Increase In Fibroblast Growth Factor 23 Research Articles

New biomarkers of bone remodelling regulation in patients with acromegaly and endogenous hypercortisolism

Background: Bone tissue is a non-classical endocrine organ, which produces at least two hormones: fibroblast growth factor 23 (FGF-23) and decarboxylated osteocalcin (OC). In addition to this, recent studies demonstrate that specific proteins involved in the paracrine regulation of bone remodelling can be measured in peripheral serum samples and may serve as additional biomarkers of bone metabolism.
 Aims: to evaluate the serum levels of biomarkers related to endocrine and paracrine function of bone tissue in patients with Cushings disease (CD) and acromegaly.
 Materials and methods: The study was conducted according to the cross-sectional case-control type. Fasting serum samples were taken between 810 a.m. from patients with CD, acromegaly and age-, sex- and BMI-matched healthy volunteers and stored at -40 C. Commercially available kits for enzyme-linked immunosorbent assay (ELISA) were used to determine the serum levels of FGF-23, co-factor (co-receptor) Klotho, cathepsin K, sclerostin, P1NP. Insulin-like growth factor-1 (IGF-1) was measured by the immunochemiluminescence assay, late-night (11 p.m.) salivary cortisol (LNSC) was evaluated using the electrochemiluminescence method. Non-parametric tests (the Kruskal-Wallis test and the Mann-Whitney test) were used to assess the differences between the groups of patients.
 Results: The study includes 78 patients, (37.6 years old, 95% CI 34.7540.46): 29 patients with CD (group 1), 22 with acromegaly (group 2), and 27 healthy individuals (group 3), matched by sex, age and BMI (p = 0.432, 0.373 and 0.725 between groups, respectively). LNSC in patients with CD and IGF-1 in patients with acromegaly were significantly higher compared to the control group (p = 0.004 and p 0.001, respectively). In patients with acromegaly, a statistically significant increase in FGF-23 (1.13 (0.78;1.49) vs 0.78 (0.54;1.09)) and phosphorus (1.38 (1.24;1.52) vs 1.16 (1.12;1.29)) (p = 0.01 and p 0.001, respectively) was observed along with increased levels of bone remodelling markers. In patients with CD, bone formation markers were suppressed, but differences in the levels of other biomarkers could not be identified.
 Conclusions: Acromegaly leads to hyperphosphatemia and increase in FGF-23, which is most likely due to the development of resistance to FGF-23, and the intensification of bone remodelling. With CD, another bone hormone, osteocalcin, is suppressed along with the suppression of P1NP.

The Association of Fibroblast Growth Factor-23 with Mineral Factors (Ca, P, and Mg), Parathyroid Hormone, and 25-Hydroxyvitamin D in Hemodialysis Patients: A Multicenter Study

Background: Fibroblast growth factor-23 (FGF23) is a phosphaturic factor that is released from bone. A variety of bone diseases can occur in renal diseases. Objectives: This study aimed to investigate the association of FGF23 with mineral factors, PTH, and 25-hydroxyvitamin D among hemodialysis patients. Methods: This cross-sectional multicenter study was performed on 135 patients aged 18 years or over with end-stage renal disease treated with hemodialysis maintenance. FGF-23, phosphorus, Ca, Mg, PTH, 25-hydroxyvitamin D, Uric Acid, Na, and K were measured in each patient’s fasting blood sample. We used univariate and multivariate linear regressions. Results: The mean age of patients was 56.45 ± 13.64 years. The mean and median FGF23 concentration in patients were 855.07 ± 43.33 and 762.6 (IQR = 456.6 - 1430.3) pg/mL, respectively. Different variables did not show any significant difference between the two sexes. After adjustment for age, sex, dialysis time, uric acid, Na, K, and kt/V, FGF23 had a linear association with 25-hydroxyvitamin D and every 10-unit (pg/mL) increase in FGF23 was significantly associated with a 0.03 mg/mL increase in 25-hydroxyvitamin D (P = 0.04). In addition, other variables showed no significant association with FGF23. Conclusions: According to the results, FGF23 had a linear association with vitamin D and an increase in FGF23 was significantly associated with an increase in vitamin D. In addition, there was no significant association between mineral factors and PTH, and FGF23.

