Fibroblast growth factor 23 production in bone is directly regulated by 1α,25-dihydroxyvitamin D, but not PTH

Saji, Fumie; Sügimura, Takashi; Sakaguchi, Toshifumi; Ohya, Masaki; Orita, Hikari; Maeda, Yuka; Ooura, Maki; Mima, Toru; Negi, Shigeo

doi:10.1152/ajprenal.00169.2010

Cited by 77 publications

(51 citation statements)

References 40 publications

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“…Some researchers reported that calcitriol stimulates FGF23 synthesis in the calvarium of rats (29) and increases circulating FGF23 levels in thyroparathyroidectomized rats (30). These reports collectively indicate that PTH may indirectly stimulate FGF23 secretion by stimulation of calcitriol synthesis.…”

Section: Resultsmentioning

confidence: 94%

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: Resultsmentioning

confidence: 94%

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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“…7) Regarding the regulatory mechanisms of Fgf23 gene expression, it has been shown that Fgf23 expression is directly induced in osteocytes by ligand-bound vitamin D receptor. 19) Recently, Meir et al reported that an orphan nuclear receptor, Nurr1 also mediates increased Fgf23 expression by parathyroid hormone. 20) In this report, we revealed that NF-κB, a common mediator of TLR signaling, is essential for Fgf23 induction at least in cultured DCs.…”

Section: Discussionmentioning

confidence: 99%

Expression of Fgf23 in Activated Dendritic Cells and Macrophages in Response to Immunological Stimuli in Mice

Masuda

Ohta

Morita

et al. 2015

Biological & Pharmaceutical Bulletin

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Fibroblast growth factors (Fgfs) are polypeptide growth factors with diverse biological activities. While several studies have revealed that Fgf23 plays important roles in the regulation of phosphate and vitamin D metabolism, the additional physiological roles of Fgf23 remain unclear. Although it is believed that osteoblasts/osteocytes are the main sources of Fgf23, we previously found that Fgf23 mRNA is also expressed in the mouse thymus, suggesting that it might be involved in the immune system. In this study we examined the potential roles of Fgf23 in immunological responses. Mouse serum Fgf23 levels were significantly increased following inoculation with Escherichia coli or Staphylococcus aureus or intraperitoneal injection of lipopolysaccharide. We also identified activated dendritic cells and macrophages that potentially contributed to increased serum Fgf23 levels. Nuclear factor-kappa B (NF-κB) signaling was essential for the induction of Fgf23 expression in dendritic cells in response to immunological stimuli. Moreover, we examined the effects of recombinant Fgf23 protein on immune cells in vitro. Fgfr1c, a potential receptor for Fgf23, was abundantly expressed in macrophages, suggesting that Fgf23 might be involved in signal transduction in these cells. Our data suggest that Fgf23 potentially increases the number in macrophages and induces expression of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine. Collectively, these data suggest that Fgf23 might be intimately involved in inflammatory processes.Key words fibroblast growth factor (Fgf); Fgf23; macrophage; dendritic cell; inflammationThe fibroblast growth factors (Fgfs) family consists of 22 polypeptide growth factors that are widely expressed in developing and adult tissues and regulate diverse biological processes, including angiogenesis, mitogenesis, cellular differentiation, and tissue repair. 1,2) Fgfs can be classified into three groups, canonical, intracellular, and hormone-like Fgfs. The canonical Fgfs bind to and activate Fgf receptors (Fgfrs) on the cell surface, resulting in the activation of several cytoplasmic signal transduction pathways. These canonical Fgfs function in a paracrine manner. The intracellular Fgfs act as intracellular signaling molecules in an Fgfr-independent manner. Hormone-like Fgfs, including Fgf15/19, Fgf21, and Fgf23, depends on Fgfrs to elicit biological responses, although they potentially function in an endocrine manner. 3) One of these hormone-like Fgfs, Fgf23, was originally identified in mice and humans by a DNA database search and was a well-known physiological regulator of phosphate and vitamin D metabolisms. [3][4][5][6] Fgf23 is produced by osteoblasts/osteocytes in response to 1,25-dihydroxyvitamine D, the biologically active form of vitamin D. 3,5,6) Secreted Fgf23 increases urinary phosphate excretion by reducing luminal expression of sodium-phosphate co-transporters in the proximal tubule. Secreted Fgf23 also attenuates systemic levels of 1,25-dihydroxyvitamine D, which stimulates phosphate...

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“…effect on fgf23 expression in bone cells (13,14), raising uncertainty as to whether PTH directly affects FGF23 synthesis at all. Further studies are needed to reconcile these results and to clarify the direct effects (1-34) PTH on FGF23 expression.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, continuous subcutaneous infusion of (1-34) PTH increased circulating FGF23 levels in mice and in parathyroidectomized rats (10,12). Notably, however, other studies showed opposite effects (13)(14)(15).…”

Section: Introductionmentioning

confidence: 96%

(1-34) Parathyroid Hormone Infusion Acutely Lowers Fibroblast Growth Factor 23 Concentrations in Adult Volunteers

Gutiérrez

Smith

Barchi-Chung

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Fibroblast growth factor 23 (FGF23) regulates phosphorus and vitamin D metabolism. Parathyroid hormone (PTH) infusion for 24 hours stimulated FGF23 secretion in healthy volunteers. The extent to which this was due to a direct stimulatory effect of PTH versus an indirect effect of increasing 1,25-dihydroxyvitamin D [1,25(OH) 2 D] levels was unclear.Design, setting, participants, & measurements Changes in FGF23 in 26 adults undergoing 6-hour (1-34) PTH infusion were examined, focusing particularly on the effects of PTH on FGF23 in the early period of infusion before sustained increases in 1,25(OH) 2 D.Results FGF23 levels declined in parallel with serum phosphate during infusion (P,0.05 for both), with both analytes decreasing within the first hour and reaching their respective nadirs at 6 hours. These changes were observed despite no change in 1,25(OH) 2 D levels during the first hour and a significant increase in 1,25(OH) 2 D from baseline after 6 hours (P,0.001). There were no differences in these responses by race. However, modest racial differences in the phosphaturic response to (1-34) PTH were observed (P=0.04 for interaction), with a higher rate of increase in fractional phosphate excretion in blacks than in whites.Conclusions During short-term (1-34) PTH infusion, FGF23 levels decreased in parallel with serum phosphate levels and despite significant increases in 1,25(OH) 2 D. When coupled with the results of prior longer-term infusion studies, these findings suggest that acute increases in PTH initially act to suppress FGF23 secretion, perhaps to mitigate urinary phosphate losses, before the stimulatory effect of 1,25(OH) 2 D on FGF23 eventually begins to predominate.

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Fibroblast growth factor 23 production in bone is directly regulated by 1α,25-dihydroxyvitamin D, but not PTH

Cited by 77 publications

References 40 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

Expression of Fgf23 in Activated Dendritic Cells and Macrophages in Response to Immunological Stimuli in Mice

(1-34) Parathyroid Hormone Infusion Acutely Lowers Fibroblast Growth Factor 23 Concentrations in Adult Volunteers

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