Plasma Fibroblast Growth Factor 21 Levels Research Articles

Loss-of-Function ENPP1 Mutations Cause Both Generalized Arterial Calcification of Infancy and Autosomal-Recessive Hypophosphatemic Rickets

The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis; for example, fibroblast growth factor 23 (FGF23), which inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Here, we report presumable loss-of-function mutations in the ENPP1 gene (ectonucleotide pyrophosphatase/phosphodiesterase) in members of four families affected with hypophosphatemic rickets. We provide evidence for the conclusion that ENPP1 is the fourth gene-in addition to PHEX, FGF23, and DMP1-that, if mutated, causes hypophosphatemic rickets resulting from elevated FGF23 levels. Surprisingly, ENPP1 loss-of-function mutations have previously been described in generalized arterial calcification of infancy, suggesting an as yet elusive mechanism that balances arterial calcification with bone mineralization.

Effects of rosiglitazone on fasting plasma fibroblast growth factor-21 levels in patients with type 2 diabetes mellitus

Fibroblast growth factor-21 (FGF-21) has recently been characterized as a potent metabolic regulator, but its pathophysiologic roles in humans remain unknown. This study aimed to investigate the effects of rosiglitazone on plasma FGF-21 levels in patients with type 2 diabetes mellitus (T2DM). Thirty patients with new-onset T2DM (nT2DM), 34 type 2 diabetic patients with poor glycemic control (pT2DM) after the treatment with single hypoglycemic agent metformin, and 30 sex- and age-matched normal glycaemic controls (NGT) participated in the study. The pT2DM group was treated with rosiglitazone for 12 weeks. Plasma FGF-21 levels were measured with a RIA. The relationship between plasma FGF-21 levels and metabolic parameters was also analyzed. Fasting plasma FGF-21 levels were higher in nT2DM and pT2DM groups than in the control (1.81+/-0.64 vs 1.87+/-0.63 vs 1.52+/-0.61 microg/l, P<0.05), but there was no difference between nT2DM and pT2DM groups. Fasting plasma FGF-21 levels were decreased significantly in pT2DM group after the treatment with rosiglitazone compared with pre-treatment (1.59+/-0.63 vs 1.87+/-0.64 micro/l, P<0.05). In all diabetic patients, multiple regression analysis showed that HbA1c, fasting insulin, and homeostasis model assessment-insulin resistance index were independently associated with plasma FGF-21 levels. In pT2DM patients, plasma FGF-21 levels are increased, but significantly decreased after the treatment with rosiglitazone on top of ongoing metformin therapy. These data suggest that rosiglitazone may play a role in lowering FGF-21 levels in T2DM patients.

Regulation of Fibroblast Growth Factor 23 Production in Bone in Uremic Rats

Background: Fibroblast growth factor 23 (FGF23) regulates renal phosphate reabsorption and 1α,25-dihydroxyvitamin D [1,25(OH)₂D₃] metabolism. Patients with chronic kidney disease (CKD) have increased levels of circulating FGF23, but the direct regulation of this elevation of FGF23 is incompletely understood. Method:We measured plasma parameters in uremic rats fed a high-phosphorus diet and then performed parathyroidectomy (PTX) to determine its effect. We also investigated FGF23 mRNA expression in various tissues to identify the major source of circulating FGF23. Result: The uremic rats displayed dramatic changes in plasma FGF23 levels, consistent with increased expression of FGF23 in bone. Elevated FGF23 was associated with phosphate and parathyroid hormone (PTH). After PTX, the elevated FGF23 had decreased, consistent with decreased expression of FGF23 in bone. Significant decreases in plasma FGF23 were associated with PTH and 1,25(OH)₂D₃, but not phosphate. Conclusion: Elevated plasma FGF23 levels in uremic rats reflect the increased expression of FGF23 in bone. The expression of FGF23 in bone may be regulated by a PTH-1,25(OH)₂D₃ axis-dependent pathway and another PTH-dependent and 1,25(OH)₂D₃-independent pathway in uremic rats. The pathway may be decided by the degree of renal dysfunction.

Fibroblast Growth Factor 23 and Matrix-Metalloproteinases in Patients with Chronic Kidney Disease: Are They Associated with Cardiovascular Disease?

