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    Association between circulating FGF23, α-Klotho, and left ventricular diastolic dysfunction among patients with preserved ejection fraction. Okamoto Yusuke,Fujita Shu-ichi,Morita Hideaki,Kizawa Shun,Ito Takahide,Sakane Kazushi,Sohmiya Koichi,Hoshiga Masaaki,Ishizaka Nobukazu Heart and vessels Besides regulating calcium-phosphate metabolism, fibroblast growth factor-23 (FGF23) and Klotho have been proposed to have other roles in heart and vasculature. For example, FGF23 has been associated with cardiac hypertrophy and reduced left ventricular ejection fraction among patients with chronic kidney disease and cardiovascular disorders. The purpose of the study was to investigate whether serum FGF23 and α-Klotho concentrations are associated with cardiac diastolic dysfunction and related parameters among cardiac patients with preserved left ventricular ejection fraction. The current study enrolled 269 patients (69 women, 200 men) who were admitted to our cardiology department between October 2012 and January 2014 and had a left ventricular ejection fraction of >50%. Cardiac diastolic function was assessed by blood flow and tissue Doppler velocities, plasma B-type natriuretic peptide (BNP) concentration, and cardiac hypertrophy. After adjusting for sex, and age, logistic regression analysis showed that log(α-Klotho), but not log(FGF23), was significantly associated with diastolic dysfunction. After further adjustment for renal function, blood hemoglobin, and serum albumin levels, the negative association between log(α-Klotho) and diastolic dysfunction retained statistical significance with an odds ratio of 0.50 (95% confidence interval 0.31-0.81, P = 0.005, per 1 standard deviation). Among patients with preserved LVEF, serum α-Klotho concentrations were negatively associated with diastolic dysfunction. Whether modulation of serum levels α-Klotho will ameliorate cardiac diastolic function among patients with this disorder awaits further investigation. 10.1007/s00380-014-0581-9
    Parathyroid hormone 1 receptor is essential to induce FGF23 production and maintain systemic mineral ion homeostasis. Fan Yi,Bi Ruiye,Densmore Michael J,Sato Tadatoshi,Kobayashi Tatsuya,Yuan Quan,Zhou Xuedong,Erben Reinhold G,Lanske Beate FASEB journal : official publication of the Federation of American Societies for Experimental Biology Parathyroid-hormone-type 1 receptor (PTH1R) is extensively expressed in key regulatory organs for systemic mineral ion homeostasis, including kidney and bone. We investigated the bone-specific functions of PTH1R in modulating mineral ion homeostasis by generating a novel mouse model in which PTH1R is ablated in the limb mesenchyme using Prx1Cre transgenic mice. Such ablation decreased FGF23 protein and serum levels by 50%, despite normal Fgf23 mRNA levels in long bones. Circulating calcium and PTH levels were unchanged, but inorganic phosphate and 1,25(OH)2D3 levels were significantly decreased and accompanied by elevated urinary calcium and phosphate wasting. Key renal genes for balancing mineral ion homeostasis, calbindinD28k, Klotho, and Napi2a were suppressed by 30-40%. Intermittent hPTH(1-34) injections increased Fgf23 mRNA (7.3-fold), Nurr1 mRNA (3.1-fold), and serum intact-FGF23 (1.6-fold) in controls, but failed to induce Fgf23, Nurr1 mRNA, or intact FGF23 production in mutants. Moreover, a significant elevation in serum C-terminal-FGF23 levels (4-fold) was detected in both genotypes. PTH markedly downregulated Galnt3 expression (2.7-fold) in controls but not in mutants. These results demonstrate the pivotal role of PTH1R in long bones to regulate systemic mineral ion homeostasis and the direct induction of FGF23 by PTH1R signaling. 10.1096/fj.15-278184
    Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23. Degirolamo Chiara,Sabbà Carlo,Moschetta Antonio Nature reviews. Drug discovery The endocrine fibroblast growth factors (FGFs), FGF19, FGF21 and FGF23, are critical for maintaining whole-body homeostasis, with roles in bile acid, glucose and lipid metabolism, modulation of vitamin D and phosphate homeostasis and metabolic adaptation during fasting. Given these functions, the endocrine FGFs have therapeutic potential in a wide array of chronic human diseases, including obesity, type 2 diabetes, cancer, and kidney and cardiovascular disease. However, the safety and feasibility of chronic endocrine FGF administration has been challenged, and FGF analogues and mimetics are now being investigated. Here, we discuss current knowledge of the complex biology of the endocrine FGFs and assess how this may be harnessed therapeutically. 10.1038/nrd.2015.9
    FGF23 in chronic kidney disease: are we lost in translation? Bacchetta Justine BoneKEy reports 10.1038/bonekey.2015.140
    The FGF23/KLOTHO Regulatory Network and Its Roles in Human Disorders. Kinoshita S,Kawai M Vitamins and hormones The functions of Klotho (KL) are multifaceted and include the regulation of aging and mineral metabolism. It was originally identified as the gene responsible for premature aging-like symptoms in mice and was subsequently shown to function as a coreceptor in the fibroblast growth factor (FGF) 23 signaling pathway. The discovery of KL as a partner for FGF23 led to significant advances in understanding of the molecular mechanisms underlying phosphate and vitamin D metabolism, and simultaneously clarified the pathogenic roles of the FGF23 signaling pathway in human diseases. These novel insights led to the development of new strategies to combat disorders associated with the dysregulated metabolism of phosphate and vitamin D, and clinical trials on the blockade of FGF23 signaling in X-linked hypophosphatemic rickets are ongoing. Molecular and functional insights on KL and FGF23 have been discussed in this review and were extended to how dysregulation of the FGF23/KL axis causes human disorders associated with abnormal mineral metabolism. 10.1016/bs.vh.2016.02.001
    The fibroblast growth factor receptor mediates the increased FGF23 expression in acute and chronic uremia. Hassan Alia,Durlacher Karina,Silver Justin,Naveh-Many Tally,Levi Ronen American journal of physiology. Renal physiology Serum FGF23 is markedly elevated in chronic kidney disease and has been associated with poor long-term outcomes. FGF23 expression is increased by activation of the FGF receptor 1 (FGFR1) in rats with normal renal function and in vitro in bone-derived osteoblast-like cells. We studied the regulation of FGF23 by FGFR1 in vivo in acute and chronic uremia in mice and rats. Folic acid-induced acute kidney injury increased calvaria FGF23 mRNA and serum FGF23 and parathyroid hormone (PTH) levels at 6 h. The FGFR1 receptor inhibitor PD173074 prevented the folic acid-induced increase in both FGF23 mRNA and serum levels but had no effect on serum PTH levels. A more prolonged uremia due to an adenine high-phosphorus diet for 14 days resulted in high levels of FGF23 mRNA and serum FGF23 and PTH. PD173074 decreased serum FGF23 and mRNA levels with no effect on PTH in the adenine high phosphorus-induced uremic rats. Therefore, a derangement in FGF23 regulation starts early in the course of acute kidney injury, is in part independent of the increase in serum PTH, and involves activation of FGFR1. It is possible that FGFR1 in the osteocyte is activated by locally produced canonical FGFs, which are increased in uremia. This is the first demonstration that activation of FGFR1 is essential for the high levels of FGF23 in acute and chronic experimental uremia. 10.1152/ajprenal.00332.2015
    Up-regulation of FGF23 release by aldosterone. Zhang Bingbing,Umbach Anja T,Chen Hong,Yan Jing,Fakhri Hajar,Fajol Abul,Salker Madhuri S,Spichtig Daniela,Daryadel Arezoo,Wagner Carsten A,Föller Michael,Lang Florian Biochemical and biophysical research communications The fibroblast growth factor (FGF23) plasma level is high in cardiac and renal failure and is associated with poor clinical prognosis of these disorders. Both diseases are paralleled by hyperaldosteronism. Excessive FGF23 levels and hyperaldosteronism are further observed in Klotho-deficient mice. The present study explored a putative aldosterone sensitivity of Fgf23 transcription and secretion the putative involvement of the aldosterone sensitive serum & glucocorticoid inducible kinase SGK1, SGK1 sensitive transcription factor NFκB and store operated Ca(2+) entry (SOCE). Serum FGF23 levels were determined by ELISA in mice following sham treatment or exposure to deoxycorticosterone acetate (DOCA) or salt depletion. In osteoblastic UMR106 cells transcript levels were quantified by qRT-PCR, cytosolic Ca(2+) concentration utilizing Fura-2-fluorescence, and SOCE from Ca(2+) entry following store depletion by thapsigargin. As a result, DOCA treatment and salt depletion of mice elevated the serum C-terminal FGF23 concentration. In UMR106 cells aldosterone enhanced and spironolactone decreased SOCE. Aldosterone further increased Fgf23 transcript levels in UMR106 cells, an effect reversed by mineralocorticoid receptor blockers spironolactone and eplerenone, SGK1 inhibitor EMD638683, NFκB-inhibitor withaferin A, and Ca(2+) channel blocker YM58483. In conclusion, Fgf23 expression is up-regulated by aldosterone, an effect sensitive to SGK1, NFκB and store-operated Ca(2+) entry. 10.1016/j.bbrc.2016.01.034
    [Epidemiology of FGF23-related hypophosophatemic diseases]. Endo Itsuro Clinical calcium Through the studies of patients with hypophosphatemic rickets/osteomalacia, fibroblast growth factor 23(FGF23)has emerged as a humoral factor that reduces serum phosphate. Discovery of FGF23 as an essential regulator of phosphate homeostasis has markedly improved our understanding of phosphate homeostasis and hypophosphatemic or hyperphosphatemic disorders. A nationwide epidemiologic survey of FGF23-related hypophosphatemic diseases indicated that the patients showed FGF23 levels of above 30 pg/mL by intact assay in the presence of hypophosphatemia. The survey also showed that prevalence and biochemical data before and after treatment of the diseases. Novel therapeutic methods for these disorders may be developed by elucidation of the mechanism of action of FGF23. CliCa1602223231
    Baseline FGF23 is Associated with Cardiovascular Outcome in Incident PD Patients. Kim Hyo Jin,Park Miseon,Park Hayne Cho,Jeong Jong Cheol,Kim Dong Ki,Joo Kwon Wook,Hwang Young-Hwan,Yang Jaeseok,Ahn Curie,Oh Kook-Hwan Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis UNLABELLED:♦ BACKGROUND:Fibroblast growth factor 23 (FGF23) is a phosphate regulating protein. Several studies demonstrated that elevated FGF23 is independently associated with mortality for early-stage chronic kidney disease and incident hemodialysis (HD) patients. However, little is known about the significance of elevated FGF23 in peritoneal dialysis (PD) patients. Here, we analyzed the association of FGF23 with cardiovascular (CV) events, all-cause mortality, residual renal function (RRF), and CV parameters in PD patients. ♦ METHODS:The present study is a single-center, retrospective study. Patients who started PD at Seoul National University Hospital between January 2005 and July 2011 and whose baseline serum samples were available were enrolled. C-terminal FGF23 was measured. Subjects were divided into 2 groups; lower 2 tertiles (FGF23 ≤ 119.0 RU/mL) and top tertile (FGF23 > 119.0 RU/mL). The primary outcome was time to fatal or non-fatal CV events. In the subgroup analysis, the associations of FGF23 with aortic stiffness or with vascular calcification were analyzed. ♦ RESULTS:A total of 205 incident PD patients were analyzed. Mean duration of follow-up was 41.6 ± 20.0 months. The baseline median FGF23 level was 78.6 RU/mL (inter-quartile range [IQR], 34.1 - 155.0). At baseline, subjects in the higher FGF23 group were younger, and had a lower RRF, lower prevalence of diabetes mellitus (DM), and cerebrovascular disease. During follow-up, 22 of the 205 patients (10.7%) reached primary outcome. After adjustment for age, DM, pre-existing coronary artery disease, cerebrovascular disease, congestive heart failure, and left ventricular mass index, the higher FGF23 group exhibited significantly higher risk of primary outcome, compared with the lower group (hazard ratio [HR], 2.54; 95% confidence interval [CI], 1.05 - 6.12; p = 0.045). There were no significant differences in all-cause mortality and development of anuria between the 2 FGF23 groups. In the subgroup analysis, FGF23 groups were not associated with pulse wave velocity and abdominal aortic calcification score. ♦ CONCLUSION:Elevated FGF23 is associated with higher risk of adverse CV outcome for incident PD patients. 10.3747/pdi.2013.00343