Fibroblast Growth Factor 23 Expression Is Increased in Multiple Organs in Mice With Folic Acid-Induced Acute Kidney Injury.

Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and vitamin D metabolism. In patients with acute kidney injury (AKI), FGF23 levels rise rapidly after onset of AKI and are associated with AKI progression and increased mortality. In mouse models of AKI, excessive rise in FGF23 levels is accompanied by a moderate increase in FGF23 expression in bone. We examined the folic acid-induced AKI (FA-AKI) mouse model to determine whether other organs contribute to the increase in plasma FGF23 and assessed the vitamin D axis as a possible trigger for increased Fgf23 gene expression. Twenty-four hours after initiation of FA-AKI, plasma intact FGF23 and 1,25(OH)2D were increased and kidney function declined. FA-treated mice developed renal inflammation as shown by increased Tnf and Tgfb mRNA expression. Fgf23 mRNA expression was 5- to 15-fold upregulated in thymus, spleen and heart of FA-treated mice, respectively, but only 2-fold in bone. Ectopic renal Fgf23 mRNA expression was also detected in FA-AKI mice. Plasma FGF23 and Fgf23 mRNA expression in thymus, spleen, heart, and bone strongly correlated with renal Tnf mRNA expression. Furthermore, Vdr mRNA expression was upregulated in spleen, thymus and heart and strongly correlated with Fgf23 mRNA expression in the same organ. In conclusion, the rapid rise in plasma FGF23 in FA-AKI mice is accompanied by increased Fgf23 mRNA expression in multiple organs and increased Vdr expression in extra osseous tissues together with increased plasma 1,25(OH)2D and inflammation may trigger the rise in FGF23 in FA-AKI.

Fibroblast Growth Factor-23, Heart Failure Risk, and Renin-Angiotensin-Aldosterone-System Blockade in Hypertension: The MESA Study.

Higher fibroblast growth factor-23 (FGF23) concentrations have been found to be associated with incident heart failure (HF). Experimental data suggest FGF23 directly stimulates myocardial hypertrophy. FGF23 may also enhance renin-angiotensin-aldosterone system activity. Whether FGF23 is associated with increased HF risk in populations with hypertension and whether this association is weaker in the presence of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy is unknown. We studied 2,858 adults with hypertension free of cardiovascular disease at baseline (65.6 ± 9.5 years, 46.2% male) participating in the Multi-Ethnic Study of Atherosclerosis (MESA). We investigated the association of baseline serum intact FGF23 with incident HF over a 14-year median follow-up and whether ACEI/ARB therapy modified this risk. We also investigated the relationship of FGF23 with aldosterone and plasma renin activity in a random subgroup of the entire MESA cohort with available assays (N = 1,642). In adjusted Cox regression models, higher FGF23 was associated with a 63% greater hazard of incident HF (hazard ratio: 1.63, 95% confidence interval: [1.13-2.36] per 1-unit increase in log-transformed FGF23), which persisted after exclusion of participants with chronic kidney disease (hazard ratio: 1.94 [1.10-3.43]). There was no heterogeneity by ACEI/ARB use (Pinteraction = 0.438). FGF23 improved model fit over covariables (likelihood ratio χ2 = 6.67, P = 0.010). In multivariable linear regression models, there was no association between FGF23 and aldosterone or plasma renin activity. Higher FGF23 concentrations are associated with a significantly increased risk of HF in hypertension but this risk did not differ by ACEI/ARB treatment status. FGF23 may be a useful biomarker for HF risk in hypertensive populations.

Incremental value of intact fibroblast growth factor 23 to natriuretic peptides for long-term risk estimation of heart failure patients

Fibroblast growth factor 23 (FGF-23), a key hormone for the regulation of the phosphorus homeostasis, has also several direct effects on cardiac function. In heart failure (HF), the increase of FGF-23 participates to cardiac hypertrophy and remodeling. Measurement of the intact, biologically active hormone is now available. We determined intact FGF-23 in HF patients with reduced ejection fraction and assess its prognosis value for cardiovascular death over a long-term follow-up. We observed that intact FGF-23 is an independent predictor of cardiovascular death in HF patients and provides added value to the standard of care, natriuretic peptide, for risk estimation.