Background: High cardiovascular risk in patients with chronic kidney disease (CKD) may be related to mineral disorder and microinflammation. Fibroblast growth factor 23 (FGF-23) is a phosphatonin and inhibitor of calcitriol synthesis, which is associated with poor prognosis in CKD patients starting dialysis. Matrix-metalloproteinases (MMP-2, MMP-9) contribute to myocardial remodeling and arterial calcification. FGF-23 and MMPs levels are altered in CKD, however, little is known about their association and relation to cardiovascular (CV) disease. Methods: Standard laboratory parameters, plasma levels of MMP-2, MMP-9, FGF-23, PAPP-A and CV disease history were assessed in 80 patients with CKD 1–5 and 44 healthy control subjects. Results: FGF-23 and MMP-2 (assessed by ELISA) were higher in CKD patients compared to controls. FGF-23 increased from CKD 3, whereas MMP-2 increased only in CKD 5. FGF-23 was positively associated with MMP-2, adjusted to age, eGFR, phosphatemia, calcitriol and parathormone. FGF-23 independently correlated with parathormone and inversely with calcitriol, whereas MMP-2 was related to phosphatemia. FGF-23 was higher in subjects with a history of CV disease compared to those free of such history (559.0 vs.184.0 RU/ml), adjusted to age and eGFR. Conclusion: Our data suggest a possible relationship between FGF-23, MMP-2 and CV disease in CKD. Potential causality of this association remains to be elucidated.

Alpha Klotho and inorganic phosphate metabolism

Recent studies have demonstrated that klotho protein plays a role in calcium/phosphate homeostasis. Urakawa et al demonstrated that the concerted action of klotho and fibroblast growth factor receptor 1 reconstitutes the fibroblast growth factor 23 (FGF23) receptor (Nature 444,770,2006). We investigated the correlation between hyperphosphatemia and Pi transport activity in klotho mutant mice (kl/kl mice). kl/kl mice displayed hyperphosphatemia, high plasma 1,25 (OH) (2)D(3) levels, increased activity of the renal and intestinal sodium-dependent P (i) cotransporters, and increased levels of the type II a, type II b, and type II c transporter proteins compared with wild-type mice. Interestingly, transcript levels of the type II a/type II c transporter mRNA abundance, but not transcripts levels of type II b transporter mRNA, were markedly decreased in kl/kl mice compared with wild-type mice. Furthermore, plasma FGF23 levels were 150-fold higher in kl/kl mice than in wild-type mice. Feeding of a low-P (i) diet induced the expression of klotho protein and decreased plasma FGF23 levels in kl/kl mice, whereas colchicine treatment experiments revealed evidence of abnormal membrane trafficking of the type IIa transporter in kl/kl mice. These results indicate that hyperphosphatemia in klotho mice is due to dysregulation of expression and trafficking of the renal type II a/ II c transporters rather than to intestinal P (i) uptake.

The adaptation and relationship of FGF‐23 to changes in mineral metabolism in Graves’ disease

The aim of this study was to observe the changes in bone and mineral metabolism and to confirm the regulation of fibroblast growth factor-23 (FGF-23) in untreated Graves' disease. The study comprised 39 patients, with or without Graves' disease. The Graves' disease group was made up of 21 newly diagnosed patients, enrolled before starting treatment. Their disease was determined by biochemical and radiological means. The control group was composed of 18 people who were proven to be euthyroid without any diseases affecting bone and mineral metabolism. FGF-23, calcium, phosphate, PTH, 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels and bone turnover markers were compared between these groups. Serum calcium and phosphate, plasma FGF-23 and free T4 were significantly higher in the Graves' disease group than in the healthy control group (P < 0.05). The bone turnover markers serum osteocalcin and C-terminal cross-linked telopeptide of type 1 collagen (s-CTx) were also significantly elevated in the Graves' disease group, and had a positive correlation with free T4 levels. However, there was no significant decrease in PTH and 1,25(OH)2D in the Graves' disease group. Plasma levels of FGF-23 exhibited a positive correlation with serum phosphate levels and with free T4 levels (P < 0.05). These findings suggest that FGF-23 is physiologically related to serum phosphate homeostasis, as indicated indirectly by the changes in bone and mineral metabolism, in untreated Graves' disease.