    FGF23 Regulates Bone Mineralization in a 1,25(OH)2 D3 and Klotho-Independent Manner. Murali Sathish Kumar,Roschger Paul,Zeitz Ute,Klaushofer Klaus,Andrukhova Olena,Erben Reinhold G Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Fibroblast growth factor-23 (Fgf23) is a bone-derived hormone, suppressing phosphate reabsorption and vitamin D hormone (1,25(OH)2 D3 ) production in the kidney. It has long been an enigma why lack of Fgf23 or of Klotho, the coreceptor for Fgf23, leads to severe impairment in bone mineralization despite the presence of hypercalcemia and hyperphosphatemia. Using Fgf23(-/-) or Klotho(-/-) mice together with compound mutant mice lacking both Fgf23 or Klotho and a functioning vitamin D receptor, we show that in Klotho(-/-) mice the mineralization defect is solely driven by 1,25(OH)2 D3 -induced upregulation of the mineralization-inhibiting molecules osteopontin and pyrophosphate in bone. In Fgf23(-/-) mice, the mineralization defect has two components, a 1,25(OH)2 D3 -driven component similar to Klotho(-/-) mice and a component driven by lack of Fgf23, causing additional accumulation of osteopontin. We found that FGF23 regulates osteopontin secretion indirectly by suppressing alkaline phosphatase transcription and phosphate production in osteoblastic cells, acting through FGF receptor-3 in a Klotho-independent manner. Hence, FGF23 secreted from osteocytes may form an autocrine/paracrine feedback loop for the local fine-tuning of bone mineralization. 10.1002/jbmr.2606
    Fibroblast growth factor receptor 4: the missing link between chronic kidney disease and FGF23-induced left ventricular hypertrophy? Wyatt Christina M,Drüeke Tilman B Kidney international Serum phosphorus and the regulatory hormone fibroblast growth factor 23 have been strongly linked to cardiovascular morbidity and mortality in patients with chronic kidney disease. A recent study identified fibroblast growth factor receptor 4 as the primary receptor mediating the effect of fibroblast growth factor 23 on left ventricular hypertrophy, providing new mechanistic insights and a potential therapeutic target to reduce cardiovascular morbidity in chronic kidney disease. 10.1016/j.kint.2015.11.012
    Serum Fibroblast Growth Factor 23 (FGF23) in Patients with Rheumatoid Arthritis. Sato Hiroe,Kazama Junichiro James,Murasawa Akira,Otani Hiroshi,Abe Asami,Ito Satoshi,Ishikawa Hajime,Nakazono Kiyoshi,Kuroda Takeshi,Nakano Masaaki,Narita Ichiei Internal medicine (Tokyo, Japan) Objective Rheumatoid arthritis (RA) is a chronic inflammatory disease accompanied by periarticular and systemic osteoporosis. Fibroblast growth factor 23 (FGF23), which is mainly produced by osteocytes, circulates to the kidneys and regulates bone metabolism. We herein assessed serum FGF23 and its relationship to inflammation and osteoporosis in patients with RA. Methods Sixty-one patients with RA were included. Serum concentrations of FGF23 were determined using a sandwich enzyme-linked immunosorbent assay. Results The mean (± standard deviation) serum FGF23 concentration was 34.9±9.2 (range, 21.0-61.0) pg/mL. The serum FGF23 level was significantly and positively correlated with the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) levels, disease activity score-28 based on the ESR (DAS-28 ESR) and DAS-28 CRP (r=0.261, p=0.044, r=0.280, p=0.029, r=0.409, p=0.001 and r=0.421, p=0.001, respectively). The serum matrix metalloproteinase-3 level was also significantly and positively correlated with the serum FGF23 level (r=0.331, p=0.015). Concentrations of type I collagen cross-linked N-telopeptide in the serum was significantly correlated with the serum FGF23 level (r=0.272, p=0.034). Neither the bone mineral density in the femoral neck nor lumbar was significantly correlated with the serum FGF23 level. Serum phosphate, calcium, 25-hydroxy vitamin D, and intact parathyroid hormone were not related to the serum FGF23 level. Conclusion In patients with RA, serum FGF23 is correlated with inflammation, the disease activity of RA, and bone absorption markers. Serum FGF23 may be associated with abnormal bone absorption related to RA inflammation. Further studies are necessary to clarify the mechanism underlying this association. 10.2169/internalmedicine.55.5507
    Intact FGF23 and α-Klotho during acute inflammation/sepsis in CKD patients. Dounousi Evangelia,Torino Claudia,Pizzini Patrizia,Cutrupi Sebastiano,Panuccio Vincenzo,D'Arrigo Graziella,Abd ElHafeez Samar,Tripepi Giovanni,Mallamaci Francesca,Zoccali Carmine European journal of clinical investigation BACKGROUND:High FGF23 and low α-Klotho levels associate with systemic inflammation and reduced nitric oxide (NO) bioavailability, but the dynamics of this relationship in patients with CKD has not been investigated. METHODS:We sequentially measured serum intact FGF23 and carboxyl-terminal (iFGF23, cFGF23), the iFGF23/cFGF23 ratio, αKlotho, biomarkers of inflammation (hs-CRP, IL-6 and TNF-α) and sepsis (procalcitonin), nitrotyrosine (reflecting NO synthesis and oxidative stress), serum iron and ferritin and CKD-MBD biomarkers, PTH, 25(OH)VD, 1,25(OH)2 VD at peak of intercurrent sepsis and after complete resolution in a series of 17 patients with CKD. RESULTS:At peak infection, biomarkers of inflammation/sepsis, ferritin and nitrotyrosine were all very high (all P < 0·01) and declined towards the normal range thereafter (P < 0·01). iFGF23 was 191 ± 10 pg/ml (geometric mean, SD) and doubled to 371 ± 8 pg/ml (P = 0·003) after the resolution of infection, while cFGF23 did not change (246 ± 5 pg/mL vs. 248 ± 5 pg/mL, P = 0·50). As a consequence, the iFGF23/cFGF23 ratio, an indicator of the proteolytic cleavage of the FGF23 molecule, was 0·78 ± 3·87 at peak infection and increased to 1·49 ± 3·00 after resolution of infection (P < 0·001). In contrast, serum α-Klotho levels were upregulated at peak infection (peak infection: 526 ± 4 pg/ml, postinfection: 447 ± 4 pg/ml, P = 0·001). The eGFR, PTH and vitamin D did not change significantly throughout. CONCLUSIONS:Acute inflammation/sepsis suppresses the active form of FGF23 and activates α-Klotho, the latter effect being likely attributable to enhance proteolysis of FGF23 molecule. iFGF23 downregulation and α-Klotho upregulation during acute sepsis may participate into the counter-regulatory response to severe inflammation in CKD patients with sepsis. 10.1111/eci.12588
    FGF23-regulated production of Fetuin-A (AHSG) in osteocytes. Mattinzoli D,Rastaldi M P,Ikehata M,Armelloni S,Pignatari C,Giardino L A,Li M,Alfieri C M,Regalia A,Riccardi D,Messa P Bone INTRODUCTION:AHSG, a serum glycoprotein with recognized anti-calcification activity, has also been suggested to modulate both bone formation and resorption. Though the bulk of AHSG is mostly synthesized in the liver, it has been claimed that also bone cells might produce it. However, the extent of the bone AHSG production and the potential controlling factors remain to be definitively proven. A relevant number of studies support the notion that FGF23, a bone-derived hormone, not only regulates the most important mineral metabolism (MM) related factors (phosphate, parathyroid hormone, vitamin D, etc.), but might be also involved in cardiovascular (CV) outcome, both in chronic kidney disease (CKD) patients and in the general population. Furthermore, in addition to some direct autocrine and paracrine effects in bone, FGF23 has been suggested to interact with AHSG. In this study we investigated if AHSG is really produced by bone cells, and if its bone production is related and/or controlled by FGF23, using cultured bone cells, according to a new method recently published by our group. RESULTS:Our data show that AHSG is consistently produced in osteocytes and to a far lesser extent in osteoblasts. Both FGF23 addition to the culture medium and its over-expression in osteocytes were associated with a consistent increase of both AHSG mRNA and protein, while FGF23 silencing was followed by opposite effects. Though most of these results were largely affected by the blockage of FGF23 receptors, the role of these receptors in the different experimental sets is still not completely clarified. In addition, we found that FGF23 and AHSG proteins co-localized both in cytoplasm and nucleus, which suggests a possible reciprocal interactivity. CONCLUSIONS:Our data not only confirm that AHSG is produced in bone, mainly in osteocytes, but show for the first time that its production is modulated by FGF23. Since both proteins play important roles in the bone and cardiovascular pathology, these results add new pieces to the puzzling relationship between bone and vascular pathology, in particular in CKD patients, prompting future investigations in this field. 10.1016/j.bone.2015.10.008
    [Inhitibion of FGF23 activities as a possible new treatment for patients with FGF23-related hypophosphatemic diseases]. Kinoshita Yuka Clinical calcium Excessive actions of fibroblast growth factor 23(FGF23)result in several kinds of hypophosphatemic rickets and osteomalacia. A combination of oral active vitamin D3 and phosphate is the current standard therapy for FGF23-related hypophosphatemia. However, these medications can lead to long-term complications, such as secondary hyperparathyroidism and renal impairment. Therefore, safer and more efficient therapy to correct excessive actions of FGF23 is needed. X-linked hypophosphatemic rickets(XLHR)is the most prevalent form of FGF23-related hypophosphatemia. The efficacy of anti-FGF23 antibody was confirmed in a Hyp mouse, a murine model of XLHR. A recent phase 1 double-blind, placebo-controlled study and the subsequent open-label phase 1/2 study in adults with XLHR showed the safety and the efficacy of human anti-FGF23 antibody, KRN23. KRN23 has a potential for effectively treating patients with XLHR and other types of FGF23-related hypophosphatemia as well. CliCa1602233239
    [FGF23 related hypophosphatemic rickets:current therapy and unresolved issues]. Harada Daisuke,Namba Noriyuki Clinical calcium FGF23-related hypophosphatemic rickets is basically treated with active vitamin D and phosphorus. The treatment goals are to minimize bone deformity and improve adult height in children, and to relieve pain and decrease osteomalacia in adult. However, since they do not target the underlying molecular defect, bone deformity can worsen during growth and adult height is suboptimal restricted. Many adult patients suffer from enthesopathy leading to symptoms such as spinal cord compression and debilitating pain. At present, no treatment is effective in preventing or revenging this complication. The recently developed anti-FGF23 antibody may potentially be a more fundamental treatment. CliCa1602269276
    FGF23-FGF Receptor/Klotho Pathway as a New Drug Target for Disorders of Bone and Mineral Metabolism. Fukumoto Seiji Calcified tissue international Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by bone and works by binding to Klotho-FGF receptor complex. Excessive and deficient actions of FGF23 result in hypophosphatemic and hyperphosphatemic diseases, respectively. Therefore, it is reasonable to think that modulating FGF23 activities may be a novel therapeutic measure for these diseases. Several preclinical reports indicate that the inhibition of FGF23 activities ameliorates hypophosphatemic rickets/osteomalacia caused by excessive actions of FGF23. In addition, phase I-II clinical trials of anti-FGF23 antibody in adult patients with X-linked hypophosphatemia rickets, the most prevalent cause of genetic FGF23-related hypophosphatemic rickets, indicated that the antibody enhances renal tubular phosphate reabsorption and increases serum phosphate. However, it is not known whether the inhibition of FGF23 activities actually brings clinical improvement of rickets and osteomalacia. Available data indicate that FGF23-FGF receptor/Klotho pathway can be a new drug target for disorders of phosphate and bone metabolism. 10.1007/s00223-015-0029-y