Consequence of Elevated Fibroblast Growth Factor 23 Levels in Acute Kidney Injury, Renal Recovery and Overall Survival in Intensive Care Unit Patients After Major Surgery.

The main goal of our study was to investigate the role of increased fibroblast growth factor 23 (FGF23) levels on renal recovery and overall survival. We conducted a prospective case-control cohort study, which included 121 adult cases who developed AKI after major surgical procedures. The subjects were followed-up until the last enrolled patient survived 180 days or until the time of death. Higher FGF23 levels positively correlated with serum creatinine levels (P < 0.05). Significantly higher number of patients without diuresis and with FGF23 ≤ 709 RU/mL survived when compared to patients without diuresis and with FGF23 ≥ 709 RU/mL (P < 0.001). FGF23 levels >709 RU/mL were a good predictive tool for overall mortality in a 6-month period (P < 0.05). This is the first study to analyze the impact of FGF23 values on short-term renal recovery and survival of patients with AKI after major surgery. The FGF23 increase related to AKI especially in more severe stages and in patients without diuresis is an independent risk factor for mortality.

In vivo evidence for an interplay of FGF23/Klotho/PTH axis on the phosphate handling in renal proximal tubules.

Phosphate homeostasis is primarily maintained in the renal proximal tubules, where the expression of sodium/phosphate cotransporters (Npt2a and Npt2c) is modified by the endocrine actions of both fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH). However, the specific contribution of each regulatory pathway in the proximal tubules has not been fully elucidated in vivo. We have previously demonstrated that proximal tubule-specific deletion of the FGF23 coreceptor Klotho results in mild hyperphosphatemia with little to no change in serum levels of FGF23, 1,25(OH)2D3, and PTH. In the present study, we characterized mice in which the PTH receptor PTH1R was specifically deleted from the proximal tubules, either alone or in combination with Klotho ( PT-PTH1R-/- and PT-PTH1R/KL-/-, respectively). PT-PTH1R-/- mice showed significant increases in serum FGF23 and PTH levels, whereas serum phosphate levels were maintained in the normal range, and Npt2a and Npt2c expression in brush border membrane (BBM) did not change compared with control mice. In contrast, PT-PTH1R/KL-/- mice displayed hyperphosphatemia and an increased abundance of Npt2a and Npt2c in the renal BBM, along with increased circulating FGF23 levels. While serum calcium was normal, 1,25(OH)2D3 levels were significantly decreased, leading to extremely high levels of PTH. Collectively, mice with a deletion of PTH1R alone in proximal tubules results in only minor changes in phosphate regulation, whereas deletion of both PTH1R and Klotho leads to a severe disturbance, including hyperphosphatemia with increased sodium/phosphate cotransporter expression in BBM. These results suggest an important interplay between the PTH/PTH1R and FGF23/Klotho pathways to affect renal phosphate handling in the proximal tubules.

Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease

The high serum fibroblast growth factor 23 (FGF23) levels in patients with acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with increased morbidity and mortality. Mice with folic acid-induced AKI had an increase in bone FGF23 mRNA expression together with an increase in serum FGF23 and several circulating cytokines including interleukin-6 (IL-6). Dexamethasone partially prevented the increase in IL-6 and FGF23 in the AKI mice. IL-6 knock-out mice fed an adenine diet to induce CKD failed to increase bone FGF23 mRNA and had a muted increase in serum FGF23 levels, compared with the increases in wild-type mice with CKD. Therefore, IL-6 contributes to the increase in FGF23 observed in CKD. Hydrodynamic tail injection of IL-6/soluble IL-6 receptor (sIL-6R) fusion protein hyper IL-6 (HIL-6) plasmid increased serum FGF23 levels. Circulating sIL-6R levels were increased in both CKD and AKI mice, suggesting that IL-6 increases FGF23 through sIL-6R-mediated trans-signaling. Renal IL-6 mRNA expression was increased in mice with either AKI or CKD, suggesting the kidney is the source for the increased serum IL-6 levels in the uremic state. HIL-6 also increased FGF23 mRNA in calvaria organ cultures and osteoblast-like UMR106 cells in culture, demonstrating a direct effect of IL-6 on FGF23 expression. HIL-6 increased FGF23 promoter activity through STAT3 phosphorylation and its evolutionarily conserved element in the FGF23 promoter. Thus, IL-6 increases FGF23 transcription and contributes to the high levels of serum FGF23 in both acute and chronic kidney disease.

