Serum FGF23 Concentration Research Articles

Osteocyte-specific deletion of Fgfr1 suppresses FGF23.

Increases in fibroblastic growth factor 23 (FGF23 or Fgf23) production by osteocytes result in hypophosphatemia and rickets in the Hyp mouse homologue of X-linked hypophosphatemia (XLH). Fibroblastic growth factor (FGF) signaling has been implicated in the pathogenesis of Hyp. Here, we conditionally deleted FGF receptor 1 (FGFR1 or Fgfr1) in osteocytes of Hyp mice to investigate the role of autocrine/paracrine FGFR signaling in regulating FGF23 production by osteocytes. Crossing dentin matrix protein 1 (Dmp1)-Cre;Fgfr1 null/+ mice with female Hyp;Fgfr1 flox/flox mice created Hyp and Fgfr1 (Fgfr1Dmp1-cKO)-null mice (Hyp;Fgfr1 Dmp1-cKO) with a 70% decrease in bone Fgfr1 transcripts. Fgfr1Dmp1-cKO-null mice exhibited a 50% reduction in FGF23 expression in bone and 3-fold reduction in serum FGF23 concentrations, as well as reductions in sclerostin (Sost), phosphate regulating endopeptidase on X chromosome (PHEX or Phex), matrix extracellular phosphoglycoprotein (Mepe), and Dmp1 transcripts, but had no demonstrable alterations in phosphate or vitamin D homeostasis or skeletal morphology. Hyp mice had hypophosphatemia, reductions in 1,25(OH)2D levels, rickets/osteomalacia and elevated FGF2 expression in bone. Compared to Hyp mice, compound Hyp;Fgfr1 Dmp1-cKO-null mice had significant improvement in rickets and osteomalacia in association with a decrease in serum FGF23 (3607 to 1099 pg/ml), an increase in serum phosphate (6.0 mg/dl to 9.3 mg/dl) and 1,25(OH)2D (121±23 to 192±34 pg/ml) levels, but only a 30% reduction in bone FGF23 mRNA expression. FGF23 promoter activity in osteoblasts was stimulated by FGFR1 activation and inhibited by overexpression of a dominant negative FGFR1(TK−), PLCγ and MAPK inhibitors. FGF2 also stimulated the translation of an FGF23 cDNA transfected into osteoblasts via a FGFR1 and PI3K/Akt-dependent mechanism. Thus, activation of autocrine/paracrine FGF pathways is involved in the pathogenesis of Hyp through FGFR1-dependent regulation of FGF23 by both transcriptional and post-transcriptional mechanisms. This may serve to link local bone metabolism with systemic phosphate and vitamin D homeostasis.

Activation of FGF-23 mediated vitamin D degradative pathways by cholecalciferol.

The optimal circulating concentration of 25(OH) vitamin D is controversial. The aim was to investigate if FGF-23 and 24,25(OH)2D can guide cholecalciferol replacement. Oral cholecalciferol (10,000 IU weekly) administered to subjects with 25(OH)D levels < 20 ηg/mL and eGFR > 60 mL/min/1.73 m(2) (n = 25), chronic kidney disease (CKD) (n = 27), or end stage renal disease (ESRD) (n = 14). The study was conducted at the Veterans Affairs clinics. Serum FGF-23, PTH, 25(OH)D, 1,25(OH)2D, 24,25(OH)2D, calcium, and phosphorous concentrations, and urinary excretion of calcium and phosphorus at baseline and after 8 weeks of treatment. Cholecalciferol treatment increased concentrations of serum 25(OH)D by (19.3 ± 8 ηg/mL, P = .001; 12.2 ± 9 ηg/mL, P = .0001) and 24,25(OH)2D (1.14 ± 0.89 ηg/mL, P = .0024; 1.0 ± 0.72 ηg/mL P = .0002), and reduced serum PTH (-11 ± 21 pg/mL, P = .0292; -42 ± 68 pg/mL, P = .0494) in normal and CKD subjects, respectively. Cholecalciferol increased serum FGF-23 levels only in normal subjects (44 ± 57 ηg/mL, P = .01). Increments in serum 25(OH)D positively correlated with serum FGF-23 and 24,25(OH)2D and negatively correlated with PTH. In ESRD, cholecalciferol administration increased 25(OH)D by (16.6 ± 6.6 ηg/mL P ≤ .05) without changing 24,25(OH)2D, FGF-23 or PTH levels. Modest elevations of serum 25(OH)D levels after cholecalciferol treatment are sufficient to induce compensatory degradative pathways in patients with sufficient renal reserves, suggesting that optimal circulating 25(OH)D levels are approximately 20 ηg/mL. In addition, catabolism of 25(OH)D may also contribute to the low circulating vitamin D levels in CKD, since elevations of FGF-23 in CKD are associated with increased 24,25(OH)2D after cholecalciferol administration.