    Associations of FGF23 With Change in Bone Mineral Density and Fracture Risk in Older Individuals. Isakova Tamara,Cai Xuan,Lee Jungwha,Katz Ronit,Cauley Jane A,Fried Linda F,Hoofnagle Andrew N,Satterfield Suzanne,Harris Tamara B,Shlipak Michael G,Sarnak Mark J,Ix Joachim H, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Elevated levels of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23) have been linked to greater risk of fractures in some studies, especially among individuals with chronic kidney disease (CKD). We evaluated FGF23 as a risk factor for bone loss and fractures in the Health, Aging, and Body Composition (Health ABC) study, which is a prospective biracial cohort of well-functioning adults aged 70 to 79 years recruited at two clinical centers in the United States. The sample for the bone mineral density (BMD) analyses consisted of 2234 participants who had at least two serial total hip areal BMD measures. The fracture analyses included 2786 participants, 567 of whom sustained a fracture during a median follow up of 4.95 years. Linear mixed-effects models were used for longitudinal measurements of total hip areal BMD and the proportional subdistribution hazard regression model subject to competing risks of death was used for risk of fracture. The median FGF23 was 46.7 (interquartile range [IQR] 36.7 to 60.2) pg/mL. The mean annualized percent change in total hip areal BMD did not vary significantly according to FGF23 quartile in all participants (p for trend = 0.70), but the effect was modified by CKD status (adjusted p for interaction <0.001). Among participants with CKD, the unadjusted mean annualized percent change in total hip areal BMD was greater with higher levels of FGF23 (unadjusted p for trend = 0.02), but the trend was attenuated with adjustment for estimated glomerular filtration rate and parathyroid hormone (adjusted p for trend = 0.30). FGF23 was not significantly associated with fracture risk in crude (hazard ratio [HR] per doubling of FGF23, 0.97; 95% CI, 0.85 to 1.12) or adjusted models (HR per doubling of FGF23, 1.02; 95% CI, 0.86 to 1.22), and these findings were not modified by gender or CKD status. FGF23 levels are not associated with bone loss or fracture risk in older adults with low prevalence of CKD. 10.1002/jbmr.2750
    FGF23 signaling impairs neutrophil recruitment and host defense during CKD. Rossaint Jan,Oehmichen Jessica,Van Aken Hugo,Reuter Stefan,Pavenstädt Hermann J,Meersch Melanie,Unruh Mark,Zarbock Alexander The Journal of clinical investigation Chronic kidney disease (CKD) has been associated with impaired host response and increased susceptibility to infections. Leukocyte recruitment during inflammation must be tightly regulated to protect the host against pathogens. FGF23 levels are increased in blood during CKD, and levels of this hormone have been associated with a variety of adverse effects in CKD patients. Here, we have shown that CKD impairs leukocyte recruitment into inflamed tissue and host defense in mice and humans. FGF23 neutralization during CKD in murine models restored leukocyte recruitment and host defense. Intravital microscopy of animals with chronic kidney failure showed that FGF23 inhibits chemokine-activated leukocyte arrest on the endothelium, and downregulation of FGF receptor 2 (FGFR2) on PMNs rescued host defense in these mice. In vitro, FGF23 inhibited PMN adhesion, arrest under flow, and transendothelial migration. Mechanistically, FGF23 binding to FGFR2 counteracted selectin- and chemokine-triggered β2 integrin activation on PMNs by activating protein kinase A (PKA) and inhibiting activation of the small GTPase Rap1. Moreover, knockdown of PKA abolished the inhibitory effect of FGF23 on integrin activation. Together, our data reveal that FGF23 acts directly on PMNs and dampens host defense by direct interference with chemokine signaling and integrin activation. 10.1172/JCI83470
    Elevation of circulating but not myocardial FGF23 in human acute decompensated heart failure. Andersen Ingrid A,Huntley Brenda K,Sandberg Sharon S,Heublein Denise M,Burnett John C Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association BACKGROUND:Elevated plasma fibroblast growth factor 23 (FGF23) is a prognostic marker in chronic kidney disease. Recently, FGF23 was reported to also be a predictive factor in chronic congestive heart failure (HF). To date however, plasma levels in acute decompensated HF (ADHF) have not been reported and myocardial production and distribution of FGF23 in HF is poorly defined. We aimed to determine plasma levels and myocardial production of FGF23 in ADHF. METHODS:Plasma FGF23, N-terminal pro B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR) were assessed in 21 ADHF patients and 19 controls. Myocardial gene expression and distribution of FGF23 was determined on left ventricular samples from HF patients and normal controls. RESULTS:Plasma FGF23 was markedly higher in ADHF patients compared with controls (1498 ± 1238 versus 66 ± 27 RU/mL, P < 0.0001). There were no correlations between FGF23 and eGFR, NT-proBNP, ejection fraction or age. ADHF subjects with eGFR >60 mL/min/1.73 m(2) had FGF23 levels of 1526 ± 1601 RU/mL versus 55 ± 20 RU/mL in controls (P = 0.007). Quantified myocardial FGF23 gene expression was similar between HF patients and controls. Myocardial FGF23 immunostaining was similar between HF patients and controls, with equal distribution throughout cardiomyocytes. CONCLUSION:Patients with ADHF had markedly elevated plasma FGF23 levels. Myocardial FGF23 gene expression was present in HF at a similar level as normal controls, and immunohistochemistry showed similar cellular distribution of FGF23 in HF and controls, suggesting that the myocardium does not contribute to the elevated circulating FGF23 in HF. 10.1093/ndt/gfv398
    Prognostic value of FGF23 among patients with end-stage renal disease: a systematic review and meta-analysis. Yang Hongliu,Luo Han,Tang Xi,Zeng Xiaoxi,Yu Yang,Ma Liang,Fu Ping Biomarkers in medicine AIMS:Prognostic value of FGF23 in end-stage renal disease (ESRD) patients is controversial. A systematic review was conducted to quantify the association between elevated FGF23 and overall mortality among ESRD patients. METHODS:MEDLINE, EMBASE, PubMed and reference lists were searched. Quality of the included studies was evaluated using Newcastle-Ottawa Scale checklist. Pooled effects were calculated as hazard ratio using fixed-effect models, and chi-square test was used for heterogeneity testing. RESULTS:Seven studies (1406 patients) were included. Patients were at mean age of 62.3. Mean follow-up was 29.4 months. From the pooled analysis, elevated FGF23 was significantly associated with increased all-cause mortality (hazard ratio: 1.53; 95% CI: 1.05-2.25). p-value for heterogeneity was 0.10, I(2) = 48%. CONCLUSIONS:ESRD patients with elevated FGF23 concentration have higher risk of death. 10.2217/bmm.16.11
    Phosphate and FGF23 in the renoprotective benefit of RAAS inhibition. de Seigneux Sophie,Martin Pierre-Yves Pharmacological research Renin angiotensin-aldosterone system (RAAS) blockade is a mainstay of chronic kidney disease (CKD) treatment given its beneficial effects on proteinuria, nephroprotection, heart disease and global mortality. The FGF23/Klotho/phosphate axis is crucial for phosphate excretion. During CKD, loss of Klotho, decreased phosphate excretion and FGF23 elevation are early events contributing both to renal disease progression and to cardiovascular complications. Experimental evidence suggests that Klotho replacement may improve renal and cardiovascular disease during CKD. Recent evidence suggests that both RAAS activation and proteinuria decrease Klotho expression and lead to phosphate retention and FGF23 elevation. In opposition RAAS blockade may reverse Klotho loss during CKD in both experimental and human studies, with direct and indirect expected beneficial effects on the kidney and cardiovascular system. This effect of RAAS blockade on the FGF23/Klotho/phosphate axis may participate in explaining some of the beneficial effects of these drugs during CKD. In this article we review the evidence linking RAAS blockade to modulation of the FGF23/Klotho/phosphate axis and the beneficial effects of these regulations. 10.1016/j.phrs.2016.02.015
    FGF23 from bench to bedside. Kovesdy Csaba P,Quarles L Darryl American journal of physiology. Renal physiology There is a strong association between elevated circulating fibroblast growth factor-23 (FGF23) levels and adverse outcomes in patients with chronic kidney disease (CKD) of all stages. Initially discovered as a regulator of phosphate and vitamin D homeostasis, FGF23 has now been implicated in several pathophysiological mechanisms that may negatively impact the cardiovascular and renal systems. FGF23 is purported to have direct (off-target) effects in the myocardium, as well as canonical effects on FGF receptor/α-klotho receptor complexes in the kidney to activate the renin-angiotensin-aldosterone system, modulate soluble α-klotho levels, and increase sodium retention, to cause left ventricular hypertrophy (LVH). Conversely, FGF23 could be an innocent bystander produced in response to chronic inflammation or other processes associated with CKD that cause LVH and adverse cardiovascular outcomes. Further exploration of these complex mechanisms is needed before modulation of FGF23 can become a legitimate clinical target in CKD. 10.1152/ajprenal.00606.2015
    More trouble with FGF23: a novel role in systemic immunosuppression. Abdullah Zeinab,Kurts Christian Kidney international A recent study describes impaired neutrophil function as another adverse effect of the excessive levels of FGF23 found in the circulation of patients with chronic kidney disease. These findings shed light on the mechanisms by which chronic kidney disease leads to systemic immunosuppression. 10.1016/j.kint.2016.04.002
    Stability and degradation of fibroblast growth factor 23 (FGF23): the effect of time and temperature and assay type. El-Maouche D,Dumitrescu C E,Andreopoulou P,Gafni R I,Brillante B A,Bhattacharyya N,Fedarko N S,Collins M T Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA UNLABELLED:There is growing need for a reliable assay for measuring fibroblast growth factor 23 (FGF23), a regulator of phosphorus and vitamin D. In this work, we analyze and compare the performance of three available assays, including the effect of temperature and time. This knowledge will allow for better understanding of FGF23 in the future. INTRODUCTION:Intact and C-terminal FGF23 (iFGF23 and cFGF23) concentrations are important in the diagnosis of hypo- and hyperphosphatemic diseases. The effects of temperature, storage, and specimen handling on FGF23 levels are not well known. We investigated the effects of various factors on plasma and serum measurement of FGF23 using three different assays. METHODS:Serum and plasma FGF23 were measured using three commercially available ELISA assays-two measuring iFGF23 and one measuring cFGF23. Samples from subjects with known FGF23 disorders were stored at 4, 22, and 37 °C and analyzed at different intervals up to 48 hours (h). A subset of samples underwent repeated freeze-thaw cycles, and samples frozen at -80 °C for up to 60 months were reanalyzed. The effect of adding a furin convertase inhibitor on FGF23 degradation was investigated using samples stored at 37 °C for 48 h. Intact FGF23 levels were measured from plasma samples of four different groups to test the correlation of the two assays. RESULTS:Plasma FGF23 levels were stable when stored at 4 and 22 °C for 48 h. Both plasma and serum FGF23 levels demonstrated relative stability after five freeze-thaw cycles. Long-term storage at -80 °C for 40 months induced some variability in FGF23 levels. The addition of a furin inhibitor did not affect FGF23 degradation. Intact FGF23 levels showed good correlation only at the upper limit of the assay range when comparing the two assays. CONCLUSIONS:Sample type, handling, and choice of assay are factors that affect FGF23 levels and should be considered when measuring this hormone. 10.1007/s00198-016-3543-5
    Association between FGF23, α-Klotho, and Cardiac Abnormalities among Patients with Various Chronic Kidney Disease Stages. Tanaka Suguru,Fujita Shu-Ichi,Kizawa Shun,Morita Hideaki,Ishizaka Nobukazu PloS one BACKGROUND:Several experimental studies have demonstrated that fibroblast growth factor 23 (FGF23) may induce myocardial hypertrophy via pathways independent of α-Klotho, its co-factor in the induction of phosphaturia. On the other hand, few studies have clearly demonstrated the relationship between FGF23 level and left ventricular hypertrophy among subjects without chronic kidney disease (CKD; i.e., CKD stage G1 or G2). PURPOSE:To investigate the data from 903 patients admitted to the cardiology department with various degrees of renal function, including 234 patients with CKD stage G1/G2. METHODS AND RESULTS:Serum levels of full-length FGF23 and α-Klotho were determined by enzyme immunoassay. After adjustment for sex, age, and estimated glomerular filtration rate (eGFR), the highest FGF23 tertile was significantly associated with left ventricular hypertrophy among patients with CKD stage G1/G2 and those with CKD stage G3a/G3b/G4 as compared with the lowest FGF23 tertile, and the association retained significance after further adjustment for serum levels of corrected calcium, inorganic phosphate, and C-reactive protein, as well as diuretic use, history of hypertension, and systolic blood pressure. FGF23 was also associated with low left ventricular ejection fraction among patients with CKD stage G1/G2 and those with CKD stage G3a/G3b/G4 after adjusting for age, sex, eGFR, corrected calcium, and inorganic phosphate. On the other hand, compared with the highest α-Klotho tertile, the lowest α-Klotho tertile was associated with left ventricular hypertrophy and systolic dysfunction only among patients with CKD stage G3b and stage G3a, respectively. CONCLUSIONS:An association between FGF23 and cardiac hypertrophy and systolic dysfunction was observed among patients without CKD as well as those with CKD after multivariate adjustment. However, the association between α-Klotho and cardiac hypertrophy and systolic dysfunction was significant only among patients with CKD G3b and G3a, respectively. 10.1371/journal.pone.0156860