Insulin suppresses the production of fibroblast growth factor 23 (FGF23)

Fibroblast growth factor 23 (FGF23) is produced by bone cells and regulates renal phosphate and vitamin D metabolism, as well as causing left ventricular hypertrophy. FGF23 deficiency results in rapid aging, whereas high plasma FGF23 levels are found in several disorders, including kidney or cardiovascular diseases. Regulators of FGF23 production include parathyroid hormone (PTH), calcitriol, dietary phosphate, and inflammation. We report that insulin and insulin-like growth factor 1 (IGF1) are negative regulators of FGF23 production. In UMR106 osteoblast-like cells, insulin and IGF1 down-regulated FGF23 production by inhibiting the transcription factor forkhead box protein O1 (FOXO1) through phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/Akt signaling. Insulin deficiency caused a surge in the serum FGF23 concentration in mice, which was reversed by administration of insulin. In women, a highly significant negative correlation between FGF23 plasma concentration and increase in plasma insulin level following an oral glucose load was found. Our results provide strong evidence that insulin/IGF1-dependent PI3K/PKB/Akt/FOXO1 signaling is a powerful suppressor of FGF23 production in vitro as well as in mice and in humans.

Cardiac hypertrophy elevates serum levels of fibroblast growth factor 23

Several experimental studies have shown that fibroblast growth factor 23 (FGF23) induces left ventricular hypertrophy (LVH). However, the opposite directional relationship, namely a potential effect of LVH on FGF23, remains uncertain. Here we evaluated the effects of LVH on FGF23 using cardiomyocyte-specific calcineurin A transgenic mice. At six weeks, these mice showed severe LVH, with elevated levels of serum intact FGF23. FGF23 levels were elevated in cardiomyocytes, but not osteocytes, of the transgenic animals. Moreover, transverse aortic constriction also upregulated myocardial FGF23 expression in wild type mice. The promoter region of the FGF23 gene contains two putative nuclear factors of activated T cells (NFAT)-binding sites, with NFAT1 activating the promoter in a proximal NFAT-binding site dependent manner. Neither serum, urinary, or fractional excretion values of calcium and phosphate nor serum levels of 1,25(OH)2 vitamin D were different between wild type and transgenic mice. Moreover, the renal expression of FGF receptors and α-Klotho was comparable. However, plasma levels of antidiuretic hormone were significantly increased in the transgenic mice, and aquaporin-2 immunohistochemical staining was mainly positive in the apical membrane of the collecting duct, compared to a primarily cytoplasmic staining in wild type mice. Real-time PCR analyses of kidney CYP27B1 and CYP24A1 expression in wild type mice showed that exogenous antidiuretic hormone blocked FGF23's actions on these vitamin D activating or inactivating enzymes. Finally, the renal resistance of transgenic mice to FGF23 was partly overcome by tolvaptan. Thus, LVH in transgenic mice is associated with an increase in myocardial and serum intact FGF23, with the kidneys being protected against FGF23 excess by elevated antidiuretic hormone levels.

Abstract P303: Racial Differences in the Associations Between Food Insecurity and Fibroblast Growth Factor 23 (FGF23) in The Coronary Artery Risk Development in Young Adults (CARDIA) Study

