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/jci200419081

Cited by 1,282 publications

(603 citation statements)

References 24 publications

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“…Other down‐regulating factors that are present in CKD patients include low availability of 25(OH)D, hyperphosphatemia, metabolic acidosis, and uraemia itself. Additionally, elevated FGF23 activates the enzyme 24‐hydroxylase (CYP24), hydroxylating both 25(OH)D and 1,25(OH) 2 D. 24‐hydroxylase limits the amount of 1,25(OH) 2 D in target tissues both by producing 24,25(OH) 2 D (thus decreasing the availability of 25(OH)D for 1 hydroxylation) or by accelerating the catabolism of 1,25(OH) 2 D to 1,24,25(OH) 3 D resulting in calcitroic acid, which is biologically inactive 76, 77. CKD is also considered as a state of vitamin D resistance, because VDR expression in bone cells and in nodular parathyroid glands is reduced 78.…”

Section: Vitamin D Metabolism In Chronic Kidney Diseasementioning

confidence: 99%

Vitamin D, a modulator of musculoskeletal health in chronic kidney disease

Molina

Carrero

Bover

et al. 2017

J cachexia sarcopenia muscle

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The spectrum of activity of vitamin D goes beyond calcium and bone homeostasis, and growing evidence suggests that vitamin D contributes to maintain musculoskeletal health in healthy subjects as well as in patients with chronic kidney disease (CKD), who display the combination of bone metabolism disorder, muscle wasting, and weakness. Here, we review how vitamin D represents a pathway in which bone and muscle may interact. In vitro studies have confirmed that the vitamin D receptor is present on muscle, describing the mechanisms whereby vitamin D directly affects skeletal muscle. These include genomic and non‐genomic (rapid) effects, regulating cellular differentiation and proliferation. Observational studies have shown that circulating 25‐hydroxyvitamin D levels correlate with the clinical symptoms and muscle morphological changes observed in CKD patients. Vitamin D deficiency has been linked to low bone formation rate and bone mineral density, with an increased risk of skeletal fractures. The impact of low vitamin D status on skeletal muscle may also affect muscle metabolic pathways, including its sensitivity to insulin. Although some interventional studies have shown that vitamin D may improve physical performance and protect against the development of histological and radiological signs of hyperparathyroidism, evidence is still insufficient to draw definitive conclusions.

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Section: Vitamin D Metabolism In Chronic Kidney Diseasementioning

confidence: 99%

Vitamin D, a modulator of musculoskeletal health in chronic kidney disease

Molina

Carrero

Bover

et al. 2017

J cachexia sarcopenia muscle

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“…Excitingly, results from other recent studies have indicated that osteocyte-derived fibroblast growth factor 23 (FGF23) functions in an endocrine manner. Since its identification in 2000, FGF23 has been shown be most highly expressed in bone (osteocyte), acting as an important hormone in regulating serum phosphate levels primarily via actions on the kidney (Shimada et al 2004) (reviewed in Bonewald & Wacker (2013)). In addition to the role of FGF23 in phosphate homoeostasis and bone mineralisation, the PHEX, DMP1, FGF23, KLOTHO and the MEPE/ASARM peptide axis has been demonstrated to be involved in the regulation of energy metabolism via the bone (David et al 2009a,b).…”

Section: Osteocyte and Energymentioning

confidence: 99%

Endocrine role of bone: recent and emerging perspectives beyond osteocalcin

Oldknow

MacRae

Farquharson

2015

Journal of Endocrinology

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Recent developments in endocrinology, made possible by the combination of mouse genetics, integrative physiology and clinical observations have resulted in rapid and unanticipated advances in the field of skeletal biology. Indeed, the skeleton, classically viewed as a structural scaffold necessary for mobility, and regulator of calcium-phosphorus homoeostasis and maintenance of the haematopoietic niche has now been identified as an important regulator of male fertility and whole-body glucose metabolism, in addition to the classical insulin target tissues. These seminal findings confirm bone to be a true endocrine organ. This review is intended to detail the key events commencing from the elucidation of osteocalcin (OC) in bone metabolism to identification of new and emerging candidates that may regulate energy metabolism independently of OC.Key WordsJournal of Endocrinology (2015) 225, R1-R19

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“…The clue to understand Klotho protein function was the fact that FGF23-deficient mice and Klothodeficient mice develop identical phenotypes consisting of premature-aging syndrome and hyperphosphatemia (7,8).…”

Section: Introductionmentioning

confidence: 99%

The effect of GH treatment on serum FGF23 and Klotho in GH-deficient children

Efthymiadou

Kritikou

Mantagos

et al. 2016

European Journal of Endocrinology

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Background: Normal phosphate homeostasis is essential for normal linear growth. The phosphaturic fibroblast growth factor 23 (FGF23)/Klotho axis is a major regulator of phosphate homeostasis; therefore, an intact FGF23/Klotho axis is important for normal linear growth. On the other hand, GH/IGF1 axis has opposing effects on phosphate homeostasis, but the underline mechanisms remain unclear. Aim: The main objective of this study was to investigate the possible interactions of FGF23 and its co-receptor Klotho, with growth hormone (GH)/IGF1 axis in the regulation of phosphate metabolism in GH-deficient children under GH treatment. Methods: We studied 23 GH-deficient children, before and 3 months after the onset of GH treatment. Anthropometry and assessment of biochemical parameters were performed, as well as measurement of FGF23 (intact FGF23/iFGF23 and C-terminal FGF23/cFGF23) and soluble a-Klotho (sKlotho) levels. Results: After 3 months on GH treatment, the elevation of serum phosphate and TmPO4/GFR (P!0.0001 and P!0.01 respectively) was accompanied by a significant increase in cFGF23 (P!0.01), iFGF23 (P!0.0001), sKlotho (P!0.0001) and IGF1 (P!0.0001). Serum phosphate and TmPO4/GFR were positively associated with iFGF23 (P!0.01 and P!0.05) and IGF1 (P!0.05 and P!0.05). iFGF23 levels were positively correlated with sKlotho (P!0.001), IGF1 (P!0.0001) and height SDS (P!0.0001), whereas sKlotho was positively associated with IGF1 (P!0.0001) and height SDS (P!0.001). Conclusion: The increase in serum phosphate, which we found in GH-deficient children under GH treatment, is not associated with suppression but rather than with upregulation of the phosphaturic FGF23/Klotho axis.

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

Cited by 1,282 publications

References 24 publications

Vitamin D, a modulator of musculoskeletal health in chronic kidney disease

Vitamin D, a modulator of musculoskeletal health in chronic kidney disease

Endocrine role of bone: recent and emerging perspectives beyond osteocalcin

The effect of GH treatment on serum FGF23 and Klotho in GH-deficient children

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