    [Role of parathyroid hormone in Klotho-FGF23 system]. Kimura Takaaki,Shiizaki Kazuhiro,Kuro-O Makoto Clinical calcium Klotho was originally identified as an anti-aging gene that accelerated aging when disrupted and extended life span when overexpressed in mice. The Klotho gene encodes a single-pass transmembrane protein and is expressed in the kidney and parathyroid gland. Klotho protein functions as an obligate subunit of the receptor for fibroblast growth factor 23 (FGF23). FGF23 is a hormone secreted from osteocytes and osteoblasts and acts on renal tubular cells to promote phosphate excretion into the urine and suppress synthesis of active form of vitamin D (1,25-dihydroxyvitamin D3;1,25(OH)(2)D(3)). Decreased Klotho expression due to the kidney damage including CKD might increase the circulating level of FGF23 and trigger disturbed mineral-bone metabolism, leading to CKD-MBD. Characteristic features of CKD-MBD including hyperphosphatemia, hypocalcemia, and decreased serum 1,25(OH)(2)D(3) can be explained by (mal) adaptation of the Klotho-FGF23 system, which also contributes to the pathophysiology of secondary hyperparathyroidism (SHPT). In addition to its function as a receptor for FGF23, the extracellular domain of Klotho is secreted by ectodomain shedding and functions as a humoral factor that regulates multiple ion channels and transporters. Thus, Klotho has emerged as a key regulator of mineral metabolism in health and disease. CliCa1606859866
    Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease. Leifheit-Nestler Maren,Große Siemer Robert,Flasbart Kathrin,Richter Beatrice,Kirchhoff Felix,Ziegler Wolfgang H,Klintschar Michael,Becker Jan U,Erbersdobler Andreas,Aufricht Christoph,Seeman Tomas,Fischer Dagmar-Christiane,Faul Christian,Haffner Dieter Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association BACKGROUND:In chronic kidney disease (CKD), serum concentrations of fibroblast growth factor 23 (FGF23) increase progressively as glomerular filtration rate declines, while renal expression of the FGF23 coreceptor Klotho decreases. Elevated circulating FGF23 levels are strongly associated with mortality and with left ventricular hypertrophy (LVH), which is a major cause of cardiovascular death in CKD patients. The cardiac FGF23/FGF receptor (FGFR) system and its role in the development of LVH in humans have not been addressed previously. METHODS:We conducted a retrospective case-control study in 24 deceased patients with childhood-onset end-stage renal disease (dialysis: n = 17; transplanted: n = 7), and 24 age- and sex-matched control subjects. Myocardial autopsy samples of the left ventricle were evaluated for expression of endogenous FGF23, FGFR isoforms, Klotho, calcineurin and nuclear factor of activated T-cells (NFAT) by immunohistochemistry, immunofluorescence microscopy, qRT-PCR and western blotting. RESULTS:The majority of patients presented with LVH (67%). Human cardiomyocytes express full-length FGF23, and cardiac FGF23 is excessively high in patients with CKD. Enhanced myocardial expression of FGF23 in concert with Klotho deficiency strongly correlates with the presence of LVH. Cardiac FGF23 levels associate with time-averaged serum phosphate levels, up-regulation of FGFR4 and activation of the calcineurin-NFAT signaling pathway, an established mediator of cardiac remodelling and LVH. These changes are detected in patients on dialysis but not in those with a functioning kidney transplant. CONCLUSIONS:Our results indicate a strong association between LVH and enhanced expression levels of FGF23, FGFR4 and calcineurin, activation of NFAT and reduced levels of soluble Klotho in the myocardium of patients with CKD. These alterations are not observed in kidney transplant patients. 10.1093/ndt/gfv421
    Bone mineral disorder in chronic kidney disease: Klotho and FGF23; cardiovascular implications. Salanova Villanueva Laura,Sánchez González Carmen,Sánchez Tomero José Antonio,Aguilera Abelardo,Ortega Junco Esther Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia Cardiovascular factors are one of the main causes of morbidity and mortality in patients with chronic kidney disease. Bone mineral metabolism disorders and inflammation are pathological conditions that involve increased cardiovascular risk in chronic kidney disease. The cardiovascular risk involvement of bone mineral metabolism classical biochemical parameters such as phosphorus, calcium, vitamin D and PTH is well known. The newest markers, FGF23 and klotho, could also be implicated in cardiovascular disease. 10.1016/j.nefro.2016.01.011
    Klotho modulates FGF23-mediated NO synthesis and oxidative stress in human coronary artery endothelial cells. Richter Beatrice,Haller Jacqueline,Haffner Dieter,Leifheit-Nestler Maren Pflugers Archiv : European journal of physiology Chronic kidney disease (CKD) is a state of Klotho deficiency and excess of the phosphaturic hormone fibroblast growth factor 23 (FGF23). Both dysregulations were shown to be associated with endothelial dysfunction in humans, but direct vascular effects of FGF23 remain largely elusive. In vitro experiments were performed to assess the effects of FGF23 (10 ng/mL) in relation to its co-receptor Klotho on nitric oxide (NO) synthesis and reactive oxygen species (ROS) formation and detoxification in human coronary artery endothelial cells (HCAEC). Membrane-bound Klotho is expressed in HCAEC, and FGF23 increases the expression of the Klotho shedding protease ADAM17, and consequently the secretion of soluble Klotho. FGF23 activates FGF receptor 1 and stimulates NO release via Akt-dependent activation of endothelial NO synthase (eNOS). Both FGF receptor (FGFR)-dependent ROS formation via activation of NADPH oxidase 2 (Nox2) as well as ROS degradation via superoxide dismutase 2 (SOD2) and catalase (CAT) is stimulated by FGF23. Pre-incubation with a Klotho inhibitor blunts the FGF23-stimulated Akt-eNOS activation and NO synthesis, and decreases ROS degradation by blocking SOD2 and CAT enzymes, whereas FGF23-stimulated ROS synthesis via Nox2 is unaffected, resulting in low NO bioavailability and increased oxidative stress. Our data indicate that in the presence of Klotho, FGF23 induces NO release in HCAEC and its stimulating effects on ROS production are counterbalanced by increased ROS degradation. In states of Klotho deficiency, e.g., CKD, FGF23-mediated NO synthesis is blunted and ROS formation overrules ROS degradation. Thus, FGF23 excess may primarily promote oxidative stress and thus endothelial dysfunction. 10.1007/s00424-016-1858-x
    The rise of FGF23: should insights from population-based studies inform future clinical trials? Wetmore James B Kidney international Research on the potential effects of fibroblast growth factor 23 (FGD23) in chronic kidney disease (CKD) has been galvanized by work suggesting that the FGF23 level rises even before the parathyroid hormone (PTH) level. However, new work suggests that the levels of both FGF23 and PTH may begin to rise much earlier than previously appreciated, indeed well before the establishment of clinically evident CKD. These findings challenge previous understanding and could affect the design of interventional trials designed to lower FGF23 levels. 10.1016/j.kint.2016.06.005
    [FGF23 and osteonetwork]. Fukumoto Seiji Clinical calcium Fibroblast growth factor 23(FGF23)is produced mainly by osteocytes and works as a hormone that reduces serum phosphate level in a Klotho-dependent manner. The identification of FGF23 revealed that bone works as an endocrine organ. On the other hand, FGF23 has been shown to be high in patients with chronic kidney disease and suggested to cause several adverse events including left ventricular hypertrophy and impaired immune function in a Klotho-independent manner. However, it is not known how FGF23 can work without Klotho. CliCa160811431147
    The FGF23/Klotho axis in the regulation of mineral and metabolic homeostasis. Kawai Masanobu Hormone molecular biology and clinical investigation The function of fibroblast growth factor (FGF) 23 has been suggested to be multifaceted beyond its canonical function as a regulator of mineral metabolism. FGF23 was originally shown to play a central role in phosphate (Pi) and vitamin D metabolism, and a number of diseases associated with dysregulated Pi metabolism have been attributed to abnormal FGF23 signaling activities. The discovery of Klotho as a co-receptor for FGF23 signaling has also accelerated understanding on the molecular mechanisms underlying Pi and vitamin D metabolism. In addition to these canonical functions, FGF23 has recently been implicated in a number of metabolic diseases including chronic kidney disease-associated complications, cardiovascular diseases, and obesity-related disorders; however, the physiological significance and molecular mechanisms of these emerging roles of FGF23 remain largely unknown. Molecular and functional insights into the FGF23 pathway will be discussed in the present review, with an emphasis on its role in human disorders related to dysregulated Pi metabolism as well as metabolic disorders. 10.1515/hmbci-2015-0068
    Update on FGF23 and Klotho signaling. Erben Reinhold G Molecular and cellular endocrinology Fibroblast growth factor-23 (FGF23) is a bone-derived hormone known to suppress phosphate reabsorption and vitamin D hormone production in the kidney. Klotho was originally discovered as an anti-aging factor, but the functional role of Klotho is still a controversial issue. Three major functions have been proposed, a hormonal function of soluble Klotho, an enzymatic function as glycosidase, and the function as an obligatory co-receptor for FGF23 signaling. The purpose of this review is to highlight the recent advances in the area of FGF23 and Klotho signaling in the kidney, in the parathyroid gland, in the cardiovascular system, in bone, and in the central nervous system. During recent years, major new functions of FGF23 and Klotho have been discovered in these organ systems. Based on these novel findings, FGF23 has emerged as a pleiotropic endocrine and auto-/paracrine factor influencing not only mineral metabolism but also cardiovascular function. 10.1016/j.mce.2016.05.008
    Serum FGF23 levels may not be associated with serum phosphate and 1,25-dihydroxyvitamin D levels in patients with Fanconi syndrome-induced hypophosphatemia. Goto Shunsuke,Fujii Hideki,Kono Keiji,Watanabe Kentaro,Nakai Kentaro,Nishi Shinichi Clinical kidney journal Fibroblast growth factor 23 (FGF23) is regulated by sustained phosphate supplementation and restriction. However, few studies have investigated FGF23 levels in patients with Fanconi syndrome. Therefore, we evaluated intact and C-terminal FGF23 and FGF23-associated parameters in four patients with Fanconi syndrome. Serum intact and C-terminal FGF23 levels were extremely low. Although serum phosphate and 1,25-dihydroxyvitamin D levels improved to or above the normal range within 1 year of treatment with oral phosphate and calcitriol, serum FGF23 levels remained low. Serum FGF23 levels in patients with Fanconi syndrome might be regulated by novel factors other than serum phosphate and 1,25-dihydroxyvitamin D levels. 10.1093/ckj/sfw086
