[Clinical study on growth impairment induced by oral glucocorticoids based on FGF23/Klotho homeostasis observations]. / 基于FGF23/Klothoç¨³æ€è§‚å¯Ÿå£æœç³–çš®è´¨æ¿€ç´ è‡´ç”Ÿé•¿éšœç¢çš„ä¸´åºŠç ”ç©¶.

OBJECTIVES: To observe the correlation between growth impairment induced by long-term oral glucocorticoids (GC) therapy and the ratio of FGF23/Klotho in children with primary nephrotic syndrome (PNS). METHODS: A prospective study was conducted on 56 children with GC-sensitive PNS who had discontinued GC therapy for more than 3 months and revisited the Department of Pediatrics of the First Affiliated Hospital of Henan University of Traditional Chinese Medicine between June 2022 and December 2022. After monitoring qualitative and quantitative urine protein levels upon admission, the children with proteinuria relapse were treated with GC (GC group; n=29), while those without relapse did not receive GC treatment (non-GC group; n=27). In addition, 29 healthy children aged 3 to prepuberty were selected as the control group. Height, bone age, growth rate, and the FGF23/Klotho ratio were compared among the groups. The correlations of the FGF23/Klotho ratio with height, bone age, and growth rate were analyzed. RESULTS: The FGF23/Klotho ratio in the GC group was significantly higher than that in the non-GC group after 1 month of GC therapy (P<0.05), and the height and bone age growth rates within 6 months were lower than those in the non-GC group (P<0.05). Correlation analysis showed significant negative correlations between the FGF23/Klotho ratio after 1 month of treatment and the growth rates of height and bone age within 6 months in children with PNS (r=-0.356 and -0.436, respectively; P<0.05). CONCLUSIONS: The disturbance in FGF23/Klotho homeostasis is one of the mechanisms underlying the growth impairment caused by long-term oral GC therapy.

Effects of Nicotinamide and Lanthanum Carbonate on Serum Phosphate and Fibroblast Growth Factor-23 in CKD: The COMBINE Trial.

BACKGROUND: Higher serum phosphate and fibroblast growth factor-23 (FGF23) levels may be modifiable to prevent cardiovascular disease in CKD. Short-term studies have reported modest efficacy in phosphate and FGF23 reduction with intestinal phosphate binders in CKD. METHODS: To investigate effects of lanthanum carbonate (LC; a phosphate binder) and/or nicotinamide (NAM; an inhibitor of active intestinal phosphate transport) on serum phosphate and FGF23 in stage 3b/4 CKD, we conducted a randomized trial among individuals with eGFR 20-45 ml/min per 1.73 m2 to NAM (750 mg twice daily) plus LC (1000 mg thrice daily), NAM plus LC placebo, LC plus NAM placebo, or double placebo for 12 months. Dual primary end points were change from baseline in serum phosphate and intact FGF23 concentrations. RESULTS: Mean eGFR for the 205 participants was 32ml/min per 1.73 m2. At baseline, serum phosphate was 3.7 mg/dl and median FGF23 was 99 pg/ml (10th, 90th percentiles: 59, 205). Mean rates of change in phosphate increased slightly over 12 months in all groups and did not differ significantly across arms. Similarly, percent changes in FGF23 per 12 months increased for all arms except LC plus placebo, and did not differ significantly across arms. Gastrointestinal symptoms limited adherence. Adverse events rates were similar across arms. CONCLUSIONS: LC and/or NAM treatment did not significantly lower serum phosphate or FGF23 in stage 3b/4 CKD over 12 months. Although these agents appeared safe, intestinal symptoms limited adherence. Reducing phosphate and FGF23 in nondialysis CKD will require new approaches.

Effect of prolactin and estrogen on the serum level of 1,25-dihydroxy vitamin D and FGF23 in female rats.