Effect of Niacin on FGF23 Concentration in Chronic Kidney Disease

Background: Elevated serum phosphorus and FGF23 are independent cardiovascular risk factors in patients with chronic kidney disease. In a randomized controlled trial of patients with dyslipidemia assigned to either extended release niacin (ERN) alone, ERN combined with the selective prostaglandin D₂ receptor subtype 1 inhibitor laropiprant (ERN-L) or placebo, niacin lowered serum phosphorus; however, it is not known if it lowers FGF23 concentrations. Methods: This is an ancillary study to a multicenter, randomized, double-blind, placebo-controlled trial among patients with dyslipidemia and an estimated glomerular filtration rate (eGFR) of 30-74 ml/min/1.73 m². Participants were randomized to ERN-L (n = 162), ERN (n = 97), or placebo (n = 68) in a 3:2:1 ratio for 24 weeks. The primary outcome was a change in serum FGF23 concentrations, and secondary outcomes were changes in other mineral metabolism parameters. Results: Both the ERN and ERN-L groups showed significant declines in serum phosphorus, calcium and calcium·phosphorus product at 24 weeks compared to placebo. A significant decline from baseline (10.9%, p < 0.01) in the serum FGF23 concentration was observed in the ERN group compared to placebo, but not in the ERN-L group compared to placebo (p = 0.36 and 0.97 for ERN-L and placebo, respectively), despite equivalent declines in serum phosphorus. Similarly, the most marked declines in PTH occurred in the ERN-only group versus placebo; no change in PTH was observed in the ERN-L group. Conclusions: In this ancillary study of hyperlipidemic patients with an eGFR of 30-74 ml/min/1.73 m², ERN alone but not in combination with laropiprant lowered FGF23 and PTH concentrations. If confirmed, niacin may provide a novel strategy to decrease phosphorus, FGF23, and PTH concentrations in patients with chronic kidney disease.

OSR1-Sensitive Renal Tubular Phosphate Reabsorption

Background: The oxidative stress-responsive kinase 1 (OSR1) participates in the WNK-(with no K) kinase dependent regulation of renal salt excretion and blood pressure. Little is known, however, about the role of OSR1 in the regulation of further renal transport systems. The present study analyzed the effect of OSR1 on NaPiIIa, the major renal tubular phosphate transporter. Methods: Immunohistochemistry and confocal microscopy were employed to determine renal localization of OSR1 and NaPiIIa. To elucidate the effect of OSR on NaPiIIa activity, cRNA encoding NaPiIIa was injected into Xenopus oocytes with or without additional injection of cRNA encoding OSR1, and phosphate transport was estimated from phosphateinduced currents determined with dual electrode voltage clamp. To elucidate the in vivo significance of OSR1 serum phosphate and hormone concentrations as well as urinary phosphate output of mice carrying one allele of WNK-resistant OSR1 (osr1tg/⁺) were compared to the respective values of wild type mice (osr1^+/+). Results: NaPiIIa and OSR1 were both expressed in proximal renal tubule cells. Coexpression of OSR1 significantly up-regulated phosphate-induced currents in NaPiIIa-expressing Xenopus oocytes. Despite decreased serum phosphate concentration urinary phosphate excretion was significantly increased and NaPiIIa protein abundance in the brush border membrane significantly reduced in osr1tg/⁺ mice as compared to osr1^+/+ mice. Serum PTH and calcitriol levels were similar in osr1tg/⁺ mice and in osr1^+/+ mice, serum FGF23 concentration was, however, significantly higher in osr1tg/⁺ mice than in osr1^+/+ mice. Conclusions: OSR1 is expressed in proximal renal tubules and participates in the regulation of FGF23 release and renal tubular phosphate transport.

Increased circulating levels of FGF23: an adaptive response in primary hyperparathyroidism?

Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) are major players in the bone-parathyroid-kidney axis controlling phosphate homeostasis. In patients with primary hyperparathyroidism (PHPT), data on the relationship between PTH and FGF23 are scarce and not always concordant. The aim of our study was to evaluate the relationship between PTH and FGF23 in patients with PHPT and in euparathyroid patients cured after successful parathyroidectomy (PTx). Twenty-one patients with PHPT and 24 patients in long-term cure after successful PTx (EuPTH) were studied. All patients underwent biochemical evaluation of renal function, parathyroid status, vitamin D status, bone turnover markers, and serum intact FGF23 levels. Mean serum FGF23 concentration was significantly higher in PHPT than in EuPTH patients (50.8±6.1 vs 33.1±2.6 pg/ml, P=0.01). FGF23 levels significantly correlated with PTH levels (r=0.361, P=0.02), also after correction for 1,25(OH)(2)D levels (r=0.419, P=0.01). FGF23 levels showed a significant negative correlation with 1,25(OH)(2)D, which was more pronounced in PHPT than in EuPTH patients (r=-0.674, P=0.001, vs r=-0.509, P=0.01). Our findings suggest that in PHPT, FGF23 levels are increased independent of 1,25(OH)(2)D levels. The more pronounced negative relationship between FGF23 and 1,25(OH)(2)D in the presence of high circulating PTH levels suggests that the increase in FGF23 levels may be an adaptive mechanism to counteract the PTH-induced increase in 1,25(OH)(2)D levels, although not completely overriding it.