    Fgf23 and parathyroid hormone signaling interact in kidney and bone. Andrukhova Olena,Streicher Carmen,Zeitz Ute,Erben Reinhold G Molecular and cellular endocrinology Fibroblast growth factor-23 (FGF23) is a bone-derived hormone, suppressing renal phosphate reabsorption and vitamin D hormone synthesis in proximal tubules, and stimulating calcium reabsorption in distal tubules of the kidney. Here, we analyzed the long term sequelae of deficient Fgf23 signaling on bone and mineral metabolism in 9-month-old mice lacking both Fgf23 or Klotho and a functioning vitamin D receptor (VDR). To prevent hypocalcemia in VDR deficient mice, all mice were kept on a rescue diet enriched with calcium, phosphate, and lactose. VDR mutants were normocalcemic and normophosphatemic, and had normal tibial bone mineral density. Relative to VDR mutants, Fgf23/VDR and Klotho/VDR compound mutants were characterized by hypocalcemia, hyperphosphatemia, and very high serum parathyroid hormone (PTH). Despite ∼10-fold higher serum PTH levels in compound mutants, urinary excretion of phosphate and calcium as well as osteoclast numbers in bone remained unchanged relative to VDR mutants. The increase in plasma cAMP after hPTH(1-34) injection was similar in all genotypes. However, a 5-day infusion of hPTH(1-34) via osmotic minipumps resulted in reduced phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) in bone and kidney of Fgf23/VDR and Klotho/VDR compound mutants, relative to VDR and WT controls. Similarly, the PTH-mediated ERK1/2 phosphorylation was reduced in primary osteoblasts isolated from Fgf23 and Klotho deficient mice, but was restored by concomitant treatment with recombinant FGF23. Collectively, our data indicate that the phosphaturic, calcium-conserving, and bone resorption-stimulating actions of PTH are blunted by Fgf23 or Klotho deficiency. Hence, FGF23 may be an important modulator of PTH signaling in bone and kidney. 10.1016/j.mce.2016.07.035
    Energy-dense diets increase FGF23, lead to phosphorus retention and promote vascular calcifications in rats. Raya Ana I,Rios Rafael,Pineda Carmen,Rodriguez-Ortiz Maria E,Diez Elisa,Almaden Yolanda,Muñoz-Castañeda Juan R,Rodriguez Mariano,Aguilera-Tejero Escolastico,Lopez Ignacio Scientific reports Rats with normal renal function (Experiment 1, n = 12) and uninephrectomized (1/2Nx) rats (Experiment 2, n = 12) were fed diets with normal P (NP) and either normal (NF) or high fat (HF). Rats with intact renal function (Experiment 3, n = 12) were also fed NF or HF diets with high P (HP). Additionally, uremic (5/6Nx) rats (n = 16) were fed HP diets with NF or HF. Feeding the HF diets resulted in significant elevation of plasma FGF23 vs rats fed NF diets: Experiment 1, 593 ± 126 vs 157 ± 28 pg/ml (p < 0.01); Experiment 2, 538 ± 105 vs 250 ± 18 pg/ml (p < 0.05); Experiment 3, 971 ± 118 vs 534 ± 40 pg/ml (p < 0.01). Rats fed HF diets showed P retention and decreased renal klotho (ratio klotho/actin) vs rats fed NF diets: Experiment 1, 0.75 ± 0.06 vs 0.97 ± 0.02 (p < 0.01); Experiment 2, 0.69 ± 0.07 vs 1.12 ± 0.08 (p < 0.01); Experiment 3, 0.57 ± 0.19 vs 1.16 ± 0.15 (p < 0.05). Uremic rats fed HF diet showed more severe vascular calcification (VC) than rats fed NF diet (aortic Ca = 6.3 ± 1.4 vs 1.4 ± 0.1 mg/g tissue, p < 0.001). In conclusion, energy-rich diets increased plasma levels of FGF23, a known risk factor of cardiovascular morbidity and mortality. Even though FGF23 has major phosphaturic actions, feeding HF diets resulted in P retention, likely secondary to decreased renal klotho, and aggravated uremic VC. 10.1038/srep36881
    Effects of intravenous iron on fibroblast growth factor 23 (FGF23) in haemodialysis patients: a randomized controlled trial. Roberts Matthew A,Huang Louis,Lee Darren,MacGinley Robert,Troster Stefanie M A,Kent Annette B,Bansal Sukhvinder S,Macdougall Iain C,McMahon Lawrence P BMC nephrology 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). 10.1186/s12882-016-0391-7
    The Pas de Trois of Vitamin D, FGF23, and PTH. Naveh-Many Tally,Silver Justin Journal of the American Society of Nephrology : JASN 10.1681/ASN.2016090944
    Ironing out the cross talk between FGF23 and inflammation. David Valentin,Francis Connor,Babitt Jodie L American journal of physiology. Renal physiology The bone-secreted hormone fibroblast growth factor 23 (FGF23) has an essential role in phosphate homeostasis by regulating expression of the kidney proximal tubule sodium-phosphate cotransporters as well as parathyroid hormone levels. Induction of FGF23 early in chronic kidney disease (CKD) helps to maintain normal phosphorous levels. However, high FGF23 levels become pathological as kidney disease progresses and are associated with an increased risk of CKD progression, cardiovascular events, and death. The factors responsible for increasing FGF23 levels early in CKD are unknown, but recent work has proposed a role for inflammation and disordered iron homeostasis. Notably, FGF23 has recently been shown to elicit an inflammatory response and to display immunomodulatory properties. Here, we will review emerging evidence on the cross talk between inflammation, iron, FGF23, and bone and mineral metabolism and discuss the relevance for CKD patients. 10.1152/ajprenal.00359.2016
    Novel Faces of Fibroblast Growth Factor 23 (FGF23): Iron Deficiency, Inflammation, Insulin Resistance, Left Ventricular Hypertrophy, Proteinuria and Acute Kidney Injury. Kanbay Mehmet,Vervloet Marc,Cozzolino Mario,Siriopol Dimitrie,Covic Adrian,Goldsmith David,Solak Yalcin Calcified tissue international FGF23 is a hormone that appears as the core regulator of phosphate metabolism. Great deal of data has accumulated to demonstrate increased FGF23 secretion from the bone to compensate for even subtle increases in serum phosphorus long before intact PTH. However, recent evidence points to the fact that actions and interactions of FGF23 are not limited solely to phosphate metabolism. FGF23 may be implicated in iron metabolism and erythropoiesis, inflammation, insulin resistance, proteinuria, acute kidney injury and left ventricular hypertrophy. In this review, we will summarize latest experimental and clinical data examining impact of FGF23 on aforementioned pathophysiologic pathways/disorders. 10.1007/s00223-016-0206-7
    The FGF23 and Klotho system beyond mineral metabolism. Kuro-O Makoto Clinical and experimental nephrology FGF23 is a bone-derived hormone that acts primarily on the kidney to induce phosphaturia and suppress synthesis of 1,25-dihydroxyvitamin D. The unique feature of FGF23 is that it requires Klotho as an obligate co-receptor. The FGF23-Klotho system has emerged as an endocrine axis indispensable for maintaining phosphate homeostasis. Mineral and bone disorders associated with chronic kidney disease (CKD-MBD) can be viewed as a series of events triggered by a compensatory response of the FGF23-Klotho system to excess phosphate intake relative to the residual nephron number. Furthermore, the fact that disruption of the FGF23-Klotho system causes phosphate retention and a syndrome resembling aging in mammals has led to the notion that phosphate accelerates aging. The aging-like pathology caused by phosphate, or phosphatopathy, may be unique to the higher organisms having the Klotho gene and provides new insights into the molecular mechanism of aging in humans. 10.1007/s10157-016-1357-6
    Extrarenal effects of FGF23. Haffner Dieter,Leifheit-Nestler Maren Pediatric nephrology (Berlin, Germany) Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular mortality, infections, and impaired cognitive function. It is characterized by excessively increased levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23) and a deficiency of its co-receptor Klotho. Despite the important physiological effect of FGF23 in maintaining phosphate homeostasis, there is increasing evidence that higher FGF23 levels are a risk factor for mortality and cardiovascular disease. FGF23 directly induces left ventricular hypertrophy via activation of the FGF receptor 4/calcineurin/nuclear factor of activated T cells signaling pathway. By contrast, the impact of FGF23 on endothelial function and the development of atherosclerosis are poorly understood. The results of recent experimental studies indicate that FGF23 directly impacts on hippocampal neurons and may thereby impair learning and memory function in CKD patients. Finally, it has been shown that FGF23 interferes with the immune system by directly acting on polymorphonuclear leukocytes and macrophages. In this review, we discuss recent data from clinical and experimental studies on the extrarenal effects of FGF23 with respect to the cardiovascular, central nervous, and immune systems. 10.1007/s00467-016-3505-3
    Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho. Yamada Shunsuke,Giachelli Cecilia M Bone Vascular calcification (VC) is highly prevalent in aging, diabetes mellitus, and chronic kidney disease (CKD). VC is a strong predictor of cardiovascular morbidity and mortality in the CKD population. Complex pathological mechanisms are involved in the development of VC, including osteochondrogenic differentiation and apoptosis of vascular smooth muscle cells, instability and release of extracellular vesicles loaded calcium and phosphate, and elastin degradation. Elevated serum phosphate is a late manifestation of CKD, and has been shown to accelerate mineral deposition in both the vessel wall and heart valves. α-Klotho and fibroblast growth factor 23 (FGF23) are emerging factors in CKD-mineral and bone disorder (CKD-MBD) and are thought to be involved in the pathogenesis of uremic VC. There are discordant reports regarding the biomedical effects of FGF23 on VC. In contrast, mounting evidence supports a well-supported protective role for α-Klotho on VC. Further studies are warranted to elucidate potential roles of FGF23 and α-Klotho in VC and to determine where and how they are synthesized in normal and disease conditions. A thorough systemic evaluation of the biomedical interplay of phosphate, FGF23, and α-Klotho may potentially lead to new therapeutic options for patients with CKD-MBD. 10.1016/j.bone.2016.11.012
    Klotho/FGF23 Axis in Chronic Kidney Disease and Cardiovascular Disease. Lu Xiang,Hu Ming Chang Kidney diseases (Basel, Switzerland) BACKGROUND:Membrane αKlotho (hereinafter called Klotho) is highly expressed in the kidney and functions as a coreceptor of FGF receptors (FGFRs) to activate specific fibroblast growth factor 23 (FGF23) signal pathway. FGF23 is produced in bones and participates in the maintenance of mineral homeostasis. The extracellular domain of transmembrane Klotho can be cleaved by secretases and released into the circulation as soluble Klotho. Soluble Klotho does not only weakly activate FGFRs to transduce the FGF23 signaling pathway, but also functions as an enzyme and hormonal substance to play a variety of biological functions. FGF23 exerts its biological effects through activation of FGFRs in a Klotho-dependent manner. However, extremely high FGF23 can exert its pathological action in a Klotho-independent manner. SUMMARY:The decline in serum and urinary Klotho followed by a rise in serum FGF23 at an early stage of chronic kidney disease (CKD) functions as an early biomarker for kidney dysfunction and can also serve as a predictor for risk of cardiovascular disease (CVD) and mortality in both CKD patients and the general population. Moreover, Klotho deficiency is a pathogenic factor for CKD progression and CVD. FGF23 may also contribute to CVD. Prevention of Klotho decline, reactivation of endogenous Klotho production, or supplementation of exogenous Klotho attenuate renal fibrosis, retard CKD progression, improve mineral metabolism, ameliorate cardiomyopathy, and alleviate vascular calcification in CKD. However, the poor CVD outcome after depletion of FGF23 with FGF23 antibody stimulates the generation of a more specific inhibitor of FGF23 for CKD treatment. KEY MESSAGE:Klotho/FGF23 may not only be diagnostic and/or prognostic biomarkers for CKD and CVD, but are also pathogenic contributors to CKD progression and CVD development. The Klotho/FGF23 axis should be a novel target for renal clinics. 10.1159/000452880
    FGF23-Klotho signaling axis in the kidney. Erben Reinhold G,Andrukhova Olena Bone Fibroblast growth factor-23 (FGF23) is a bone-derived hormone protecting against the potentially deleterious effects of hyperphosphatemia by suppression of phosphate reabsorption and of active vitamin D hormone synthesis in the kidney. The kidney is one of the main target organs of FGF23 signaling. The purpose of this review is to highlight the recent advances in the area of FGF23-Klotho signaling in the kidney. During recent years, it has become clear that FGF23 acts independently on proximal and distal tubular epithelium. In proximal renal tubules, FGF23 suppresses phosphate reabsorption by a Klotho dependent activation of extracellular signal-regulated kinase-1/2 (ERK1/2) and of serum/glucocorticoid-regulated kinase-1 (SGK1), leading to phosphorylation of the scaffolding protein Na/H exchange regulatory cofactor (NHERF)-1 and subsequent internalization and degradation of sodium-phosphate cotransporters. In distal renal tubules, FGF23 augments calcium and sodium reabsorption by increasing the apical membrane expression of the epithelial calcium channel TRPV5 and of the sodium-chloride cotransporter NCC through a Klotho dependent activation of with-no-lysine kinase-4 (WNK4). In proximal and distal renal tubules, FGF receptor-1 is probably the dominant FGF receptor mediating the effects of FGF23 by forming a complex with membrane-bound Klotho in the basolateral membrane. The newly described sodium- and calcium-conserving functions of FGF23 may have major implications for the pathophysiology of diseases characterized by chronically increased circulating FGF23 concentrations such as chronic kidney disease. 10.1016/j.bone.2016.09.010