INTRODUCTION: Estrogen and prolactin affect vitamin D metabolism. In conditions such as pregnancy and lactation, their interaction in regulating vitamin D metabolism and circulating FGF23 is not clearly defined. The aim of this study is to investigate this interaction in female rats. METHOD: This study was performed on 50 female adult rats, which were divided into five groups of Sham, ovariectomized rats (O), and three groups of ovariectomized rats were indicated with prolactin alone (OP), estradiol alone (OE), and a combination of estradiol and prolactin (OEP). Serum levels of 25(OH)D, 1,25(OH)2D3, FGF23, PTH, vitamin D-binding protein, calcium, and phosphorous were evaluated. RESULTS: Serum 1,25(OH)2D3 and PTH in OE were higher than the O group (P < 0.001 and P = 0.003, respectively). Serum FGF23 in the OE group was lower than the O group (P = 0.016). Serum 1,25(OH)2D3 increased in OP compared to the O group (P < 0.001) and OE group (P < 0.001). Serum FGF23 in OP was lower than the O group (P = 0.04). Furthermore, combining estradiol and prolactin showed no extra effect on increasing serum 1,25(OH)2D3. Serum 1,25(OH)2D3 was positively correlated with serum prolactin levels (r = 0.318, P = 0.017) in all five groups. CONCLUSION: It is suggested that estradiol could increase 1,25(OH)2D3 by elevating PTH and decreasing serum FGF23; however, prolactin was able to increase 1,25(OH)2D3 by lowering serum FGF23. Moreover, prolactin was shown to be more potent in augmenting serum 1,25(OH)2D3 than estrogen itself, which is important in maternal and fetal calcium supply during late pregnancy and lactation.

Identification of a crucial amino acid responsible for the loss of specifying FGFR1-KLB affinity of the iodinated FGF21.

Previous studies suggest that specific binding to the complex consisting of fibroblast growth factor receptor-1 (FGFR1) and the coreceptor beta-Klotho (KLB) is the premise for human FGF19 and FGF21 activating the downstream signaling cascades, and regulating the metabolic homeostasis. However, it was found that human FGF21 loses its ability to bind to FGFR1-KLB after iodination with Na125 I and chloramine T, whereas human FGF19 retained its affinity for FGFR1-KLB even after iodination. The molecular mechanisms underlying these differences remained elusive. In this study, we first demonstrated that an intramolecular disulfide bond was formed between cysteine-102 and cysteine-121 in FGF21, implying that the oxidation of the cysteine to cysteic acid, which may interfere with the active conformation of FGF21, did not occur during the iodination procedures, and thus ruled out the possibility of the two conserved cysteine residues mediating the loss of FGF21 binding affinity to FGFR1-KLB upon iodination. Site-directed mutagenesis and molecular modeling were further applied to determine the residue(s) responsible for the loss of FGFR1-KLB affinity. The results showed that mutation of a single tyrosine-207, but not the other five tyrosine residues in FGF21, to a phenylalanine retained the FGFR1-KLB affinity of FGF21 even after iodination, whereas replacing the corresponding phenylalanine residue with tyrosine in FGF19 did not alter its binding affinity to FGFR1-KLB, but decreased the receptor binding ability of the iodinated protein, suggesting that tyrosine-207 is the crucial amino acid responsible for the loss of specifying FGFR1-KLB affinity of the iodinated FGF21.

Effect of ferric citrate on serum phosphate and fibroblast growth factor 23 among patients with nondialysis-dependent chronic kidney disease: path analyses.

BACKGROUND: Among patients with nondialysis-dependent chronic kidney disease (NDD-CKD) and iron-deficiency anemia (IDA), ferric citrate increases hemoglobin and iron parameters and reduces serum phosphate and fibroblast growth factor 23 (FGF23), a key phosphate-regulating hormone. We conducted post hoc analyses of a phase 3 trial to explore associations between iron replacement, serum phosphate changes and FGF23 regulation. METHODS: We employed multivariable regression and longitudinal mixed-effects models to identify and confirm, respectively, whether baseline demographic and laboratory variables were associated with ferric citrate-induced changes in serum phosphate or FGF23 concentrations. We employed path analyses to determine whether changes in FGF23 concentrations were mediated via changes in serum phosphate and/or transferrin saturation (TSAT). RESULTS: We analyzed a total of 117 and 115 ferric citrate-treated and placebo-treated patients, respectively. At 16 weeks, ferric citrate significantly reduced serum phosphate versus placebo (P = 0.006) only among patients with elevated baseline serum phosphate (≥4.5 mg/dL) and did not reduce serum phosphate among patients with baseline serum phosphate within the population reference range. Ferric citrate reduced intact FGF23 and C-terminal FGF23 partially via changes in TSAT (for C-terminal FGF23) and serum phosphate (for intact FGF23) and partially via unknown/unmeasured mechanisms. CONCLUSIONS: Ferric citrate reduced serum FGF23 concentrations (partially via effects on serum phosphate and iron balance) and did not reduce serum phosphate among patients with baseline serum phosphate concentrations within the population reference range.