Introduction: Elevated Fibroblast Growth Factor 23 (FGF23) - an endocrine hormone linked to cardiovascular and kidney disease outcomes - is a compensatory response to high dietary phosphate load or chronic kidney disease. Large quantities of inorganic phosphates additives are found in processed foods, and food insecurity is associated with higher consumption of processed foods. Hypothesis: We hypothesized that developing food insecurity is associated with an increase in FGF23. Methods: We included CARDIA study participants with a stored plasma sample available from at least two consecutive exams at years 20, 25, and 30 (N=3,421). Food insecurity was assessed through a single question about ability to afford quantity and quality of food. FGF23 levels were assessed using a commercial c-terminal ELISA. Due to a strong right skew in FGF23 levels, we divided FGF23 in quartiles and compared the highest quartile to the combined lower three quartiles using logistic regression. Econometric fixed effects models that adjust by design for all time-invariant covariates were used to model the longitudinal association between simultaneous within-person change in food insecurity and FGF23. Due to an interaction between food insecurity and race ( p =0.002), we stratified by race. Results: About 29% of blacks and 14% of whites experienced change in food insecurity during follow-up. Developing food insecurity was associated with a 1.46 greater odds of increasing to the highest quartile of FGF23 (95% CI: 1.02,2.10) among blacks; however, there was no significant longitudinal association among whites (OR=1.05; 95% CI: 0.62,1.77). Conclusions: Using models that tightly control for all time-invariant confounding, we found that developing food insecurity was associated with increases in FGF23 among blacks. The differential increases in blacks as compared to whites may be due to differences in dietary changes in response to developing food insecurity. Previous research has shown racial differences in dietary quality by food insecurity.

Longitudinal FGF23 Trajectories and Mortality in Patients with CKD.

Elevated fibroblast growth factor 23 (FGF23) levels, measured at a single time, are strongly associated with increased risk of mortality in patients with CKD. There are minimal data on serial FGF23 measurements in CKD. In a prospective case-cohort study of the Chronic Renal Insufficiency Cohort, we measured FGF23 at two to five annual time points (mean 4.0±1.2) in a randomly selected subcohort of 1135 participants, of whom 203 died, and all remaining 390 participants who died through mid-2013. Higher FGF23 was independently associated with increased risk of death in multivariable-adjusted analyses of time-varying FGF23 (hazard ratio per 1-SD increase in ln-transformed FGF23, 1.84; 95% CI, 1.67 to 2.03). Median FGF23 was stable over 5 years of follow-up, but its gradually right-skewed distribution suggested a subpopulation with markedly elevated FGF23. Trajectory analysis revealed three distinct trajectories: stable FGF23 in the majority of participants (slope of lnFGF23 per year =0.03, 95% CI, 0.02 to 0.04, n=724) and smaller subpopulations with slowly (slope=0.14, 95% CI, 0.12 to 0.16, n=486) or rapidly (slope=0.46, 95% CI, 0.38 to 0.54, n=99) rising levels. Compared with stable FGF23, participants with slowly rising FGF23 trajectories were at 4.49-fold higher risk of death (95% CI, 3.17 to 6.35) and individuals with rapidly rising FGF23 trajectories were at 15.23-fold higher risk of death (95% CI, 8.24 to 28.14) in fully adjusted analyses. Trajectory analyses that used four or three annual FGF23 measurements yielded qualitatively similar results. In conclusion, FGF23 levels are stable over time in the majority of patients with CKD, but serial measurements identify subpopulations with rising levels and exceptionally high risk of death.

Erythropoietin induces bone marrow and plasma fibroblast growth factor 23 during acute kidney injury

It is accepted that osteoblasts/osteocytes are the major source for circulating fibroblast growth factor 23 (FGF23). However, erythropoietic cells of bone marrow also express FGF23. The modulation of FGF23 expression in bone marrow and potential contribution to circulating FGF23 has not been well studied. Moreover, recent studies show that plasma FGF23 may increase early during acute kidney injury (AKI). Erythropoietin, a kidney-derived hormone that targets erythropoietic cells, increases in AKI. Here we tested whether an acute increase of plasma erythropoietin induces FGF23 expression in erythropoietic cells of bone marrow thereby contributing to the increase of circulating FGF23 in AKI. We found that erythroid progenitor cells of bone marrow express FGF23. Erythropoietin increased FGF23 expression invivo and in bone marrow cell cultures via the homodimeric erythropoietin receptor. In experimental AKI secondary to hemorrhagic shock or sepsis in rodents, there was a rapid increase of plasma erythropoietin, and an induction of bone marrow FGF23 expression together with a rapid increase of circulating FGF23. Blockade of the erythropoietin receptor fully prevented the induction of bone marrow FGF23 and partially suppressed the increase of circulating FGF23. Finally, there was an early increase of both circulating FGF23 and erythropoietin in a cohort of patients with severe sepsis who developed AKI within 48 hours of admission. Thus, increases in plasma erythropoietin and erythropoietin receptor activation are mechanisms implicated in the increase of plasma FGF23 in AKI.

