Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism

Shimada, Takashi; Kakitani, Makoto; Yamazaki, Y.; Higuchi, Hisashi; Takeuchi, Yasuhiro; Fujita, Toshiro; Fukumoto, Seiji; Tomizuka, Kazuma; Yamashita, Takefumi

doi:10.1172/jci19081

Cited by 709 publications

(656 citation statements)

References 30 publications

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“…Most canonical FGFs have essential roles as proliferation or differentiation factors in the development of various organs and tissues. In contrast, hFGFs have important roles as hormones that regulate bile acid metabolism, phosphate and vitamin D metabolism, and energy metabolism at postnatal stages (Shimada et al, 2004;Inagaki et al, 2005;Inagaki et al, 2007;Badman et al, 2007). Several of the Fgfs that exhibit early embryonic lethality as null mutations have also been studied later in development by conditional gene targeting and have been found to have many additional activities.…”

Section: Perspectivesmentioning

confidence: 99%

Functional evolutionary history of the mouse Fgf gene family

Itoh

Ornitz

2007

Developmental Dynamics

353

313

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Section: Perspectivesmentioning

confidence: 99%

Functional evolutionary history of the mouse Fgf gene family

Itoh

Ornitz

2007

Developmental Dynamics

353

313

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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%

“…Both Fgf-23 null and klotho mutant mice have shown to have increased renal expression of the 1α(OH)ase gene, accompanied by elevated serum levels of active vitamin-D, 1,25(OH) 2 D 3 (Shimada et al, 2004a;Sitara et al, 2004;Sitara et al, 2006;Tsujikawa et al, 2003); a significant rescue of premature aging-like features has been achieved by either reducing vitamin-D activities or genetically ablating vitamin-D activities from Fgf-23 null and klotho mutant mice Tsujikawa et al, 2003). Reducing vitamin-D activities in klotho ablated mice by feeding a vitamin-D deficient diet has resulted, not only in disappearance of ectopic calcifications, but also in gain of fertility, and most importantly prolonged survival; these observations suggest that the premature aging-like features in klotho mutant mice are downstream events resulting from increased activity of vitamin-D (Tsujikawa et al, 2003).…”

Section: Effects Of Fgf-23 or Klotho Ablation On Vitamin-d Homeostasimentioning

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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“…(1)(2)(3) We recently demonstrated that FGF23 elevates levels of membrane-associated klotho in the kidney, as well as free klotho in serum, suggesting that the kidney is a major source of soluble klotho. (2) This notion is supported by the observations that serum klotho levels decline as renal function worsens.…”

Section: Introductionmentioning

confidence: 99%

Xeno-Klotho Inhibits Parathyroid Hormone Signaling

Takenaka

Inoue

Miyazaki

et al. 2015

Journal of Bone and Mineral Research

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Although fibroblast growth factor (FGF) 23 was recently identified as a phosphatonin that influences vitamin D metabolism, the underlying signaling mechanisms remain unclear. FGF23 elevates the renal levels of membrane-associated klotho as well as soluble klotho. Klotho is expressed on distal tubules. Upon enzymatic cleavage, soluble klotho is released into the renal interstitial space and then into the systemic circulation. The expression of 25-hydroxyvitamin D 3 1a-hydroxylase (1-OH) on proximal tubular cells is controlled by parathyroid hormone (PTH). Klotho binds to various membrane proteins to alter their function. Here, the interaction between the PTH receptor and klotho was studied using various approaches, including immunoprecipitation, in vitro cell culture, and in vivo animal experiments. Immunoprecipitation studies demonstrate, for the first time, that recombinant human klotho protein interacts with human PTH receptors to inhibit the binding of human PTH. Furthermore, when applied to human proximal tubular cells, recombinant human klotho suppresses PTH-stimulated generation of inositol trisphosphate in vitro. Moreover, PTHinduced increase of cyclic AMP secretion and 1a,25-dihydroxyvitamin D 3 (1,25VD) was attenuated by recombinant human klotho in vivo. In addition, recombinant human klotho inhibits the expression of 1-OH by PTH both in vitro and in vivo. These results suggest that free klotho mediates the FGF23-induced inhibition of 1,25VD synthesis.

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Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism

Cited by 709 publications

References 30 publications

Functional evolutionary history of the mouse Fgf gene family

Functional evolutionary history of the mouse Fgf gene family

Premature aging in klotho mutant mice: Cause or consequence?

Xeno-Klotho Inhibits Parathyroid Hormone Signaling

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