    FGF23-αKlotho as a paradigm for a kidney-bone network. Kuro-O Makoto,Moe Orson W Bone The vertebrate endoskeleton is not a mere frame for muscle attachment to facilitate locomotion, but is a massive organ integrated with many physiologic functions including mineral and energy metabolism. Mineral balance is maintained by tightly controlled ion fluxes that are external (intestine and kidney) and internal (between bone and other organs), and are regulated and coordinated by many endocrine signals between these organs. The endocrine fibroblast growth factors (FGFs) and Klotho gene families are complex systems that co-evolved with the endoskeleton. In particular, FGF23 and αKlotho which are primarily derived from bone and kidney respectively, are critical in maintaining mineral metabolism where each of these proteins serving highly diverse roles; abound with many unanswered questions regarding their upstream regulation and downstream functions. Genetic lesions of components of this network produce discreet disturbances in many facets of mineral metabolism. One acquired condition with colossal elevations of FGF23 and suppression of αKlotho is chronic kidney disease where multiple organ dysfunction contributes to the morbidity and mortality. However, the single most important group of derangements that encompasses the largest breadth of complications is mineral metabolism disorders. Mineral metabolic disorders in CKD impact negatively and significantly on the progression of renal disease as well as extra-renal complications. Knowledge of the origin, nature, and impact of phosphate, FGF23, and αKlotho derangements is pivotal to understanding the pathophysiology and treatment of CKD. 10.1016/j.bone.2016.11.013
    FGF23 in hemodialysis patients is associated with left ventricular hypertrophy and reduced ejection fraction. Nielsen Ture Lange,Plesner Louis Lind,Warming Peder Emil,Mortensen Ole Hartvig,Iversen Kasper Karmark,Heaf James Goya Nefrologia BACKGROUND:Fibroblast growth factor 23 (FGF23) is known to cause left ventricular hypertrophy (LVH), but controversy exists concerning its effect in dialysis. This study evaluated associations between FGF23 levels, echocardiography and prognosis in patients on hemodialysis (HD). METHODS:Patients >18 years on chronic HD were included in this cross-sectional study. Plasma C-terminal FGF23 concentration was measured with ELISA and transthoracic echocardiography was performed, both before and after HD treatment. RESULTS:239 haemodialysis (HD) patients were included in the study. The FGF23 was median 3560RU/ml (IQR 1447-9952). The mean left ventricular mass index (LVMI) was 110.2±26.7g/m and the left ventricular ejection fraction (LVEF) was 52.7±9.9%. Defined by LVMI, LVH was found in 110 patients (46%), of which 92 (84%) had hypertension (p<0.01). Patients with LVH had FGF23 levels of 5319 RU/ml (IQR 1858-12,859) and those without 2496 RU/ml (IQR 1141-7028) (p<0.01). FGF23 was significant positive correlated with LVMI (p<0.01), and negatively to LVEF (p<0.01). In a multivariate analysis, FGF23 was correlated with LVEF (p<0.01), but only marginally to LVMI (p<0.01). Cardiovascular events in the follow up period was not correlated with FGF23. Furthermore, FGF23 was independently correlated with overall mortality (p<0.001). CONCLUSION:FGF23 was positively correlated with LVH and negatively to LVEF. FGF23 was an independent predictor for overall mortality. 10.1016/j.nefro.2018.10.007
    Editorial: Endocrine and Paracrine Role of FGF23 and Klotho in Health and Disease. Erben Reinhold G Frontiers in endocrinology 10.3389/fendo.2019.00002
    Cardiac FGF23: new insights into the role and function of FGF23 after acute myocardial infarction. Schumacher David,Alampour-Rajabi Setareh,Ponomariov Victor,Curaj Adelina,Wu Zhuojun,Staudt Mareike,Rusu Mihaela,Jankowski Vera,Marx Nikolaus,Jankowski Joachim,Brandenburg Vincent,Liehn Elisa A,Schuh Alexander Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology OBJECTIVE:We aimed to elucidate the local role of FGF23 after myocardial infarction in a mouse model induced by left anterior descending artery (LAD) ligation. APPROACH AND RESULTS: (C57BL/6 N) mice underwent MI via LAD ligation and were sacrificed at different time-points post MI. The expression and influence of FGF23 on fibroblast and macrophages was also analyzed using isolated murine cells. We identified enhanced cardiac FGF23 mRNA expression in a time-dependent manner with an early increase, already on the first day after MI. FGF23 protein expression was abundantly detected in the infarcted area during the inflammatory phase. While described to be primarily produced in bone or macrophages, we identified cardiac fibroblasts as the only source of local FGF23 production after MI. Inflammatory mediators, such as IL-1β, IL-6 and TNF-α, were able to induce FGF23 expression in these cardiac fibroblasts. Interestingly, we were not able to detect FGF23 at later time points after MI in mature scar tissue or remote myocardium, most likely due to TGF-β1, which we have shown to inhibit the expression of FGF23. We identified FGFR1c to be the most abundant receptor for FGF23 in infarcted myocardium and cardiac macrophages and fibroblasts. FGF23 increased migration of cardiac fibroblast, as well as expression of Collagen 1, Periostin, Fibronectin and MMP8. FGF23 also increased expression of TGF-β1 in M2 polarized macrophages. CONCLUSION:In conclusion, cardiac fibroblasts in the infarcted myocardium produce and express FGF23 as well as its respective receptors in a time-dependent manner, thus potentially influencing resident cell migration. The transitory local expression of FGF23 after MI points towards a complex role of FGF23 in myocardial ischemia and warrants further exploration, considering its role in ventricular remodeling. 10.1016/j.carpath.2019.02.001
    Effects of vitamin D supplementation on FGF23: a randomized-controlled trial. Trummer Christian,Schwetz Verena,Pandis Marlene,Grübler Martin R,Verheyen Nicolas,Gaksch Martin,Zittermann Armin,März Winfried,Aberer Felix,Steinkellner Julia,Friedl Claudia,Brandenburg Vincent,Voelkl Jakob,Alesutan Ioana,Obermayer-Pietsch Barbara,Pieber Thomas R,Tomaschitz Andreas,Pilz Stefan European journal of nutrition 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. 10.1007/s00394-018-1672-7
    Plasma FGF23 does not rise during physical exercise as a physiological model of sympathetic activation. Emrich Insa E,Baier Marc,Zawada Adam M,Meyer Tim,Fliser Danilo,Scharhag Jürgen,Heine Gunnar H Clinical research in cardiology : official journal of the German Cardiac Society 10.1007/s00392-018-1347-7
    Plasmatic Klotho and FGF23 Levels as Biomarkers of CKD-Associated Cardiac Disease in Type 2 Diabetic Patients. Silva Ana Paula,Mendes Filipa,Carias Eduarda,Gonçalves Rui Baptista,Fragoso André,Dias Carolina,Tavares Nelson,Café Hugo Mendonça,Santos Nélio,Rato Fátima,Leão Neves Pedro,Almeida Edgar International journal of molecular sciences BACKGROUND:Research over the past decade has focused on the role of Klotho as a cardio protective agent that prevents the effects of aging on the heart and reduces the burden of cardiovascular disease CVD. The role of the interaction between fibroblast growth factor 23-(FGF-23)/Klotho in Klotho-mediated actions is still under debate. The main objective was to ascertain the potential use of plasmatic Klotho and FGF23 as markers for CKD-associated cardiac disease and mortality. METHODS:This was a prospective analysis conducted in an outpatient diabetic nephropathy clinic, enrolling 107 diabetic patients with stage 2⁻3 CKD. Patients were divided into three groups according to their left ventricular mass index and relative wall thickness. RESULTS:Multinomial regression analysis demonstrated that low Klotho and higher FGF-23 levels were linked to a greater risk of concentric hypertrophy. In the generalized linear model (GLM), Klotho, FGF-23 and cardiac geometry groups were statistically significant as independent variables of cardiovascular hospitalization ( = 0.007). According to the Cox regression model, fatal cardiovascular events were associated with the following cardiac geometric classifications; eccentric hypertrophy ( = 0.050); concentric hypertrophy ( = 0.041), and serum phosphate ≥ 3.6 mg/dL ( = 0.025), FGF-23 ≥ 168 ( = 0.0149), α-klotho < 313 ( = 0.044). CONCLUSIONS:In our population, Klotho and FGF23 are associated with cardiovascular risk in the early stages of CKD. 10.3390/ijms20071536
    The EPO-FGF23 Signaling Pathway in Erythroid Progenitor Cells: Opening a New Area of Research. van Vuren Annelies J,Gaillard Carlo A J M,Eisenga Michele F,van Wijk Richard,van Beers Eduard J Frontiers in physiology We provide an overview of the evidence for an erythropoietin-fibroblast growth factor 23 (FGF23) signaling pathway directly influencing erythroid cells in the bone marrow. We outline its importance for red blood cell production, which might add, among others, to the understanding of bone marrow responses to endogenous erythropoietin in rare hereditary anemias. FGF23 is a hormone that is mainly known as the core regulator of phosphate and vitamin D metabolism and it has been recognized as an important regulator of bone mineralization. Osseous tissue has been regarded as the major source of FGF23. Interestingly, erythroid progenitor cells highly express FGF23 protein and carry the FGF receptor. This implies that erythroid progenitor cells could be a prime target in FGF23 biology. FGF23 is formed as an intact, biologically active protein (iFGF23) and proteolytic cleavage results in the formation of the presumed inactive C-terminal tail of FGF23 (cFGF23). FGF23-knockout or injection of an iFGF23 blocking peptide in mice results in increased erythropoiesis, reduced erythroid cell apoptosis and elevated renal and bone marrow erythropoietin mRNA expression with increased levels of circulating erythropoietin. By competitive inhibition, a relative increase in cFGF23 compared to iFGF23 results in reduced FGF23 receptor signaling and mimics the positive effects of FGF23-knockout or iFGF23 blocking peptide. Injection of recombinant erythropoietin increases FGF23 mRNA expression in the bone marrow with a concomitant increase in circulating FGF23 protein. However, erythropoietin also augments iFGF23 cleavage, thereby decreasing the iFGF23 to cFGF23 ratio. Therefore, the net result of erythropoietin is a reduction of iFGF23 to cFGF23 ratio, which inhibits the effects of iFGF23 on erythropoiesis and erythropoietin production. Elucidation of the EPO-FGF23 signaling pathway and its downstream signaling in hereditary anemias with chronic hemolysis or ineffective erythropoiesis adds to the understanding of the pathophysiology of these diseases and its complications; in addition, it provides promising new targets for treatment downstream of erythropoietin in the signaling cascade. 10.3389/fphys.2019.00304
    FGF23 Synthesis and Activity. Noonan Megan L,White Kenneth E Current molecular biology reports Purpose of Review:The phosphaturic hormone FGF23 is produced primarily in osteoblasts/osteocytes and is known to respond to increases in serum phosphate and 1,25(OH) vitamin D (1,25D). Novel regulators of FGF23 were recently identified, and may help explain the pathophysiologies of several diseases. This review will focus on recent studies examining the synthesis and actions of FGF23. Recent Findings:The synthesis of FGF23 in response to 1,25D is similar to other steroid hormone targets, but the cellular responses to phosphate remain largely unknown. The activity of intracellular processing genes control FGF23 glycosylation and phosphorylation, providing critical functions in determining the serum levels of bioactive FGF23. The actions of FGF23 largely occur through its co-receptor αKlotho (KL) under normal circumstances, but FGF23 has KL-independent activity during situations of high concentrations. Summary:Recent work regarding FGF23 synthesis and bioactivity, as well as considerations for diseases of altered phosphate balance will be reviewed. 10.1007/s40610-019-0111-8