Effect of variations in dietary Pi intake on intestinal Pi transporters (NaPi-IIb, PiT-1, and PiT-2) and phosphate-regulating factors (PTH, FGF-23, and MEPE).

Hyperphosphatemia is a common condition in patients with chronic kidney disease (CKD) and can lead to bone disease, vascular calcification, and increased risks of cardiovascular disease and mortality. Inorganic phosphate (Pi) is absorbed in the intestine, an important step in the maintenance of homeostasis. In CKD, it is not clear to what extent Pi absorption is modulated by dietary Pi. Thus, we investigated 5/6 nephrectomized (Nx) Wistar rats to test whether acute variations in dietary Pi concentration over 2days would alter hormones involved in Pi metabolism, expression of sodium-phosphate cotransporters, apoptosis, and the expression of matrix extracellular phosphoglycoprotein (MEPE) in different segments of the small intestine. The animals were divided into groups receiving different levels of dietary phosphate: low (Nx/LPi), normal (Nx/NPi), and high (Nx/HPi). Serum phosphate, fractional excretion of phosphate, intact serum fibroblast growth factor 23 (FGF-23), and parathyroid hormone (PTH) were significantly higher and ionized calcium was significantly lower in the Nx/HPi group than in the Nx/LPi group. The expression levels of NaPi-IIb and PiT-1/2 were increased in the total jejunum mucosa of the Nx/LPi group compared with the Nx/HPi group. Modification of Pi concentration in the diet affected the apoptosis of enterocytes, particularly with Pi overload. MEPE expression was higher in the Nx/HPi group than in the Nx/NPi. These data reveal the importance of early control of Pi in uremia to prevent an increase in serum PTH and FGF-23. Uremia may be a determining factor that explains the expressional modulation of the cotransporters in the small intestine segments.

Changes in Serum Fibroblast Growth Factor 23 in Patients With Acute Myocardial Infarction.

Fibroblast growth factor 23 (FGF23) induces cardiac remodeling. We investigated the changes in serum FGF23 levels in patients diagnosed with acute myocardial infarction (AMI).Methods and Results:A total of 44 patients diagnosed with AMI were included in the current study. All patients underwent emergency percutaneous coronary intervention (PCI). The median of peak creatine kinase (CK) and CKMB values was 1,816 U/L and 159 U/L, respectively. Serum levels of FGF23, calcium, and inorganic phosphate (iP) were measured before PCI, and on days 1, 3, 5, 7 after PCI. Serum FGF23 levels showed a slight, but significant decrease on days 1 and 3 after PCI, and a 1.5- and 2.0-fold increase on days 5 and 7, respectively, after PCI. As compared with propensity score-matched patients without AMI, serum FGF23 was significantly lower among the current cohort of AMI patients. In 22 subjects who underwent a follow-up echocardiographic examination at 6 months after the onset of AMI, the log-transformed relative increase in FGF23 on day 7 significantly and negatively correlated with changes between LVEF on admission and that at 6 months afterward. After a slight decrease on days 1 and 3 after admission, serum FGF23 increased significantly on days 5 and 7. The underlying mechanism and potential clinical importance of these observations require further investigation.

