Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo

López, Ignacio; Rodríguez‐Ortiz, María E.; Almadén, Yolanda; Guerrero, Fatima; de, Addy Montes; Pineda, Carmen; Shalhoub, V.; Rodríguez, Mariano; Aguilera–Tejero, Escolástico

doi:10.1038/ki.2011.107

Cited by 132 publications

(112 citation statements)

References 30 publications

(36 reference statements)

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“…These findings suggested that oral phosphorus administration secondarily increased plasma FGF23 levels at least partially via stimulation of PTH secretion. Some researchers reported that PTH increased FGF23 mRNA levels in vitro (26) and circulating FGF23 levels in vivo (12), which supports our results. Our findings also suggested that elevated plasma phosphorus levels per se did not stimulate FGF23 secretion as suggested previously (27).…”

Section: Resultssupporting

confidence: 82%

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Oral Phosphorus Supplementation Secondarily Increases Circulating Fibroblast Growth Factor 23 Levels at Least Partially via Stimulation of Parathyroid Hormone Secretion

Takasugi

Akutsu

Nagata

2014

J Nutr Sci Vitaminol

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Phosphorus is an essential nutrient for many biological functions, including cellular signal transduction, mineral metabolism, and energy exchange. On the other hand, a relatively high serum phosphorus level is reportedly a risk factor for cardiovascular disease (1, 2) because inorganic phosphates have been shown to stimulate differentiation of vascular smooth muscle cells into calcifying vascular cells (3). Therefore, serum phosphorus regulation may help to prevent cardiovascular diseases.Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that plays a regulatory role in phosphorus homeostasis. FGF23 has been shown to reduce serum phosphorus levels by inhibition of proximal tubular phosphorus reabsorption through decreased expression of types 2a and 2c sodium-phosphate cotransporters and by decreasing intestinal phosphorus absorption through inhibiting calcitriol synthesis in the kidney (4). Moreover, FGF23-null mice were shown to exhibit severe vascular calcification with concomitant hyperphosphatemia (5). These facts suggest that FGF23 may have a protective effect on vascular calcification by hyperphosphatemia suppression. In contrast, several hemodialysis studies reported that elevated FGF23 levels were associated with aortic calcification (6) and mortality (7, 8) independent of serum phosphorus levels. Elevated serum FGF23 levels, even within the normal range, are reportedly associated with increased left ventricular mass index and increased risk for the presence of left ventricular hypertrophy in elderly subjects (9). Furthermore, a recent study suggested that elevated FGF23 levels contributed directly to high rates of left ventricular hypertrophy and mortality in individuals with chronic kidney diseases (10). Thus, FGF23 regulation may also play a clinically significant role in the prevention of cardiovascular diseases.Oral phosphorus supplementation is known to stimulate FGF23 secretion, although the underlying mechanism has not been clarified. In our preliminary study, we found that plasma FGF23 levels in rats increased after oral phosphorus administration at a physiological dose; however, this increase slowly began around the time that plasma phosphorus levels had decreased (unpublished data). Based on these findings, we reasoned that oral phosphorus supplementation may secondarily increase FGF23 secretion. Parathyroid hormone (PTH) is also secreted in response to phosphorus administration (11) and subsequently increases urinary phosphorus excre- Note Oral Phosphorus Supplementation Secondarily Increases Circulating Fibroblast Growth Factor 23 Levels at Least Partially via Stimulation of Parathyroid Hormone SecretionSatoshi Takasugi, Miho Akutsu and Masashi Nagata Food Science Research Laboratories, Division of Research and Development, Meiji Co., Ltd., 540 Naruda, Odawara, Kanagawa 250-0862, Japan (Received August 20, 2013) Summary Oral phosphorus supplementation stimulates fibroblast growth factor 23 (FGF23) secretion; however, the underlying mechanism remains unclear. The aim of this ...

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Section: Resultssupporting

confidence: 82%

“…These reports collectively indicate that PTH may indirectly stimulate FGF23 secretion by stimulation of calcitriol synthesis. On the other hand, López et al (12) reported that PTH can also modify FGF23 under conditions in which calcitriol is controlled. Furthermore, PTH was reported to increase FGF23 mRNA levels in vitro (26).…”

Section: Resultsmentioning

confidence: 99%

Oral Phosphorus Supplementation Secondarily Increases Circulating Fibroblast Growth Factor 23 Levels at Least Partially via Stimulation of Parathyroid Hormone Secretion

Takasugi

Akutsu

Nagata

2014

J Nutr Sci Vitaminol

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“…We have previously observed in parathyroidectomized (PTX) rats with decreased serum levels of calcium and calcitriol that despite an increase in phosphorus levels, the concentration of FGF23 is below that in control intact rats. 12,13 We also have observed in PTX rats that replacement with calcitriol sufficient to normalize serum calcitriol levels resulted in normalization of FGF23. In an experimental model of primary hyperparathyroidism, FGF23 is increased, suggesting that PTH may directly increase FGF23 and may also increase FGF23 through stimulation of calcitriol.…”

mentioning

confidence: 81%

“…(B) The relationship between log-transformed serum FGF23 concentration and serum PTH concentration in the same groups of rats shown in A. normal diet: r that high PTH levels are not always associated with increased production of FGF23. In a previous study, 13 we observed in an experimental model of primary hyperparathyroidism in rats that high PTH was associated with hypercalcemia and high FGF23. In the present experiment, the excess of PTH was secondary to hypocalcemia.…”