    Prediabetes is Characterized by Higher FGF23 Levels and Higher Prevalence of Vitamin D Deficiency Compared to Normal Glucose Tolerance Subjects. Gateva Antoaneta,Assyov Yavor,Tsakova Adelina,Kamenov Zdravko Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme In the last years there is an increasing interest towards the bone as an endocrine organ and the role of bone and calcium-phosphate metabolism markers in a range of metabolic disturbances. The aim of the present study is to assess the changes of calcium phosphate metabolism markers in patients with prediabetes compared to normogycemic controls and their link to glucose disturbances and cardiovascular risk factors. In this study, 80 patients with mean age 50.4±10.6 years were included, divided into 2 age- and BMI-matched groups - group 1 with obesity without glycemic disturbances (n=41) and group 2 with obesity and prediabetes (n=39). Oral glucose tolerance test (OGTT) with measurement of immunoreactive insulin was performed in all participants and levels of PTH, 25(OH)D, FGF23, and Klotho were measured. We found significantly higher levels of FGF23 in patients with prediabetes compared to normal glucose tolerance subjects (10.4±10.7 vs. 5.8±7.3 pg/ml; p=0.03). FGF23 showed a weak positive correlation to fasting blood glucose (r=0.224; p=0.048) but not to blood glucose on the first and second hour of oral glucose tolerance test or insulin levels. There was extremely high prevalence of vitamin D deficiency in both groups. Lower levels of 25(OH)D were observed in prediabetes group, although without statistical significance (p=0.57). Patients with prediabetes have higher FGF23 levels and higher prevalence of vitamin D deficiency compared to normal glucose tolerance subjects. Elevated FGF23 levels seem to be correlated more to elevated fasting blood glucose levels than to insulin resistance state of the patients. 10.1055/a-0813-3164
    FGF23 and Fetuin-A Interaction and Mesenchymal Osteogenic Transformation. Mattinzoli Deborah,Ikehata Masami,Tsugawa Koji,Alfieri Carlo M,Barilani Mario,Lazzari Lorenza,Andreetta Paola,Elli Francesca M,Mantovani Giovanna,Messa Piergiorgio International journal of molecular sciences Recently, we found a strict bone association between Fibroblast growth factor 23 (FGF23) and Fetuin-A, both involved in cardiovascular and mineral bone disorders. In this study, an uninvestigated bone marrow positivity for both was found. Though the role of exogenous FGF23 on mesenchymal cells (MSCs) was reported, no information is as yet available on the possible production of this hormone by MSCs. To further analyze these uninvestigated aspects, we studied human primary cells and mouse and human cell lines by means of immunostaining, qRT-PCR, enzyme linked immunosorbent assays, chromatin immunoprecipitation, transfection, and a streamlined approach for the FGF23⁻Fetuin-A interaction called Duolink proximity ligation assay. Mesenchymal cells produce but do not secrete FGF23 and its expression increases during osteo-differentiation. Fibroblast growth factor 23 is also involved in the regulation of Fetuin-A by binding directly to the Fetuin-A promoter and then activating its transcription. Both FGF23 overexpression and addition induced an upregulation of Fetuin-A in the absence of osteo-inducer factors. Fibroblast growth factor 23 and Fetuin-A promoter were increased by osteo-inducer factors with this effect being abolished after FGF23 silencing. In conclusion, both FGF23 and Fetuin-A are present and strictly linked to each other in MSCs with FGF23 driving Fetuin-A production. This mechanism suggests a role for these two proteins in the osteoblast differentiation. 10.3390/ijms20040915
    Increased FGF23 protects against detrimental cardio-renal consequences during elevated blood phosphate in CKD. Clinkenbeard Erica L,Noonan Megan L,Thomas Joseph C,Ni Pu,Hum Julia M,Aref Mohammad,Swallow Elizabeth A,Moe Sharon M,Allen Matthew R,White Kenneth E JCI insight The phosphaturic hormone FGF23 is elevated in chronic kidney disease (CKD). The risk of premature death is substantially higher in the CKD patient population, with cardiovascular disease (CVD) as the leading mortality cause at all stages of CKD. Elevated FGF23 in CKD has been associated with increased odds for all-cause mortality; however, whether FGF23 is associated with positive adaptation in CKD is unknown. To test the role of FGF23 in CKD phenotypes, a late osteoblast/osteocyte conditional flox-Fgf23 mouse (Fgf23fl/fl/Dmp1-Cre+/-) was placed on an adenine-containing diet to induce CKD. Serum analysis showed casein-fed Cre+ mice had significantly higher serum phosphate and blood urea nitrogen (BUN) versus casein diet and Cre- genotype controls. Adenine significantly induced serum intact FGF23 in the Cre- mice over casein-fed mice, whereas Cre+ mice on adenine had 90% reduction in serum intact FGF23 and C-terminal FGF23 as well as bone Fgf23 mRNA. Parathyroid hormone was significantly elevated in mice fed adenine diet regardless of genotype, which significantly enhanced midshaft cortical porosity. Echocardiographs of the adenine-fed Cre+ hearts revealed profound aortic calcification and cardiac hypertrophy versus diet and genotype controls. Thus, these studies demonstrate that increased bone FGF23, although associated with poor outcomes in CKD, is necessary to protect against the cardio-renal consequences of elevated tissue phosphate. 10.1172/jci.insight.123817
    FGF23: Clinical usefulness and analytical evolution. Fauconnier Charlotte,Roy Tatiana,Gillerot Gaëlle,Roy Clotilde,Pouleur Anne-Catherine,Gruson Damien Clinical biochemistry Fibroblast Growth Factor 23 (FGF23) is a key hormone for the regulation of phosphate homeostasis. Over the past decades, FGF23 was the subject of intense research in the fields of nephrology and the cardiology. It presents a remarkable correlation with well-established biomarkers of cardiovascular disorders in both chronic kidney disease (CKD) and heart failure (HF) patients. The interest of FGF23 lies in its early-onset in the primary course of CKD as well as in the incremental prognosis information it conveys in both CKD and HF. Different types of assays of FGF-23 testing exist, those targeting the intact form (iFGF23), the other one detecting terminal fragments (cFGF23). The issue is still pending which assay suits best for clinical use. Recently, the implementation of this biomarker on multianalyzer platforms, on which other markers of phospho-calcic balance are set up, allows a rapid turn-around-time and a potential financial gain. However, despite the good analytical performances of the automated methods, there is a poor harmonization between assays. The introduction of an international certified reference material should standardize the measurement and improve the harmonization of results from different laboratories. A deeper understanding of physio-pathological mechanisms and processing of FGF-23 should reinforce its clinical indications and might also identify new therapeutic targets for the treatment of CKD and HF. 10.1016/j.clinbiochem.2019.03.002
    FGF23, Biomarker or Target? Rodelo-Haad Cristian,Santamaria Rafael,Muñoz-Castañeda Juan R,Pendón-Ruiz de Mier M Victoria,Martin-Malo Alejandro,Rodriguez Mariano Toxins Fibroblast growth factor 23 (FGF23) plays a key role in the complex network between the bones and other organs. Initially, it was thought that FGF23 exclusively regulated phosphate and vitamin D metabolism; however, recent research has demonstrated that an excess of FGF23 has other effects that may be detrimental in some cases. The understanding of the signaling pathways through which FGF23 acts in different organs is crucial to develop strategies aiming to prevent the negative effects associated with high FGF23 levels. FGF23 has been described to have effects on the heart, promoting left ventricular hypertrophy (LVH); the liver, leading to production of inflammatory cytokines; the bones, inhibiting mineralization; and the bone marrow, by reducing the production of erythropoietin (EPO). The identification of FGF23 receptors will play a remarkable role in future research since its selective blockade might reduce the adverse effects of FGF23. Patients with chronic kidney disease (CKD) have very high levels of FGF23 and may be the population suffering from the most adverse FGF23-related effects. The general population, as well as kidney transplant recipients, may also be affected by high FGF23. Whether the association between FGF23 and clinical events is causal or casual remains controversial. The hypothesis that FGF23 could be considered a therapeutic target is gaining relevance and may become a promising field of investigation in the future. 10.3390/toxins11030175
    PKC regulates the production of fibroblast growth factor 23 (FGF23). Bär Ludmilla,Hase Philipp,Föller Michael PloS one Serine/threonine protein kinase C (PKC) is activated by diacylglycerol that is released from membrane lipids by phospholipase C in response to activation of G protein-coupled receptors or receptor tyrosine kinases. PKC isoforms are particularly relevant for proliferation and differentiation of cells including osteoblasts. Osteoblasts/osteocytes produce fibroblast growth factor 23 (FGF23), a hormone regulating renal phosphate and vitamin D handling. PKC activates NFκB, a transcription factor complex controlling FGF23 expression. Here, we analyzed the impact of PKC on FGF23 synthesis. Fgf23 expression was analyzed by qRT-PCR in UMR106 osteoblast-like cells and in IDG-SW3 osteocytes, and FGF23 protein was measured by ELISA. Phorbol ester 12-O-tetradecanoylphorbol-13-acetate (PMA), a PKC activator, up-regulated FGF23 production. In contrast, PKC inhibitors calphostin C, Gö6976, sotrastaurin and ruboxistaurin suppressed FGF23 formation. NFκB inhibitor withaferin A abolished the stimulatory effect of PMA on Fgf23. PKC is a powerful regulator of FGF23 synthesis, an effect which is at least partly mediated by NFκB. 10.1371/journal.pone.0211309
    FGF23 and Klotho Levels are Independently Associated with Diabetic Foot Syndrome in Type 2 Diabetes Mellitus. Donate-Correa Javier,Martín-Núñez Ernesto,Ferri Carla,Hernández-Carballo Carolina,Tagua Víctor G,Delgado-Molinos Alejandro,López-Castillo Ángel,Rodríguez-Ramos Sergio,Cerro-López Purificación,López-Tarruella Victoria Castro,Arévalo-González Miguel Angel,Pérez-Delgado Nayra,Mora-Fernández Carmen,Navarro-González Juan F Journal of clinical medicine BACKGROUND:Diabetic foot syndrome (DFS) is a prevalent complication in the diabetic population and a major cause of hospitalizations. Diverse clinical studies have related alterations in the system formed by fibroblast growth factor (FGF)-23 and Klotho (KL) with vascular damage. In this proof-of-concept study, we hypothesize that the levels of FGF23 and Klotho are altered in DFS patients. METHODS:Twenty patients with limb amputation due to DFS, 37 diabetic patients without DFS, and 12 non-diabetic cadaveric organ donors were included in the study. Serum FGF23/Klotho and inflammatory markers were measured by enzyme-linked immunosorbent assay (ELISA). Protein and gene expression levels in the vascular samples were determined by immunohistochemistry and quantitative real-time PCR, respectively. RESULTS:Serum Klotho is significantly reduced and FGF23 is significantly increased in patients with DFS ( < 0.01). Vascular immunoreactivity and gene expression levels for Klotho were decreased in patients with DFS ( < 0.01). Soluble Klotho was inversely related to serum C-reactive protein ( = -0.30, < 0.05). Vascular immunoreactivities for Klotho and IL6 showed an inverse association ( = -0.29, < 0.04). Similarly, vascular gene expression of and were inversely associated ( = -0.31, < 0.05). Logistic regression analysis showed that higher Klotho serum concentrations and vascular gene expression levels were related to a lower risk of DFS, while higher serum FGF23 was associated with a higher risk for this complication. CONCLUSION:FGF23/Klotho system is associated with DFS, pointing to a new pathophysiological pathway involved in the development and progression of this complication. 10.3390/jcm8040448