MicoroRNA-297a regulates vascular calcification by targeting fibroblast growth factor 23

Objective Vascular calcification is one of the major characteristics in patients with various types of chronic inflammatory disorders. miRNAs have been shown to be involved in many normal biological functions as well as diseases, however, their role in vascular calcification has not received much attention. Methods In the current study, we built vascular calcification rat model using vitamin D3 plus nicotine and analyzed miRNA expression profile by miRNA chip assay. Potential target of one selected miRNA with sharpest variation in expression was predicted by both PicTar and TargetScan. The impact of the selected miRNA on the expression of the potential target on both mRNA and protein levels was measured by real-time quantitative polymerase chain reaction (Real-time PCR) and Western blotting, respectively. Results The mmu-miR-297a was selected as the focus of the study on the early construction of stable angiocalcified animal models; As the target gene of mmu-miR-297a, fibroblast growth factor 23 (FGF23) plays an important role in regulating vascular growth; The results of Real-time PCR showed that the expression of mmu-miR-297a was significantly reduced in the model group; Real time PCR also found that FGF23 was up-regulated in the aortic tissue of the model group, while Klotho was significantly reduced (P=0.000); The expression of Western blotting analysis protein level FGF23 and Klotho was consistent with the mRNA level results, FGF23 was up-regulated in the model group, and Klotho was significantly reduced. Conclusion Our results indicated that FGF23 was target of miR-297a and decreased miR-297a in vascular calcification lead to the increase of FGF23, which together with Klotho might enhance vascular calcification. The findings of this study could provide valuable information for the understanding of mechanisms underlying miR-dependent vascular calcification as well as potential treatment target for the disease. Key words: MicroRNAs; MicroRNA-297a; Vascular calcification; Fibroblast growth factor 23

Progression of arterial stiffness is associated with changes in bone mineral markers in advanced CKD

BackgroundArterial stiffness is an independent predictor of all-cause and cardiovascular mortality in patients with chronic kidney disease (CKD). There are limited prospective data however on progression of arterial stiffness in CKD, including evaluating associations with bone mineral markers such as fibroblast growth factor 23 (FGF23) and soluble α-klotho (sKl).MethodsIn this prospective, single-center, observational study, arterial stiffness [measured by pulse wave velocity (PWV)] and hormones influencing mineral homeostasis, including serum FGF23 and sKl, were compared between non-dialysis CKD stages 4/5 and healthy controls at baseline and 12 months (12 m). Abdominal aortic calcification (AAC) was quantitated using lateral lumbar radiography at baseline.ResultsForty patients with CKD [mean estimated glomerular filtration rate (eGFR) 19.5 ± 6.7 mL/min/1.73m2] and 42 controls (mean eGFR 88.6 ± 12.9 mL/min/1.73m2) completed follow-up. There were no differences in age, gender and body mass index between groups. A significant increase in FGF23 [240.6 (141.9–1129.8) to 396.8 (160.3–997.7) pg/mL, p = 0.001] was observed in the CKD group but serum phosphate, corrected calcium, parathyroid hormone and sKl did not change significantly over 12 m. At baseline, CKD subjects had higher AAC prevalence [83.8% versus (vs.) 43.6%, p = 0.002] and higher aortic PWV [9.7(7.6–11.7) vs. 8.1 (7.2–9.7) m/s, p = 0.047] compared to controls. At 12 m, aortic PWV increased by 1.3 m/s (95% confidence interval, 0.56 to 2.08, p < 0.001) in the CKD cohort, with 30% of subjects showing progression from normal aortic elasticity to stiffening (PWV > 10 m/s). Serum FGF23 was associated with AAC, abnormal PWV and progression of PWV at 12 m.ConclusionsArterial stiffness and serum FGF23, both of which are associated with increased cardiovascular risk, increased over one year in individuals with CKD. Additionally, a significant association was found between serum FGF23 and arterial calcification and stiffness. Larger clinical studies and further experimental work are warranted to delineate the temporal relationship as well as the pathological mechanisms linking FGF23 and vascular disease.

Effect of Calcitriol on FGF23 Level in Healthy Adults and its Dependence on Phosphate Level.