Effects of vitamin D supplementation on FGF23: a randomized-controlled trial.

PURPOSE: Fibroblast growth factor-23 (FGF23) is critical for phosphate homeostasis. Considering the high prevalence of vitamin D deficiency and the association of FGF23 with adverse outcomes, we investigated effects of vitamin D3 supplementation on FGF23 concentrations. METHODS: This is a post-hoc analysis of the Styrian Vitamin D Hypertension trial, a single-center, double-blind, randomized, placebo-controlled trial, conducted from 2011 to 2014 at the Medical University of Graz, Austria. Two hundred subjects with 25(OH)D concentrations < 30 ng/mL and arterial hypertension were randomized to receive either 2800 IU of vitamin D3 daily or placebo over 8 weeks. Primary outcome was the between-group difference in FGF23 levels at study end while adjusting for baseline values. RESULTS: Overall, 181 participants (mean ± standard deviation age, 60.1 ± 11.3; 48% women) with available c-term FGF23 concentrations were considered for the present analysis. Mean treatment duration was 54 ± 10 days in the vitamin D3 group and 54 ± 9 days in the placebo group. At baseline, FGF23 was significantly correlated with serum phosphate (r = 0.135; p = 0.002). Vitamin D3 supplementation had no significant effect on FGF23 in the entire cohort (mean treatment effect 0.374 pmol/L; 95% confidence interval - 0.024 to 0.772 pmol/L; p = 0.065), but increased FGF23 concentrations in subgroups with baseline 25(OH)D concentrations below 20 ng/mL (n = 70; mean treatment effect 0.973 pmol/L; 95% confidence interval - 0.032 to 1.979 pmol/L; p = 0.019) and 16 ng/mL (n = 40; mean treatment effect 0.593 pmol/L; 95% confidence interval 0.076 to 1.109; p = 0.022). CONCLUSIONS: Vitamin D3 supplementation had no significant effect on FGF23 in the entire study cohort. We did, however, observe an increase of FGF23 concentrations in subgroups with low baseline 25(OH)D.

FGF21 Is Associated with Metabolic Effects and Treatment Response in Depressed Bipolar II Disorder Patients Treated with Valproate.

Background: Patients with bipolar disorder are at high risk of metabolic disturbance after mood stabilizer treatment. However, the mediators linking the two conditions remain unknown. In this study, we investigated whether fibroblast growth factor-21 (FGF21) was associated with metabolic effects and treatment response in depressed bipolar disorder patients. Methods: We recruited 78 community-dwelling controls and 137 bipolar disorder patients; the latter were interviewed using the Chinese Version of the Modified Schedule of Affective Disorder and Schizophrenia-Life Time. Upon study entry, the bipolar disorder patients were all in a major depressive status, with 17-item Hamilton Depression Rating Scale (HDRS) scores >15. They received valproate (500-1000 mg daily) for 12 weeks, and fluoxetine 20 mg daily was permitted to treat depressive symptoms. Fasting plasma level of FGF21, lipid profiles, and body weight were collected at baseline and after 12 weeks of treatment. Results: At baseline, the demographic characteristics, FGF21 level, and metabolic indices did not differ significantly between the controls and bipolar disorder patients. After 12 weeks of treatment, the FGF21 level (167.7±122.0 to 207.1±162.3 pg/mL, P=.001), body weight and waist circumference had increased significantly (P<.001 and P=.028, respectively). Moreover, the change in FGF21 level was significantly correlated with the changes in HDRS score (r=0.393, P=.002), total cholesterol (r=-0.344, P=.008), and low-density lipoprotein (r=-0.347, P=.007). Conclusions: The central and peripheral mediating effects of FGF21 on bipolar disorder depression treatment might be opposite. High peripheral FGF21 levels might link regulation of metabolic effect and resistance to treatment in bipolar disorder.

