho-independent receptors in the heart and endothelium. So far, little evidence supports direct FGF-23 toxicity.

Streszczenie

Rodzina czynnika wzrostu fibroblastów (FGF) obejmuje kilkanaście peptydów zawierających wspólny, homologiczny region. FGF-23, należący do podrodziny FGF-19, który jest wydzielany przez osteoblasty oraz osteocyty, i pełni rolę głównej fosfatoniny. W osoczu peptyd ten jest wykrywany w dwóch postaciach: o pełnej długości FGF-23 (intact FGF – iFGF-23), aktywnej biologicznie, oraz C-końcowych fragmentów FGF-23 (c-FGF-23). FGF-23 przy udziale koreceptora, białka Klotho, hamuje reabsorpcję zwrotną fosforanów w cewkach nerkowych oraz syntezę kalcytriolu przez hamowanie aktywności 1α-hydroksylazy (CYP27B1), zmniejszając jelitowe wchłanianie wapnia. Duża podaż fosforanów w diecie, parathormon oraz 1,25-dihydroksywitamina D3 są głównymi bodźcami stymulującymi wydzielanie FGF-23. Nieprawidłowości metabolizmu FGF-23 prowadzą do zaburzeń gospodarki fosforanowej objawiających się krzywicą lub osteomalacją, oraz wapnieniem tkanek miękkich. FGF-23 może być także wydzielany przez komórki nowotworowe, powodując występowanie przewlekłej hipofosfatemii. Zwiększone wydzielanie FGF-23 prowadzi do wzrostu stężenia zarówno cFGF-23, jak i iFGF-23 już przy umiarkowanym upośledzeniu czynności wydalniczej nerek, w fazie 2. i 3. przewlekłej choroby nerek (p.ch.n.). Wydaje się prawdopodobne, że jest to mechanizm kompensacyjny, chroniący organizm przed kumulacją fosforanów. Zwiększenie stężenia FGF-23 przyczynia się jednak do niedoboru kalcytriolu oraz nasilenia wtórnej nadczynności przytarczyc. Przypuszcza się, że zwiększone stężenie FGF-23 może być niezależnym czynnikiem ryzyka zwiększonej śmiertelności u pacjentów z p.ch.n., dotychczas opublikowane dane są jednak niejednoznaczne. Być może stężenie FGF-23 u tych chorych odzwierciedla jedynie zaburzenia gospodarki wapniowo-fosforanowej i przez stymulację receptorów o małym powinowactwie w mięśniu sercowym i śródbłonku oraz hamowanie syntezy kalcytriolu nasila proliferację komórek, przez co pośrednio przyczynia się do powikłań p.ch.n. Ostatnio pojawiły się pierwsze dowody wskazujące na bezpośrednie toksyczne działanie FGF-23.

Key words

FGF-23, chronic kidney disease, Klotho protein

Słowa kluczowe

FGF-23, przewlekła choroba nerek, białko Klotho

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