To evaluate the short-term effects of calcitriol and sevelamer hydrochloride on fibroblast growth factor-23 (FGF23) in humans and to determine whether the effect is direct or indirect through calcitriol-induced increased absorption of phosphorus from the intestine. A total of 15 healthy individuals were tested at three time points and stages, for 24 h and at 1-week intervals. During each stage, blood samples were taken at three time points (0, 8 and 24 h); baseline stage: under no intervention; second stage, while receiving 0.5 μg calcitriol orally twice daily; and at the third stage, while receiving 0.5 μg calcitriol orally twice daily and sevelamer hydrochloride during meals. The changes in FGF23, parathyroid hormone, calcitriol, Ca, and phosphorus were determined. During calcitriol administration, the FGF23 level changed significantly (p=0.008), with the level at 24 h levels being significantly higher than at 8 h (8.8 pg/ml vs. 13.0 pg/ml, p=0.036). There was a statistically significant difference in the percentage change, among the three stages, at time 8 to 24 h and 0 to 24 h for FGF23 (p=0.014 and p=0.015, respectively), with significant differences between baseline vs. calcitriol for 8 to 24 h FGF23 change (-9.23% vs. 26.98%, p=0.003) and a trend between baseline vs. calcitriol (p=0.061) and calcitriol plus sevelamer (p=0.069) for 0 to 24 h FGF23 change. Administration of calcitriol to healthy individuals increases the circulating level of FGF23 within 24 h. Combined calcitriol and sevelamer administration restrains the increase of FGF23, suggesting that calcitriol-induced increased absorption of phosphate from the intestine might also be involved in the increase of FGF23.

Fibroblast Growth Factor-23-A Potential Uremic Toxin.

Fibroblast growth factor-23 (FGF23) is a circulating member of the FGF family produced mainly by the osteocytes and osteoblasts that can act as a hormone. The main action of FGF23 is to lower phosphatemia via the reduction of urinary phosphate reabsorption and the decrease of 1,25(OH)2-D generation in the kidney. In the course of chronic kidney disease (CKD), plasma FGF23 concentration rises early, most probably to compensate the inability of the deteriorating kidneys to excrete an adequate amount of phosphate. However, this comes at the cost of FGF23-related target organ toxicity. Results of clinical studies suggest that elevated plasma FGF23 concentration is independently associated with the increased risk of CKD progression, occurrence of cardio-vascular complications, and mortality in different stages of CKD. FGF23 also contributes to cardiomyocyte hypertrophy, vascular calcification, and endothelial dysfunction. The impact of FGF23 on heart muscle is not dependent on Klotho, but rather on the PLCγ–calcineurin–NFAT (nuclear factor of activated T-cells) pathway. Among the factors increasing plasma FGF23 concentration, active vitamin D analogues play a significant role. Additionally, inflammation and iron deficiency can contribute to the increase of plasma FGF23. Among the factors decreasing plasma FGF23, dietary phosphate restriction, some intestinal phosphate binders, cinacalcet (and other calcimimetics), and nicotinamide can be enumerated. Anti-FGF23 antibodies have also recently been developed to inhibit the action of FGF23 in target organs. Still, the best way to normalize plasma FGF23 in maintenance hemodialysis patients is restoring kidney function by successful kidney transplantation.

MicroRNA-297a regulates vascular calcification by targeting fibroblast growth factor 23.

Objective(s):Vascular calcification is one the major characteristics in patients with various types of chronic inflammatory disorders. MiRNAs have been shown to be involved in many normal biological functions as well as diseases; however, their role in vascular calcification has not received much attention.Materials and Methods:In the current study, we built a vascular calcification rat model using vitamin D3 plus nicotine and analyzed miRNA expression profile by miRNA chip assay. Potential target of one selected miRNA with sharpest variation in expression were predicted by both PicTar and TargetScan. The impact of the selected miRNA on the expression of the potential target on both mRNA and protein levels were measured by RT-PCR and Western blot, respectively.Results:Our results identified 16 dysregulated miRNAs, among which miR-297a showed the sharpest variation. Further analysis focusing on miR-297a revealed that fibroblast growth factor 23 (FGF23) was a potential target of miR297a. Measurement of FGF23 and its regulator Klotho on both mRNA and protein levels demonstrated that FGF23 was significantly increased while Klotho was decreased in rats with vascular calcification.Conclusion:Our results indicated that FGF23 was target of miR-297a and decreased miR-297a in vascular calcification lead to the increase of FGF23, which together with Klotho might enhance vascular calcification. The findings of this study could provide valuable information for the understanding of mechanisms underlying miR-dependent vascular calcification as well as potential treatment target for the disease.