Effects of vitamin D replacement therapy on serum FGF23 concentrations in vitamin D-deficient women in short term

Fibroblast growth factor 23 (FGF23), a phosphatonin, inhibits renal phosphate reabsorption and suppresses 1-α hydroxylase activity. Calcitriol stimulates FGF23 synthesis in bone. We aimed to determine the effect of vitamin D replacement therapy on serum FGF23 concentrations in vitamin D-deficient women and to compare the FGF23 concentrations of vitamin D-deficient patients with healthy subjects and patients with genetically determined hypophosphatemic rachitis. The study group was composed of vitamin D-deficient females (n=18, mean age 29.1 ± 9.9 years), vitamin D-sufficient healthy females (control group; n=19, mean age 28.5 ± 5.2 years), and patients with genetically determined hypophosphatemic rachitis (n=13, mean age 26.5 ± 15.1 years). The groups were compared for serum FGF23, 1,25-dihydroxyvitamin D3 (1,25(OH)2D), calcium, phosphate, bone turnover markers, intact parathyroid hormone (PTH), and urinary excretion of calcium and phosphate. The vitamin D-deficient group was re-evaluated after a standard treatment regimen. Serum FGF23 concentrations were significantly lower in vitamin D-deficient patients than in vitamin D-sufficient women and hypophosphatemic rachitis group. Serum FGF23 and phosphate concentrations further decreased significantly during replacement of vitamin D (P<0.05). A significant negative correlation was evident between FGF23 and PTH before vitamin D replacement in the patients (r=-0.469, P<0.05). Decreased FGF23 concentrations, which further decline during vitamin D replacement therapy, may have favorable action on bone mineralization by counterregulatory effect on phosphate homeostasis. Lower 1,25(OH)2D concentrations at baseline and hypophosphatemia during treatment may have dominating effects on FGF23 concentrations in vitamin D deficiency, leading to decreased FGF23 concentrations at baseline and during replacement therapy.

Relationship between Fibroblast Growth Factor-23 and Mineral Metabolism in Chronic Kidney Disease

Fibroblast growth factor- (FGF-)23 is a recently discovered regulator of calcium-phosphate metabolism. FGF-23 appears to decrease in synthesis and accelerated degradation of 1,25(OH)2D. Together with its cofactor Klotho, FGF-23 maintains serum phosphate levels within the normal range by increasing renal phosphate excretion. In chronic kidney disease (CKD), FGF-23 levels rise in parallel with the decline in renal function long before a significant increase in serum phosphate concentration occurs. Both Klotho and FGF-23, linked by a receptor mechanism, affect vitamin D synthesis and parathyroid hormone (PTH) secretion. Previous studies have shown a close association between reduced FGF-23 or Klotho activities and vascular calcification. The possible association of FGF-23 and left ventricular hypertrophy or vascular dysfunction has been proposed. Finally, prospective studies have shown that high serum FGF-23 concentrations predict more rapid disease progression in CKD patients who were not on dialysis and increased mortality in patients on maintenance hemodialysis. FGF-23 may therefore prove to be an important therapeutic target for the management of CKD.

Effects of gonadal steroid withdrawal on serum phosphate and FGF-23 levels in men

Fibroblast growth factor (FGF-23) is a novel phosphaturic factor. Current data suggest that serum phosphate, dietary phosphate and 1,25 dihydroxyvitamin D regulate circulating FGF-23 levels in vivo. We examined if hypogonadism-induced increases in serum phosphate are associated with increases in circulating FGF-23 in healthy men in the absence of dietary manipulation. 25 healthy men were administered goserelin acetate (GnRH analog) 3.6 mg subcutaneously every 4 weeks for 12 weeks to induce acute testosterone and estrogen deficiency. Subjects consumed an ad libitum diet. Morning fasting blood and urine samples were collected to measure serum phosphate, serum intact FGF-23, PTH, and the maximum tubular reabsorption of phosphate (T(m)P/GFR) at baseline, weeks 4 and 12. The changes in serum FGF-23 and phosphate at weeks 4 and 12 were compared to baseline using paired t-tests. Goserelin therapy decreased mean serum testosterone levels from 543+/-160 ng/dL to 33+/-15 ng/dL at week 4 (p<0.001), and to 20+/-10 ng/dL at week 12 (p<0.001). Serum phosphate increased significantly from 3.4+/-0.6 mg/dL to 3.9+/-0.4 mg/dL at week 4 (p=0.002), and to 4.3+/-0.4 mg/dL at week 12 (p<0.001). T(m)P/GFR increased significantly from 3.2+/-0.6 mg/dL to 3.6+/-0.5 mg/dL at week 4 (p<0.004), and to 4.1+/-0.6 mg/dL at week 12 (p<0.001). FGF-23 levels, however, did not change during the 12-week study. Gonadal steroid deprivation increased serum phosphate levels in men but did not affect serum FGF-23 concentrations. The absence of any change in circulating FGF-23 suggests that supraphysiologic levels of serum phosphate may be required to stimulate circulating FGF-23 or that FGF-23 production is primarily sensitive to changes in dietary phosphate or 1,25 dihydroxyvitamin D within this physiologic serum phosphate range.