Three-Month Randomized Clinical Trial of Nasal Calcitonin in Adults with X-linked Hypophosphatemia.

Previous work has demonstrated that a single subcutaneous dose of salmon calcitonin leads to a transient decline in circulating levels of FGF23 in patients with X-linked hypophosphatemia (XLH). Since the calcitonin receptor is expressed on osteocytes, this raises the possibility that interdicting signals through that receptor could modulate circulating levels of FGF23 in XLH. In the present study, 21 subjects with XLH were randomly assigned to receive either placebo nasal spray or 400 IU of nasal salmon calcitonin daily for three months. On the first and last day of the study, serial measurements of FGF23, 1,25-dihydroxyvitamin D, and TmP/GFR were made over 27 h. At the beginning of Visit 2 (the first day of month 2) and the beginning of Visit 3 (the first day of month 3), single, first-morning, fasting measurements of these same parameters were made before the next administered dose of study drug. Following the initial or final dose of study drug, there were no differences in area under the curve, based on treatment assignment, for the three principal outcome variables. Similarly, there were no differences in the fasting measures taken at the beginning of Visit 2 or Visit 3 compared to the fasting values on either day 2 of Visit 1 or the fasting values on day 2 of Visit 4. There were also no significant changes over time in serum phosphorus, serum calcium, circulating levels of PTH, CTx, or P1NP. The reasons why nasal salmon calcitonin did not recapitulate the findings with subcutaneously administered drug may relate to the kinetics of drug delivery, the bioavailability of drug or peak drug dose achieved. It remains possible, however, that other means of altering calcitonin receptor signaling may still provide an opportunity for regulating FGF23 production.

The suppressive effect of soluble Klotho on fibroblastic growth factor 23 synthesis in UMR-106 osteoblast-like cells.

Fibroblastic growth factor 23 (FGF23) is a hormone secreted primarily by bone. FGF23 is elevated in the serum of chronic kidney disease (CKD) patients, but the exact mechanism is not well known. Klotho is identified as an aging suppressor, which is mainly expressed in the kidney, and the level of soluble Klotho is negatively associated with FGF23 in CKD. The aim of this study was to investigate the effect and possible mechanism of Klotho on FGF23 synthesis in osteoblast-like UMR-106 cells. UMR-106 cells were divided into five groups: (i) control group; (ii) ß-glycerophosphate (ß-GP) group; (iii) ß-GP + Klotho group; (iv) ß-GP+ lithium chloride (LiCl, a Wnt/ß-catenin pathway agonist) group; and (v) ß-GP + Klotho + LiCl group. Subsequently, UMR-106 cells were cultured for 72 h, and the expression of FGF23, P-glycogen synthase kinase-3ß (P-GSK-3ß), and glycogen synthase kinase-3ß(GSK-3ß) were measured with Western blot analysis. The mRNA levels of FGF23 and the Wnt/ß-catenin pathway target gene c-myc were determined with RT-qPCR. The results showed that ß-GP induced increased expression of FGF23 mRNA and protein. Compared with the ß-GP group, expression of FGF23 mRNA and protein expression were downregulated in the ß-GP + Klotho group. In addition, ß-GP induced increased expression of P-GSK-3ß/GSK-3ß and c-myc, which were all downregulated in the ß-GP + Klotho group. Moreover, the expression of FGF23, P-GSK-3ß/GSK-3ß, and c-myc mRNA were upregulated when treated with LiCl. These results demonstrate that soluble Klotho suppresses FGF23 synthesis in osteoblast-like UMR-106 cells. The mechanism of this suppression may be partially through the inhibition of the Wnt/ß-catenin pathway.

Oral Versus Intravenous Iron Supplementation for the Treatment of Iron Deficiency Anemia in Patients on Maintenance Hemodialysis-Effect on Fibroblast Growth Factor-23 Metabolism.