Section: Discussionmentioning

confidence: 99%

“…In an experimental model of primary hyperparathyroidism, FGF23 is increased, suggesting that PTH may directly increase FGF23 and may also increase FGF23 through stimulation of calcitriol. 13 Our hypothesis is that because increased calcitriol values are necessary to correct hypocalcemia in conditions of calcium deficiency, a calcitriol-induced increase in FGF23 might be prevented when serum calcium levels are low. Therefore, our primary goal was to determine whether the calcium status affects FGF23 production.…”

mentioning

confidence: 99%

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Calcium Deficiency Reduces Circulating Levels of FGF23

Rodríguez‐Ortiz

López²,

Muñoz‐Castañeda³

et al. 2012

Journal of the American Society of Nephrology

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189

105

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Fibroblast growth factor (FGF) 23 inhibits calcitriol production, which could exacerbate calcium deficiency or hypocalcemia unless calcium itself modulates FGF23 in this setting. In Wistar rats with normal renal function fed a diet low in both calcium and vitamin D, the resulting hypocalcemia was associated with low FGF23 despite high parathyroid hormone (PTH) and high calcitriol levels. FGF23 correlated positively with calcium and negatively with PTH. Addition of high dietary phosphorus to this diet increased FGF23 except in rats with hypocalcemia despite high PTH levels. In parathyroidectomized rats, an increase in dietary calcium for 10 days increased serum calcium, with an associated increase in FGF23, decrease in calcitriol, and no change in phosphorus. Also in parathyroidectomized rats, FGF23 increased significantly 6 hours after administration of calcium gluconate. Taken together, these results suggest that hypocalcemia reduces the circulating concentrations of FGF23. This decrease in FGF23 could be a response to avoid a subsequent reduction in calcitriol, which could exacerbate hypocalcemia. 23: 119023: -119723: , 201223: . doi: 10.1681 Fibroblast growth factor (FGF) 23 production is stimulated by both calcitriol and phosphorus intake. FGF23 acts through FGFR-klotho receptors in the kidney to induce phosphaturia, a decrease in 1-a-hydroxylase activity, and an increase in 24-hydroxylase activity. The latter two effects decrease the synthesis and increase the degradation of calcitriol, respectively. 1-4 Parathyroid cells also possess FGFR-klotho receptors, and experimental studies have shown that FGF23 inhibits parathyroid hormone (PTH) production and secretion. [5][6][7] However, in uremic animals, hyperplastic parathyroid glands fail to respond to FGF23 because the expression of FGFR-klotho is downregulated. [7][8][9][10][11] FGF23 effectively increases the output and decreases the input of phosphorus because it directly increases phosphaturia and indirectly decreases intestinal phosphorus absorption by decreasing calcitriol values. However, a conflict will arise if high FGF23 inhibits calcitriol production in a setting of calcium deficiency/hypocalcemia, where high calcitriol is needed to increase intestinal calcium absorption. We have previously observed in parathyroidectomized (PTX) rats with decreased serum J Am Soc Nephrol

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Fibroblast growth factor (Fgf) 23 gene transcription depends on actin cytoskeleton reorganization

et al. 2016

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Edited by Lukas Alfons HuberThe consequence is a decrease in the plasma concentration of phosphate and 1,25(OH) 2 D 3 , the biologically active form of vitamin D. To mediate these renal effects, FGF23 requires aKlotho as a co-receptor [4,5].In addition, FGF23 is a powerful counteracter of aging. Mice deficient for FGF23 or for aKlotho suffer from rapid aging with a life span of a few weeks only and numerous age-related diseases [5,6]. The rapid aging is directly or indirectly dependent on the hyperphosphatemia of the mice as feeding them a low-phosphate or low-vitamin D diet greatly expands their life span [7].In contrast, excess FGF23 production due to FGF23-synthesizing tumors in men results in osteomalacia [8]. The regulation of FGF23 formation by bone cells has remained ill-defined. Among the known triggers of FGF23 expression are parathyroid hormone (PTH) [9][10][11], 1,25(OH) 2 D 3 [12,13] and increased dietary phosphorus intake [14,15]. Mutations of the dentin Abbreviations 1,25(OH) 2 D 3, calcitriol; Fgf, fibroblast growth factor; NFjB, nuclear factor kappa B; PI3, phosphoinositide-3; PTH, parathyroid hormone; PVDF, polyvinylidene fluoride; TNF, tumor necrosis factor; VDR, vitamin D receptor. 705FEBS Letters 590 (2016) 705-715 ª

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Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo

Cited by 132 publications

References 30 publications

Oral Phosphorus Supplementation Secondarily Increases Circulating Fibroblast Growth Factor 23 Levels at Least Partially via Stimulation of Parathyroid Hormone Secretion

Oral Phosphorus Supplementation Secondarily Increases Circulating Fibroblast Growth Factor 23 Levels at Least Partially via Stimulation of Parathyroid Hormone Secretion

Calcium Deficiency Reduces Circulating Levels of FGF23

Fibroblast growth factor (Fgf) 23 gene transcription depends on actin cytoskeleton reorganization

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