FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa

Shimada, Takashi; Urakawa, Itaru; Yamazaki, Y.; Higuchi, Hisashi; Hino, Rieko; Yoneya, Takashi; Takeuchi, Yasuhiro; Fujita, Toshiro; Fukumoto, Seiji; Yamashita, Takefumi

doi:10.1016/j.bbrc.2003.12.102

Cited by 399 publications

(295 citation statements)

References 23 publications

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“…Transgenic mice over-expressing FGF-23 exhibit hypophosphatemia, with no significant changes in serum levels of calcium (Bai et al, 2004;Larsson et al, 2004;Shimada et al, 2004b), while an opposing effect of high serum levels of phosphate, and increased vitamin D activities are documented in Fgf-23 null mice (Shimada et al, 2004a;Sitara et al, 2004). More importantly, the phenotype of Fgf-23 null animals mimics patients with familial tumoral calcinosis (FTC), an autosomal recessive disorder characterized by ectopic calcifications and elevated serum levels of phosphate due to inactivating mutations in the FGF-23 gene (Benet-Pages et al, 2005;Frishberg et al, 2006).…”

Section: Fibroblast Growth Factor 23mentioning

confidence: 99%

Premature aging in klotho mutant mice: Cause or consequence?

Lanske¹,

Razzaque²

2007

Ageing Research Reviews

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Suitable mammalian models for aging with wide range of age-associated pathology are desirable to study molecular mechanisms of human aging. Recent studies have identified that fibroblast growth factor 23 (Fgf-23) null mice and klotho hypomorphs could generate multiple premature aging-like features, including shortened lifespan, infertility, kyphosis, atherosclerosis, extensive soft tissue calcifications, skin atrophy, muscle wasting, T-cell dysregulation, pulmonary emphysema, osteoporosis/osteopenia, abnormal mineral ion metabolism, and impaired vitamin-D homeostasis. The strikingly similar in vivo phenotypes of two separate genetically altered mouse lines implicate that the premature aging-like features may be partly regulated through a common signaling pathway involving both Fgf-23 and klotho; such speculation is experimentally supported by the observation that Fgf-23 requires klotho as a cofactor to exert its functions. Despite about 2,000 fold higher serum levels of Fgf-23 in klotho mutants (compared to wild-type animals), these mice show physical, biochemical and morphological features similar to Fgf-23 null mice, but not as Fgf-23 transgenic mice; these observations suggest that widely encountered premature aging-like features in klotho mutant mice are due to the inability of Fgf-23 to exert its bioactivities in absence of klotho. The results of recent studies showing klotho as a cofactor in Fgf-23 signaling consequently explains that the premature aging-like features in klotho deficient mice is not a primary cause, rather a consequence of lacking Fgf-23 activity. These understandings will help us to redefine the role of klotho as an aging factor. Keywords FGF-23; Kotho; Vitamin-D; Calcification; Premature aging Phosphate homeostasisMaintaining phosphate homeostasis is of crucial biological importance, as it regulates fundamental cellular functions and skeletal mineralization; it is also an important component of nucleic acids, biologically active signaling proteins, coenzymes, and lipid bilayer of the cell membranes. Ingested phosphate is mostly absorbed in the small intestine and is either incorporated in cells in organic forms, deposited as a component of bone mineral, or eliminated by the kidney; the rate of renal reabsorption and/or excretion is determined by the specific needs of the body.Roughly 70% of the phosphate is absorbed in the duodenum and jejunum, through a sodiumdependent active transport, a process stimulated by 1,25-dihydroxyvitamin D 3 [1,25 (OH) 2 D 3 ]; besides parathyroid hormone (PTH) and low-phosphate diets can also stimulate Corresponding authors: Tel.

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Section: Fibroblast Growth Factor 23mentioning

confidence: 99%

Premature aging in klotho mutant mice: Cause or consequence?

Lanske¹,

Razzaque²

2007

Ageing Research Reviews

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“…For instance, FGF23 knockout mice develop severe hyperphosphatemia owing to increased renal reabsoption of phosphate, 26,27 whereas FGF23-overproducing transgenic mice or Hyp mice are hypophosphatemic owing to excessive urinary phosphate excretion. 28,29 Such FGF23-mediated hypophosphatemia is an alpha-klotho-dependent phenomenon, and miscommunication of FGF23 and alpha-klotho can lead to dysregulation of renal phosphate homeostasis. 1,14,30,31 Renal Phosphate Regulation Under normal physiologic conditions, the kidneys maintain serum phosphate balance by fine-tuning urinary phosphate excretion.…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity

Brown

2015

BoneKEy Reports

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Phosphate homeostasis is coordinated and regulated by complex cross-organ talk through delicate hormonal networks. Parathyroid hormone (PTH), secreted in response to low serum calcium, has an important role in maintaining phosphate homeostasis by influencing renal synthesis of 1,25-dihydroxyvitamin D, thereby increasing intestinal phosphate absorption. Moreover, PTH can increase phosphate efflux from bone and contribute to renal phosphate homeostasis through phosphaturic effects. In addition, PTH can induce skeletal synthesis of another potent phosphaturic hormone, fibroblast growth factor 23 (FGF23), which is able to inhibit renal tubular phosphate reabsorption, thereby increasing urinary phosphate excretion. FGF23 can also fine-tune vitamin D homeostasis by suppressing renal expression of 1-alpha hydroxylase (1a(OH)ase). This review briefly discusses how FGF23, by forming a bone-kidney axis, regulates phosphate homeostasis, and how its dysregulation can lead to phosphate toxicity that induces widespread tissue injury. We also provide evidence to explain how phosphate toxicity related to dietary phosphorus overload may facilitate incidence of noncommunicable diseases including kidney disease, cardiovascular disease, cancers and skeletal disorders.

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“…24 In contrast, transgenic mice with increased FGF-23 expression had decreased serum P, increased urinary excretion of P and reduced levels of Na-P cotransporters. 25,26 Later studies have assessed the role of P overload in the regulation of FGF-23 levels. In vitro studies with osteoblast-like cells have shown that P overload stimulated the FGF-23 synthesis by those cells.…”

Section: Functions Of Fgf-23mentioning

confidence: 99%

FGF-23: estado da arte

Oliveira

Moysés

2010

J. Bras. Nefrol.

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Approximately 10 years ago, a member of the family of the fibroblast growth factors, the hormone FGF-23 (fibroblast growth factor 23) was discovered. Its currently known functions involve phosphorus (P) metabolism and inhibition of 1α hydroxylase, the enzyme responsible for the synthesis of calcitriol. That discovery led to a better understanding of the mechanisms of P control, an element associated with mortality, especially in chronic kidney disease. This study reviews several aspects of that hormone, such as its discovery, function, production, mechanism of action, and the most recent clinical studies about it. Afterwards, a discussion about the possible effects of those studies on clinical practice will be presented.

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FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa

Cited by 399 publications

References 23 publications

Premature aging in klotho mutant mice: Cause or consequence?

Premature aging in klotho mutant mice: Cause or consequence?

Dysregulation of phosphate metabolism and conditions associated with phosphate toxicity

FGF-23: estado da arte

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