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: 8.56). 07/2008; 74(5):566-70. DOI: 10.1038/ki.2008.218
Source: PubMed


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
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    • "Klotho deficient mice (kl/kl) displayed increased serum levels of 1,25(OH)2D3 and widespread vascular and kidney calcifications [36], which was completely reversed when the 25-Hydroxyvitamin D3 1-alpha-hydroxylase (1α-hydroxylase, the enzyme which catalyzes the hydroxylation of calcidiol to calcitriol, the bioactive form of Vitamin D) was deleted [37]. It is also known that Pi is essential for the apoptosis of terminally differentiated hypertrophic chondrocytes in vivo [17], [38], and that high Pi led to apoptosis in osteoblasts [39] and in endothelial cells in vitro [40]. "
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    ABSTRACT: Dmp1 (dentin matrix protein1) null mice (Dmp1(-/-)) display hypophosphatemic rickets with a sharp increase in fibroblast growth factor 23 (FGF23). Disruption of Klotho (the obligatory co-receptor of FGF23) results in hyperphosphatemia with ectopic calcifications formed in blood vessels and kidneys. To determine the role of DMP1 in both a hyperphosphatemic environment and within the ectopic calcifications, we created Dmp1/Klotho compound deficient (Dmp1(-/-)kl/kl) mice. A combination of TUNEL, immunohistochemistry, TRAP, von Kossa, micro CT, bone histomorphometry, serum biochemistry and Scanning Electron Microscopy techniques were used to analyze the changes in blood vessels, kidney and bone for wild type control, Dmp1(-/-), Klotho deficient (kl/kl) and Dmp1(-/-)kl/kl animals. Interestingly, Dmp1(-/-)kl/kl mice show a dramatic improvement of rickets and an identical serum biochemical phenotype to kl/kl mice (extremely high FGF23, hyperphosphatemia and reduced parathyroid hormone (PTH) levels). Unexpectedly, Dmp1(-/-)kl/kl mice presented elevated levels of apoptosis in osteocytes, endothelial and vascular smooth muscle cells in small and large blood vessels, and within the kidney as well as dramatic increase in ectopic calcification in all these tissues, as compared to kl/kl. These findings suggest that DMP1 has an anti-apoptotic role in hyperphosphatemia. Discovering this novel protective role of DMP1 may have clinical relevance in protecting the cells from apoptosis in high-phosphate environments as observed in chronic kidney disease (CKD).
    Full-text · Article · Aug 2012 · PLoS ONE
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    • "Studies have shown that both FGF-23 and klotho knockout mice develop extensive vascular and soft tissue calcification [67, 68]. Serum calcium and 1,25 hydroxyvitamin D levels are also elevated in both Fgf23 and klotho ablated mice [69]. Moreover, increased sodium phosphate cotransporter activity in both Fgf23 and klotho ablated mice increases renal phosphate reabsorption which in turn can facilitate calcification [68]. "
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    ABSTRACT: Cardiovascular disease accounts over half of the total mortality in peritoneal dialysis (PD) patients. In addition, there is an increasing recognition of a high prevalence of vascular and valvular calcification that may contribute to the increased all-cause and cardiovascular mortality in the PD patients. Disturbed mineral metabolism in association with chronic kidney disease has been suggested as one of the major contributing factors to the increased vascular/valvular calcification in this population. In this paper, we provide an overview of the prevalence and importance of this complication in the PD patients. In addition, we review the contributing factors and some emerging mechanisms for this complication. Furthermore, we discuss some therapeutic strategies that may be useful in limiting the progression of vascular/valvular calcification in the PD population.
    Full-text · Article · Aug 2011
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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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    ABSTRACT: Fibroblast growth factor-23 (FGF23) is a hormone that modulates circulating phosphate (P(i)) levels by controlling P(i) reabsorption from the kidneys. When FGF23 levels are deficient, as in tumoral calcinosis patients, hyperphosphatemia ensues. We show here in a murine model that Fgf23 ablation disrupted morphology and protein expression within the dentoalveolar complex. Ectopic matrix formation in pulp chambers, odontoblast layer disruption, narrowing of periodontal ligament space, and alteration of cementum structure were observed in histological and electron microscopy sections. Because serum P(i) levels are dramatically elevated in Fgf23(-/-), we assayed for apoptosis and expression of members from the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, both of which are sensitive to elevated P(i) in vitro. Unlike X-linked hypophosphatemic (Hyp) and wild-type (WT) specimens, numerous apoptotic osteocytes and osteoblasts were detected in Fgf23(-/-) specimens. Further, in comparison to Hyp and WT samples, decreased bone sialoprotein and elevated dentin matrix protein-1 protein levels were observed in cementum of Fgf23(-/-) mice. Additional dentin-associated proteins, such as dentin sialoprotein and dentin phosphoprotein, exhibited altered localization in both Fgf23(-/-) and Hyp samples. Based on these results, we propose that FGF23 and (P(i)) homeostasis play a significant role in maintenance of the dentoalveolar complex.
    Full-text · Article · Jul 2010 · The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology
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