OBJECTIVE: Iron administration affects serum levels of intact (I-) fibroblast growth factor-23 (FGF23) and its cleavage product C-terminal (C-) FGF23 in iron-deficient patients on maintenance hemodialysis (MHD). The objective of this study was to compare the effect of oral or intravenous iron administration on serum levels of I-FGF23 and C-FGF23 in iron-deficient patients on MHD. DESIGN AND METHODS: A prospective randomized study. SUBJECTS: Participants on MHD with severe iron deficiency (n = 61). INTERVENTION: Participants were randomized to receive oral iron (50 mg of sodium ferrous citrate daily; oral group, n = 29) or intravenous iron (40 mg of saccharated ferric oxide weekly; IV group, n = 32). MAIN OUTCOME MEASURE: Changes in I-FGF23 and C-FGF23 after 10 weeks of treatment. RESULTS: Iron supplementation significantly increased hemoglobin, mean corpuscular volume, ferritin, and transferrin saturation rate, and decreased erythropoiesis-stimulating agent dose and erythropoiesis-stimulating agent resistance index value. Serum phosphate, calcium, and intact parathyroid hormone levels did not change significantly during the study. I-FGF23 levels increased significantly in the IV group and did not change in the oral group, whereas C-FGF23 levels were significantly reduced in both groups. Serum interleukin-6 and tumor necrosis factor-α levels were increased in both groups. Multiple regression analysis indicated the relationship between iron or erythropoiesis and FGF23 metabolism. CONCLUSION: Iron administration to patients on MHD with severe iron deficiency decreased C-FGF23 levels, whereas intravenous iron increased I-FGF23 levels though oral iron did not. If the target of chronic kidney disease-mineral and bone disorder therapy is reducing I-FGF23 levels, we suggest the use of oral iron.

The Effect of Sitagliptin on Lipid Metabolism of Fatty Liver Mice and Related Mechanisms.

BACKGROUND In clinics, patients with type 2 diabetes complicated with non-alcoholic fatty liver disease (NAFLD) have been shown to receive significant improvements in blood glucose levels, lipid levels, and liver function after sitagliptin treatment, although the mechanism of drug action remains poorly understood. This study investigated the possible mechanism of sitagliptin on lipid metabolism of NAFLD mice. MATERIAL AND METHODS Male C57/BL6 mice were induced for NAFLD via 16 weeks of a high-fat diet, and were treated with 15 mg/kg/day sitagliptin for 16 consecutive weeks. Blood lipid levels were measured and samples were stained with hematoxylin and eosin (H&E) and oil red staining for liver pathology and lipid deposition. Serum levels of fibroblast growth factor (FGF)-9 and FGF-21 were quantified by enzyme-linked immunosorbent assay (ELISA). Peroxisome proliferator-activated receptor (PPAR)-α, and cAMP reactive element binding homolog (CREBH) were measured by Western blotting, while fatty acid synthase and carnitine palmitoyltransferase 1 (CPT1) mRNA levels were assayed by RT-PCR. RESULTS Compared to the control group, the NAFLD model mice had liver fatty disease, lower serum FGF-21 and FGF-19 levels, elevated serum lipid levels, depressed PPAR-α, CREBH, and CPT1 expression, and enhanced FAS expression (p<0.05). Sitagliptin treatment depressed blood lipid levels, increased serum FGF-21 and FGF-19 levels, PPAR-α, CREBH, and CPT1 expression, and suppressed FAS expression (p<0.05). CONCLUSIONS Sitagliptin can protect liver tissue and modulate lipid metabolism in NAFLD mice via elevating FGF-21 and FGF-19, upregulating liver PPAR-a and CREBH levels, and mediating expression levels of key enzymes for lipid metabolism.

Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production.

