Does Fgf23-klotho activity influence vascular and soft tissue calcification through regulating mineral ion metabolism?

Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
Kidney International (Impact Factor: 8.52). 07/2008; 74(5):566-70. DOI: 10.1038/ki.2008.218
Source: PubMed

ABSTRACT Recent studies describe a novel role of fibroblast growth factor-23 (Fgf23)-klotho activity in the systemic regulation of calcium and phosphate homeostasis. Both Fgf23 and klotho ablated mice develop extensive vascular and soft tissue calcification. Inability to clear the required amount of phosphate by the kidney, due to the absence of Fgf23-klotho activity, leads to increased accumulation of serum phosphate in these genetically modified mice, causing extensive calcification. Serum calcium and 1,25 hydroxyvitamin D levels are also elevated in both Fgf23 and klotho ablated mice. Moreover, increased sodium phosphate co-transporter activity in both Fgf23 and klotho ablated mice increases renal phosphate reabsorption which in turn can facilitate calcification. Collectively, these observations bring new insights into our understanding of the roles of the Fgf23-klotho axis in the development of vascular and soft tissue calcification.

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Available from: Mohammed Shawkat Razzaque, Jul 18, 2015
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    • "Further, Klotho −/− mice exhibit a nearly identical physical and biochemical phenotype to Fgf23 −/− mice (e.g. elevated P i and 1,25(OH) 2 D 3 levels) although Fgf23 levels in Klotho −/− mice are elevated (Kuro-o et al., 1997; Kuro-o, 2006; Memon et al., 2008). The dental aberrations noted in Fgf23 −/− mice were similar to reports of increased apoptotic reactions and marked disturbances in odontoblasts, predentin, and dentin of incisors in Klotho −/− mice (Suzuki et al., 2005). "
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    • "LET-756 is required in muscle, suggesting that LET-756 is secreted from the muscle and acts in a paracrine manner to signal to EGL-15 in the adjacent hypodermal tissue. In mammals, FGF23- FGFR-klotho signaling has been shown to regulate ion homoeostasis not only in bone, but also in the kidney , which is the major organ to maintain fluid balance and ion homeostasis (reviewed in Kuro-o, 2006; Razzaque and Lanske, 2007; Memon et al., 2008; Nabeshima, 2008). This suggests that the hormonal functions of FGFR signaling may be evolutionarily conserved between nematodes and mam- mals. "
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    ABSTRACT: A major breakthrough in systemic phosphate homeostasis regulation was achieved by the demonstration of strikingly similar physical, morphological, and biochemical phenotypes of fibroblast growth factor 23 (Fgf23) and klotho ablated mice, which led to identification of klotho as an Fgf23 signaling cofactor. Here, we generated Fgf23 and klotho double-knockout (Fgf23(-/-)/klotho(-/-)) mice to test the hypothesis whether Fgf23 has a klotho-independent function. Fgf23(-/-)/klotho(-/-) mice are viable and have high serum phosphate levels, similar to Fgf23(-/-) and klotho(-/-) single-knockout mice. In addition, the Fgf23(-/-)/klotho(-/-) mice have increased renal expression of the sodium/phosphate cotransporter NaP(i)2a and of 1- alpha-hydroxylase concomitant with increased serum levels of 1,25-dihydroxyvitamin-D, as also observed in the Fgf23(-/-) and klotho(-/-) mice. Moreover, Fgf23(-/-)/klotho(-/-) mice show soft tissue and vascular calcification, severe muscle wasting, hypogonadism, pulmonary emphysema, distention of intestinal wall, and skin atrophy, all of which are also seen in Fgf23(-/-) and klotho(-/-) mice. Notably, injection of bioactive FGF23 protein into Fgf23(-/-)/klotho(-/-) and klotho(-/-) mice does not lower serum phosphate, whereas in wild-type and Fgf23(-/-) mice, it reduces serum phosphate. Together, these results provide compelling evidence that Fgf23 does not have a klotho-independent role in the regulation of systemic phosphate and vitamin D homeostasis.
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