Correlation between hyperphosphatemia and type II Na-Pi cotransporter activity in klotho mice

Recent studies have demonstrated that klotho protein plays a role in calcium/phosphate homeostasis. The goal of the present study was to investigate the regulation of Na-P(i) cotransporters in klotho mutant (kl/kl) mice. The kl/kl mice displayed hyperphosphatemia, high plasma 1,25(OH)(2)D(3) levels, increased activity of the renal and intestinal sodium-dependent P(i) cotransporters, and increased levels of the type IIa, type IIb, and type IIc transporter proteins compared with wild-type mice. Interestingly, transcript levels of the type IIa/type IIc transporter mRNA abundance, but not transcripts levels of type IIb transporter mRNA, were markedly decreased in kl/kl mice compared with wild-type mice. Furthermore, plasma fibroblast growth factor 23 (FGF23) levels were 150-fold higher in kl/kl mice than in wild-type mice. Feeding of a low-P(i) diet induced the expression of klotho protein and decreased plasma FGF23 levels in kl/kl mice, whereas colchicine treatment experiments revealed evidence of abnormal membrane trafficking of the type IIa transporter in kl/kl mice. Finally, feeding of a low-P(i) diet resulted in increased type IIa Na-P(i) cotransporter protein in the apical membrane in the wild-type mice, but not in kl/kl mice. These results indicate that hyperphosphatemia in klotho mice is due to dysregulation of expression and trafficking of the renal type IIa/IIc transporters rather than to intestinal P(i) uptake.

The role of fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D metabolism in patients with McCune?Albright syndrome

McCune-Albright syndrome (MAS) is sometimes complicated by hypophosphatemia and abnormally low levels of 1,25(OH)(2)D in the presence of hypophosphatemia. Recently, fibroblast growth factor 23 (FGF-23) was reported as a phosphaturic and a causal factor of abnormal vitamin D metabolism. This abnormal phosphate and vitamin D metabolism is well known to be found in oncogenic and X-linked hypophosphatemia. We furthermore reported increased circulating plasma FGF-23 levels in patients with oncogenic and X-linked hypophosphatemia. To determine whether FGF-23 may be involved in the pathogenesis of MAS, we measured plasma FGF-23 levels in six MAS patients. As a control for hypophosphatemia, we also investigated the plasma FGF-23 levels in two patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH). We also investigated the correlation of plasma FGF-23 levels with serum phosphate and 1,25(OH)(2)D levels after short-term pamidronate therapy in three MAS patients. Plasma FGF-23 levels were significantly increased in patients with MAS compared to normal controls, whereas they were not increased in HHRH patients. Serum phosphate levels of the MAS patients were significantly lower than those observed in normal controls. Plasma FGF-23 levels showed significant negative correlation with serum phosphate concentrations. In three MAS patients, pamidronate therapy decreased plasma FGF-23 levels, which showed significant negative correlation with serum 1,25(OH)(2)D concentrations. These data suggested that FGF-23 is a possible causal factor for hypophosphatemia and abnormal vitamin D metabolism in MAS.

Vitamin D and phosphate regulate fibroblast growth factor-23 in K-562 cells

Fibroblast growth factor-23 (FGF-23) has been recently identified as playing an important pathophysiological role in phosphate homeostasis and vitamin D metabolism. To elucidate the precise physiological regulation of FGF-23, we characterized the mouse FGF-23 5'-flanking region and analyzed its promoter activity. The 5'-flanking region of the mouse FGF-23 gene contained a TFIID site (TATA box) and several putative transcription factor binding sites, including MZF1, GATA-1 and c-Ets-1 motifs, but it did not contain the typical sequences of the vitamin D response element. Plasmids encoding 554-bp (pGL/-0.6), 364-bp (pGL/-0.4) and 200-bp (pGL/-0.13) promoter regions containing the TFIID element and +1-bp fragments drove the downstream expression of a luciferase reporter gene in transfection assays. We also found that FGF-23 mRNA was expressed in K-562 erythroleukemia cell lines but not in MC3T3-E1, Raji, or Hep G2 human carcinoma cells. Treatment with 1,25-dihydroxyvitamin D3 in the presence of high phosphate markedly stimulated pGL/-0.6 activity, but calcium had no effect. In addition, the plasma FGF-23 levels were affected by the dietary and plasma inorganic phosphate concentrations. Finally, the levels of plasma FGF-23 in vitamin D receptor-null mice were significantly lower than in wild-type mice. The presents study demonstrated that vitamin D and the plasma phosphate level are important regulators of the transcription of the mouse FGF-23 gene.