Circulating levels of fibroblast growth factor 23 (FGF23) are elevated in patients with chronic kidney disease (CKD), but the mechanisms are poorly understood. Here we tested whether inflammation and iron deficiency regulate FGF23. In wild-type mice, acute inflammation induced by single injections of heat-killed Brucella abortus or interleukin-1ß (IL-1ß) decreased serum iron within 6 h, and was accompanied by significant increases in osseous Fgf23 mRNA expression and serum levels of C-terminal FGF23, but no changes in intact FGF23. Chronic inflammation induced by repeated bacteria or IL-1ß injections decreased serum iron, increased osseous Fgf23 mRNA, and serum C-terminal FGF23, but modestly increased biologically active, intact FGF23 serum levels. Chronic iron deficiency mimicked chronic inflammation. Increased osseous FGF23 cleavage rather than a prolonged half-life of C-terminal FGF23 fragments accounted for the elevated C-terminal FGF23 but near-normal intact FGF23 levels in inflammation. IL-1ß injection increased Fgf23 mRNA and C-terminal FGF23 levels similarly in wildtype and Col4a3(ko) mice with CKD but markedly increased intact FGF23 levels only in the CKD mice. Inflammation increased Fgf23 transcription by activating Hif1α signaling. Thus, inflammation and iron deficiency stimulate FGF23 production. Simultaneous upregulation of FGF23 cleavage in osteocytes maintains near-normal levels of biologically active, intact circulating FGF23, whereas downregulated or impaired FGF23 cleavage may contribute to elevated intact serum FGF23 in CKD.

Effects of intravenous iron on fibroblast growth factor 23 (FGF23) in haemodialysis patients: a randomized controlled trial.

BACKGROUND: Intravenous iron affects serum levels of intact fibroblast growth factor-23 (iFGF23) and its cleavage product c-terminal FGF23 (cFGF23) in iron-deficient people with normal renal function. We hypothesized that intravenous iron modulates iFGF23 and cFGF23 in haemodialysis patients differently according to the type of iron used. METHODS: Prevalent, stable haemodialysis patients requiring protocol-based intravenous iron therapy were randomized to a single 200 mg dose of either ferric carboxymaltose (FCM) or iron sucrose (IS). The primary outcome was change in iFGF23 and cFGF23 from pre-infusion to Day 2 post-infusion. Serum hepcidin, ferritin and phosphate were also measured. Pair-wise comparisons utilised the Wilcoxon rank sum test; linear mixed models with an interaction term for treatment and time evaluated between-group effects. RESULTS: Forty-two participants completed the study. In those randomized to FCM (n = 22), median (interquartile range) values pre-infusion and Day 2, respectively, were 843 pg/mL (313-1922) and 576 pg/mL (356-1296, p = 0.05) for iFGF23, 704RU/mL (475-1204) and 813RU/mL (267-1156, p = 0.04) for cFGF23, and 1.53 mmol/L (1.14-1.71) and 1.37 (1.05-1.67, p = 0.03) for phosphate. These parameters did not change following IS. Both serum ferritin (p < 0.001) and hepcidin (p < 0.001) increased in both groups, and the increase in hepcidin was greater in the FCM group (p = 0.03 for between-group difference). CONCLUSIONS: Contrary to iron-deficient people with normal renal function, haemodialysis patients given protocol-driven intravenous FCM demonstrated a fall in iFGF23 and a rise in cFGF23, changes not evident with IS. This suggests a differential effect of intravenous iron treatment according to both formulation and renal function. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Register ACTRN12614000548639 . Registered 22 May 2014 (retrospectively registered).

Increased serum fibroblast growth factor-23 and decreased bone turnover in patients with systemic lupus erythematosus under treatment with cyclosporine and steroid but not steroid only.

SUMMARY: In patients with systemic lupus erythematosus (SLE), low bone mineral density (BMD) is associated with increased age, prolonged disease, low body mass index (BMI), and overlap with rheumatoid arthritis (RA). Elevated fibroblast growth factor (FGF)-23 in cyclosporine A (CsA) users with SLE are associated with decreased active vitamin D and osteocalcin. INTRODUCTION: The objective of this study was to investigate the steroid and CsA effect on bone metabolism and serum FGF-23 in SLE patients. METHODS: Seventy-two SLE patients and 10 age- and sex-matched healthy individuals underwent blood tests for bone metabolic biomarkers and FGF-23, and lumbar spine dual-energy X-ray absorptiometry for BMD. RESULTS: Comparisons between patients and controls were made in premenopausal women/men younger than 50 years and postmenopausal women/men older than 50 years separately. SLE patients had more frequent low Z-score (≤-2.0, 8.5 vs. 0%), osteopenia (-2.5

Fibroblast growth factor homologous factors modulate cardiac calcium channels.

