Minireview: Fibroblast Growth Factor 23 in Phosphate Homeostasis and Bone Metabolism

Hori, Michiko; Shimizu, Yuichiro; Fukumoto, Seiji

doi:10.1210/jcem.96.1.9992

Cited by 5 publications

(9 citation statements)

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“…FGF23 is thought to regulate serum phosphorus by inhibiting renal expression of the sodium‐phosphate co‐transporter IIa (NaPi2a), thereby enhancing renal phosphorus excretion. FGF23 is also stimulated by calcitriol, PTH, and high serum phosphorus, and inhibited by hypocalcemia and hypophosphatemia . Because WT and Pth ‐null mice displayed marked differences in serum calcitriol, PTH, calcium, and phosphorus during the reproductive cycle, we measured intact FGF23 at each time point (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Upregulation of calcitriol during pregnancy and skeletal recovery after lactation do not require parathyroid hormone

Kirby

Martin

et al. 2013

Journal of Bone and Mineral Research

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Pregnancy invokes a doubling of intestinal calcium absorption whereas lactation programs skeletal resorption to provide calcium to milk. Postweaning bone formation restores the skeleton's bone mineral content (BMC), but the factors that regulate this are not established. We used Pth-null mice to test whether parathyroid hormone (PTH) is required for postweaning skeletal recovery. On a normal 1% calcium diet, wild-type (WT) and Pth-null mice each gained BMC during pregnancy, declined 15% to 18% below baseline during lactation, and restored the skeleton above baseline BMC within 14 days postweaning. A 2% calcium diet reduced the lactational decline in BMC without altering the gains achieved during pregnancy and postweaning. The hypocalcemia and hyperphosphatemia of Pth-null mice normalized during lactation and serum calcium remained normal during postweaning. Osteocalcin and propeptide of type 1 collagen (P1NP) each rose significantly after lactation to similar values in WT and Pth-null. Serum calcitriol increased fivefold during pregnancy in both genotypes whereas vitamin D binding protein levels were unchanged. Absence of PTH blocked a normal rise in fibroblast growth factor-23 (FGF23) during pregnancy despite high calcitriol. A 30-fold higher expression of Cyp27b1 in maternal kidneys versus placenta suggests that the pregnancy-related increase in calcitriol comes from the kidneys. Conversely, substantial placental expression of Cyp24a1 may contribute significantly to the metabolism of calcitriol. In conclusion, PTH is not required to upregulate renal expression of Cyp27b1 during pregnancy or to stimulate recovery from loss of BMC caused by lactation. A calcium-rich diet in rodents suppresses skeletal losses during lactation, unlike clinical trials that showed no effect of supplemental calcium on lactational decline in BMC.

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Section: Resultsmentioning

confidence: 99%

“…FGF23 regulates serum phosphorus mainly by increasing renal phosphorus excretion and decreasing calcitriol synthesis; it also inhibits PTH expression . More specifically, it suppresses NaPi2a and NaPi2c expression in proximal kidney tubules, decreases expression of renal Cyp27b1 , and enhances expression of Cyp24a1 .…”

Section: Discussionmentioning

confidence: 99%

Upregulation of calcitriol during pregnancy and skeletal recovery after lactation do not require parathyroid hormone

Kirby

Martin

et al. 2013

Journal of Bone and Mineral Research

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“…Results revealed that pth4 ‐Tg fish had a significant ( P < 0.05) up‐regulation of the solute carrier family 34 type II sodium/ phosphate cotransporter member 2b gene (slc34a2b, npt2b) but a significant ( P < 0.01) down‐regulation of a set of phosphate‐regulating genes, including the endopeptidase on the X chromosome (phex), ectonucleoside triphosphate diphosphohydrolase 5 (entpd5), and solute carrier family 34 type II sodium/phosphate cotransporter member 1a (slc34a1a, npt2a). Notably, the down‐regulation of npt2a was accompanied by a significant ( P < 0.025) up‐regulation of fgf23, which has been described as a key regulator of phosphate homeostasis (44). Finally, no significant differences were found on stanniocalcin‐1‐like (stc1l) gene expression levels.…”

Section: Resultsmentioning

confidence: 99%

“…Our analysis of factors involved in the regulation of phosphate levels revealed that pth4 overexpression induced a significant increase in fgf23 and npt2b levels and a decrease in npt2a, phospho1, phex, and entpd5 expression levels. FGF23 is a key phosphaturic factor that acts in the bone‐kidney axis in mammals and provides a signal from bone to adjust phosphate fluxes through NPT2a in kidney by promoting phosphate excretion or reabsorption (44, 54). In addition, systemic phosphate levels are managed by NPT2b through active transport in the small intestine (55).…”

Section: Discussionmentioning

confidence: 99%

Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain‐to‐bone signaling pathway

et al. 2016

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Regulation of bone development, growth, and remodeling traditionally has been thought to depend on endocrine and autocrine/paracrine modulators. Recently, however, brain-derived signals have emerged as key regulators of bone metabolism, although their mechanisms of action have been poorly understood. We reveal the existence of an ancient parathyroid hormone (Pth)4 in zebrafish that was secondarily lost in the eutherian mammals' lineage, including humans, and that is specifically expressed in neurons of the hypothalamus and appears to be a central neural regulator of bone development and mineral homeostasis. Transgenic fish lines enabled mapping of axonal projections leading from the hypothalamus to the brainstem and spinal cord. Targeted laser ablation demonstrated an essential role for of pth4-expressing neurons in larval bone mineralization. Moreover, we show that Runx2 is a direct regulator of pth4 expression and that Pth4 can activate cAMP signaling mediated by Pth receptors. Finally, gain-of-function experiments show that Pth4 can alter calcium/phosphorus levels and affect expression of genes involved in phosphate homeostasis. Based on our discovery and characterization of Pth4, we propose a model for evolution of bone homeostasis in the context of the vertebrate transition from an aquatic to a terrestrial lifestyle.-Suarez-Bregua, P., Torres-Nuñez, E., Saxena, A., Guerreiro, P., Braasch, I., Prober, D. A., Moran, P., Cerda-Reverter, J. M., Du, S. J., Adrio, F., Power, D. M., Canario, A. V. M., Postlethwait, J. H., Bronner, M E., Cañestro, C., Rotllant, J. Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain-to-bone signaling pathway.

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“…The discovery that fibroblast growth factor 23 (FGF23), a member of FGF family, mediates the combined renal tubular defects in phosphate reabsorption and altered vitamin D metabolism has given a new light to understand its role in hypophosphatemic disorders [2,3 & ,4 & ]. Indeed, these disorders may be caused by mutations of genes involved in the complex regulation of phosphate metabolism.…”

Section: Introductionmentioning

confidence: 99%

Hypophosphatemic rickets

Baroncelli

Toschi

Bertelloni

2012

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Minireview: Fibroblast Growth Factor 23 in Phosphate Homeostasis and Bone Metabolism

Cited by 5 publications

References 0 publications

Upregulation of calcitriol during pregnancy and skeletal recovery after lactation do not require parathyroid hormone

Upregulation of calcitriol during pregnancy and skeletal recovery after lactation do not require parathyroid hormone

Pth4, an ancient parathyroid hormone lost in eutherian mammals, reveals a new brain‐to‐bone signaling pathway

Hypophosphatemic rickets

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