RATIONALE: Fibroblast growth factor (FGF) homologous factors (FHFs; FGF11-14) are intracellular modulators of voltage-gated Na+ channels, but their cellular distribution in cardiomyocytes indicated that they performed other functions. OBJECTIVE: We aimed to uncover novel roles for FHFs in cardiomyocytes, starting with a proteomic approach to identify novel interacting proteins. METHODS AND RESULTS: Affinity purification of FGF13 from rodent ventricular lysates followed by mass spectroscopy revealed an interaction with junctophilin-2, a protein that organizes the close apposition of the L-type Ca2+ channel CaV1.2 and the ryanodine receptor 2 in the dyad. Immunocytochemical analysis revealed that overall T-tubule structure and localization of ryanodine receptor 2 were unaffected by FGF13 knockdown in adult ventricular cardiomyocytes but localization of CaV1.2 was affected. FGF13 knockdown decreased CaV1.2 current density and reduced the amount of CaV1.2 at the surface as a result of aberrant localization of the channels. CaV1.2 current density and channel localization were rescued by expression of an shRNA-insensitive FGF13, indicating a specific role for FGF13. Consistent with these newly discovered effects on CaV1.2, we demonstrated that FGF13 also regulated Ca(2+)-induced Ca2+ release, indicated by a smaller Ca2+ transient after FGF13 knockdown. Furthermore, FGF13 knockdown caused a profound decrease in the cardiac action potential half-width. CONCLUSIONS: This study demonstrates that FHFs not only are potent modulators of voltage-gated Na+ channels but also affect Ca2+ channels and their function. We predict that FHF loss-of-function mutations would adversely affect currents through both Na+ and Ca2+ channels, suggesting that FHFs may be arrhythmogenic loci, leading to arrhythmias through a novel, dual-ion channel mechanism.

AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients.

Using MRI techniques, we show here that normalization of tumor vessels in recurrent glioblastoma patients by daily administration of AZD2171-an oral tyrosine kinase inhibitor of VEGF receptors-has rapid onset, is prolonged but reversible, and has the significant clinical benefit of alleviating edema. Reversal of normalization began by 28 days, though some features persisted for as long as four months. Basic FGF, SDF1alpha, and viable circulating endothelial cells (CECs) increased when tumors escaped treatment, and circulating progenitor cells (CPCs) increased when tumors progressed after drug interruption. Our study provides insight into different mechanisms of action of this class of drugs in recurrent glioblastoma patients and suggests that the timing of combination therapy may be critical for optimizing activity against this tumor.

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 m(2). 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 m(2), 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.

Velcalcetide (AMG 416), a novel peptide agonist of the calcium-sensing receptor, reduces serum parathyroid hormone and FGF23 levels in healthy male subjects.

CONTEXT: Velcalcetide, also known as AMG 416, is a novel, long-acting selective peptide agonist of the calcium sensing receptor. It is being developed as an intravenous treatment of secondary hyperparathyroidism (SHPT) in hemodialysis patients with chronic kidney disease-mineral and bone disorder. OBJECTIVE: To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of velcalcetide in healthy male volunteers. METHODS: The study was a double-blind, randomized, placebo-controlled, single-dose, dose-escalation study in healthy males aged 18-45 years conducted at a single center. Each cohort included eight subjects randomized 6:2 to velcalcetide or placebo. INTERVENTION: Velcalcetide at 0.5, 2, 5 and 10 mg or placebo was administered intravenously. OUTCOMES: Measurements included plasma ionized calcium (iCa), serum total calcium, intact parathyroid hormone (iPTH), phosphorus and fibroblast growth factor-23 (FGF23), 1,25-dihydroxyvitamin D, calcitonin and urine creatinine, calcium and phosphorus and plasma pharmacokinetics for velcalcetide. Vital signs, safety biochemical and hematological indices, and adverse events were monitored throughout the study. RESULTS: Intravenous administration of velcalcetide was well tolerated with no adverse reaction of nausea, vomiting or diarrhea reported. Velcalcetide mediated dose-dependent decreases in serum iPTH at 30 min, FGF23 at 24 h and iCa at 12 h post dose (P<0.05) and in urine fractional excretion of phosphorus and increases in tubular reabsorption of phosphorus. Velcalcetide plasma exposure increased in a dose-related manner and the terminal elimination of half-life was comparable across the dose range evaluated and ranged from 18.4 to 20.0 h. CONCLUSION: Single IV doses of velcalcetide were well tolerated and associated with rapid, sustained, dose-dependent reductions in serum PTH. The results support further evaluation of velcalcetide as a treatment for SHPT in hemodialysis patients.

Long-term sevelamer treatment lowers serum fibroblast growth factor 23 accompanied with increasing serum Klotho levels in chronic haemodialysis patients.

AIMS: Fibroblast growth factor 23 (FGF23) and Klotho are associated with vascular calcification and cardiovascular disease in dialysis patients. Sevelamer has been shown to reduce progression of vascular calcification. This study aimed to determine the long-term effect of sevelamer treatment on serum FGF23 and Klotho levels in chronic haemodialysis (HD) patients. METHODS: In the post-hoc analysis, we measured serum FGF23, Klotho and other biochemical factors (Ca, P, i-PTH, hsCRP, LDL-C) in 50 haemodialysis patients, who completed a 48-week, open-Label, controlled randomized parallel-group study. Twenty-three patients received sevelamer and 27 patients received calcium carbonate. RESULTS: After 48-week sevelamer treatment, there were significant changes with lower LDL-C (from 2.82 ± 0.78 to 1.65 ± 0.53 mmol/L, P = 0.000), lower FGF23 (from 2465.97 (2568.88) to 795.61 (1098.39), P = 0.000) and higher s-Klotho levels (from 189.35 (161.88) to 252.94 (517.80) pg/mL, P = 0.000). In calcium carbonate group, there were no significant changes of LDL-C and FGF23, but with a borderline significant increase of s-Klotho level (from 142.34 (265.24) to 188.57 (252.38) pg/mL, P = 0.054). Multivariate analysis showed that FGF23 decrement was associated with sevelamer treatment (ß = -0.277, P = 0.005), change of serum phosphate (ß = 0.609, P = 0.000) and calcium levels (ß = 0.635, P = 0.000). The increase of serum Klotho was associated with the decrease of serum phosphate (ß = 0.490, P = 0.019). CONCLUSION: Maintenance HD patients had lower serum FGF23 levels, accompanied with significantly increased serum Klotho levels, after 48-week sevelamer treatment. The FGF23 decrement was associated with sevelamer use, the change of serum phosphate and calcium levels. The serum Klotho increment was proportional to the phosphate-lowering power of the binders.

Serum fibroblast growth factor 21 in human obesity: regulation by insulin infusion and relationship with glucose and lipid oxidation.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) reduces plasma glucose and triglycerides, and increases free fatty acid oxidation in animal models of diabetes. The aim of the present study was to assess the relationships of serum FGF21 with glucose oxidation (GOx) and lipid oxidation (LOx) in the baseline and insulin-stimulated conditions in lean and obese subjects. DESIGN: Cross-sectional study. SUBJECTS: Eighty-four subjects with normal glucose tolerance, 42 lean (body mass index (BMI) <25 kg m(-2)) and 42 overweight or obese (BMI between 25 and 40 kg m(-2)). MEASUREMENTS: Euglycemic hyperinsulinemic clamp and indirect calorimetry in the baseline state and during last 30 min of the clamp. The change in respiratory quotient (ΔRQ) in response to insulin was used as a measure of metabolic flexibility. Serum FGF21 was determined in the baseline state and after the clamp. RESULTS: Obese subjects had higher LOx in the baseline and insulin-stimulated conditions, lower insulin-stimulated GOx and ΔRQ (all P<0.05). Fasting serum FGF21 did not differ between the groups. Insulin infusion resulted in an increase in serum FGF21 in the obese (P=0.0001), but not in the lean group (P=0.76). Postclamp serum FGF21 was higher in the obese subjects (P=0.0007). In this group, postclamp FGF21 was related to LOx during the clamp (r=0.32, P=0.044), change in GOx and LOx in response to insulin (r=-0.44, P=0.005; r=0.47, P=0.002; respectively) and ΔRQ (r=-0.50, P=0.001). CONCLUSIONS: An increase in serum FGF21 in response to insulin in obese subjects might represent inappropriate response, possibly associated with metabolic inflexibility in obesity and insulin resistance.