    Activation of unliganded FGF receptor by extracellular phosphate potentiates proteolytic protection of FGF23 by its O-glycosylation. Takashi Yuichi,Kosako Hidetaka,Sawatsubashi Shun,Kinoshita Yuka,Ito Nobuaki,Tsoumpra Maria K,Nangaku Masaomi,Abe Masahiro,Matsuhisa Munehide,Kato Shigeaki,Matsumoto Toshio,Fukumoto Seiji Proceedings of the National Academy of Sciences of the United States of America Fibroblast growth factor (FGF) 23 produced by bone is a hormone that decreases serum phosphate (Pi). Reflecting its central role in Pi control, serum FGF23 is tightly regulated by serum Pi alterations. FGF23 levels are regulated by the transcriptional event and posttranslational cleavage into inactive fragments before its secretion. For the latter, O-glycosylation of FGF23 by gene product prevents the cleavage, leading to an increase in serum FGF23. However, the molecular basis of Pi sensing in the regulation of serum FGF23 remains elusive. In this study, we showed that high Pi diet enhanced the skeletal expression of , but not , with expected increases in serum FGF23 and Pi in mice. induction by high Pi was further observed in osteoblastic UMR 106 cells, and this was mediated by activation of the extracellular signal-regulated kinase (ERK) pathway. Through proteomic searches for the upstream sensor for high Pi, we identified one subtype of the FGF receptor (FGFR1c), which was phosphorylated by high Pi in the absence of FGFs. The mode of unliganded FGFR activation by high Pi appeared different from that of FGFR bound to a canonical FGFR ligand (FGF2) when phosphorylation of the FGFR substrate 2α and ERK was monitored. Finally, we showed that an FGFR inhibitor and conditional deletion of in osteoblasts/osteocytes abrogated high Pi diet-induced increases in serum FGF23 and femoral expression in mice. Thus, these findings uncover an unrecognized facet of unliganded FGFR function and illustrate a Pi-sensing pathway involved in regulation of FGF23 production. 10.1073/pnas.1815166116
    FGF23, Hypophosphatemia, and Emerging Treatments. Imel Erik A,Biggin Andrew,Schindeler Aaron,Munns Craig F JBMR plus FGF23 is an important hormonal regulator of phosphate homeostasis. Together with its co-receptor Klotho, it modulates phosphate reabsorption and both 1α-hydroxylation and 24-hydroxylation in the renal proximal tubules. The most common FGF23-mediated hypophosphatemia is X-linked hypophosphatemia (XLH), caused by mutations in the gene. FGF23-mediated forms of hypophosphatemia are characterized by phosphaturia and low or low-normal calcitriol concentrations, and unlike nutritional rickets, these cannot be cured with nutritional vitamin D supplementation. Autosomal dominant and autosomal recessive forms of FGF23-mediated hypophosphatemias show a similar pathophysiology, despite a variety of different underlying genetic causes. An excess of FGF23 activity has also been associated with a number of other conditions causing hypophosphatemia, including tumor-induced osteomalacia, fibrous dysplasia of the bone, and cutaneous skeletal hypophosphatemia syndrome. Historically phosphate supplementation and therapy using analogs of highly active vitamin D (eg, calcitriol, alfacalcidol, paricalcitol, eldecalcitol) have been used to manage conditions involving hypophosphatemia; however, recently a neutralizing antibody for FGF23 (burosumab) has emerged as a promising treatment agent for FGF23-mediated disorders. This review discusses the progression of clinical trials for burosumab for the treatment of XLH and its recent availability for clinical use. Burosumab may have potential for treating other conditions associated with FGF23 overactivity, but these are not yet supported by trial data. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research. 10.1002/jbm4.10190
    Pre-analytical stability of FGF23 with the contemporary immunoassays. Dirks Niek F,Smith Edward R,van Schoor Natasja M,Vervloet Marc G,Ackermans Mariëtte T,de Jonge Robert,Heijboer Annemieke C Clinica chimica acta; international journal of clinical chemistry BACKGROUND:Several publications have reported on the pre-analytical stability of fibroblast growth factor 23 (FGF23) and some recommend coating blood collecting tubes with protease inhibitors, in order to prevent degradation. These recommendations are based on observations for a first generation assay for the measurement of intact FGF23. However, if this also applies for the contemporary immunoassays, and at what stage of pre-analysis, is unknown. METHODS:We reviewed data from these previous reports on the issue of FGF23 stability and complemented these findings with data from novel experiments. RESULTS:We concluded that the contemporary intact FGF23 assays by Immutopics, Kainos, Millipore and DiaSorin do not suffer from immediate loss of FGF23 signal and do not require blood withdrawal in protease inhibitor-coated collecting tubes. Nevertheless, FGF23 concentrations do decline when centrifugation is delayed up to 8 h and prompt centrifugation is therefore advised. 10.1016/j.cca.2019.02.032
    High FGF23 levels are associated with impaired trabecular bone microarchitecture in patients with osteoporosis. Rupp T,Butscheidt S,Vettorazzi E,Oheim R,Barvencik F,Amling M,Rolvien T Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA This cross-sectional study examined the associations between c-terminal FGF23 levels, laboratory markers of bone metabolism and bone microarchitecture in 82 patients with osteoporosis. Higher FGF23 levels were associated with impaired trabecular but not cortical bone microarchitecture, and this was confirmed after adjusting for confounding variables such as age or BMI. INTRODUCTION:Fibroblast growth factor 23 (FGF23) is an endocrine hormone-regulating phosphate and vitamin D metabolism. While its mode of action is well understood in diseases such as hereditary forms of rickets or tumor-induced osteomalacia, the interpretation of FGF23 levels in patients with osteoporosis with regard to bone microarchitecture is less clear. METHODS:C-terminal FGF23 levels and bone turnover markers were assessed in 82 patients with osteoporosis (i.e., DXA T-score ≤ - 2.5 at the lumbar spine or total hip). Bone microarchitecture was measured by high-resolution peripheral quantitative computed tomography (HR-pQCT) at the distal radius and tibia. Data were analyzed in a cross-sectional design using correlation and regression models. RESULTS:We found a significant negative logarithmic correlation between FGF23 levels and trabecular but not cortical bone microarchitecture at both skeletal sites. Furthermore, using a multiple linear regression model, we confirmed FGF23 as a predictor for reduced trabecular parameters even when adjusting for confounding factors such as age, BMI, phosphate, bone-specific alkaline phosphatase, vitamin D3, and PTH. CONCLUSIONS:Taken together, high FGF23 levels are associated with impaired trabecular bone microarchitecture in osteoporosis patients, and this association seems to occur after adjustment of confounding variables including phosphate and vitamin D. Future longitudinal studies are now needed to validate our findings and investigate FGF23 in relation to fracture risk. 10.1007/s00198-019-04996-7
    Soluble klotho regulates TRPC6 calcium signaling lipid rafts, independent of the FGFR-FGF23 pathway. Wright Jon D,An Sung-Wan,Xie Jian,Lim Carmay,Huang Chou-Long FASEB journal : official publication of the Federation of American Societies for Experimental Biology Soluble klotho (sKlotho), the shed ectodomain of α-klotho, protects the heart by down-regulating transient receptor potential canonical isoform 6 (TRPC6)-mediated calcium signaling. Binding to α2-3-sialyllactose moiety of gangliosides in lipid rafts and inhibition of raft-dependent signaling underlies the mechanism. A recent 3-Å X-ray structure of sKlotho in complex with fibroblast growth factor receptor (FGFR) and fibroblast growth factor 23 (FGF23) indicates that its β6α6 loop might block access to the proposed binding site for α2-3-sialyllactose. It was concluded that sKlotho only functions in complex with FGFR and FGF23 and that sKlotho's pleiotropic effects all depend on FGF23. Here, we report that sKlotho can inhibit TRPC6 channels expressed in cells lacking endogenous FGFRs. Structural modeling and molecular docking show that a repositioned β6α6 loop allows sKlotho to bind α2-3-sialyllactose. Molecular dynamic simulations further show the α2-3-sialyllactose-bound sKlotho complex to be stable. Domains mimicking sKlotho's sialic acid-recognizing activity inhibit TRPC6. The results strongly support the hypothesis that sKlotho can exert effects independent of FGF23 and FGFR.-Wright, J. D., An, S.-W., Xie, J., Lim, C., Huang, C.-L. Soluble klotho regulates TRPC6 calcium signaling lipid rafts, independent of the FGFR-FGF23 pathway. 10.1096/fj.201900321R
    Regulation of fibroblast growth factor 23 (FGF23) in health and disease. Bär Ludmilla,Stournaras Christos,Lang Florian,Föller Michael FEBS letters Fibroblast growth factor 23 (FGF23) is mainly produced in the bone and, upon secretion, forms a complex with a FGF receptor and coreceptor αKlotho. FGF23 can exert several endocrine functions, such as inhibiting renal phosphate reabsorption and 1,25-dihydroxyvitamin D3 production. Moreover, it has paracrine activities on several cell types, including neutrophils and hepatocytes. Klotho and Fgf23 deficiencies result in pathologies otherwise encountered in age-associated diseases, mainly as a result of hyperphosphataemia-dependent calcification. FGF23 levels are also perturbed in the plasma of patients with several disorders, including kidney or cardiovascular diseases. Here, we review mechanisms controlling FGF23 production and discuss how FGF23 regulation is perturbed in disease. 10.1002/1873-3468.13494
    Klotho/FGF23 axis mediates high phosphate-induced vascular calcification in vascular smooth muscle cells via Wnt7b/β-catenin pathway. Chen Yan-Xia,Huang Chong,Duan Zhi-Bing,Xu Cheng-Yun,Chen Yan The Kaohsiung journal of medical sciences Vascular calcification (VC) plays as a critical role on cardiovascular disease (CVD) and acts as a notable risk factor in cardiovascular system. Vascular smooth muscle cells (VSMCs) calcification can be triggered by high phosphate treatment; however, the explicit mechanism remains unclear. In the present study, we isolated VSMCs from primary rat artery, applied β-GP (β-glycerophosphate) for inducing VSMCs calcification in vitro to explore the mechanism of phosphate-induced calcification in VSMCs. Alizarin red staining was performed to assess the mineralization in VSMCs. Calcium deposition experiment was taken to evaluate the calcium content. ALP staining was determined to assess the ALP activity. The recombinant adenoviruses were constructed for the overexpression of Klotho and FGF23, respectively. qRT-PCR and western blot analysis were subjected to measure the expression of Klotho/FGF23 and correlated genes among Wnt7b/β-catenin pathway. We found that the calcium content was obviously increased and Alizarin red staining was positive in calcification group exposure with high phosphate in a time-dependent manner. The expression of Klotho and FGF23 was significantly decreased in the calcification group. However, overexpression of Klotho and FGF23 markedly reversed VSMCs calcification stimulating with high phosphate treatment. Moreover, Wnt7b/β-catenin inhibitor DKK1 could partly attenuate the effect of high phosphate on calcified VSMCs. These findings demonstrated that Klotho/FGF23 axis could modulate high phosphate-induced VSMCs calcification via Wnt7b/β-catenin signaling pathway. Our findings unravel that Klotho/FGF23- Wnt7b/β-catenin axis functions as a crucial role in the VSMCs calcification. 10.1002/kjm2.12072
    Investigating the Relationship Between Blood Pressure and Serum FGF23 Level in Patients Undergoing Hemodialysis in Guilan Province, A Cross Sectional Study. Ramezanzade Elham,Minoo Farzanehsadat,Lebadi Mohamad Kazem,Jedinia Alieh,Saheli Yalda Haghdar,Aghajanzadeh Pegah,Monfared Ali,Khosravi Masoud Iranian journal of kidney diseases INTRODUCTION:The aim of current study is investigation of theimpact of serum FGF23 levels on blood pressure of patients withend-stage renal disease (ESRD) undergoing hemodialysis. METHODS:Based on registry, 68 patients who underwent hemodialysis(HD) in the dialysis center of Shahid Beheshti hospital, Anzali,north of Iran, from April 2016 to May 2017 were enrolled. Enzyme-Linked ImmunoSorbent Assay (ELISA) was used to determineserum FGF23 levels. 24 hours blood pressure monitoring method,AMBB, was used to monitor the mean arterial pressure of patients.Spearman related analysis method was used to statistically analyzethe correlation of serum FGF23 level with mean arterial pressure,age, HD duration, kt/v, URR weight gaining, cause of ESRD, andthe mentioned laboratory parameters. RESULTS:Serum FGF23 levels of ESRD patients were not significantlyrelated to age, time of HD and gaining weight. Furthermore,these parameters were not related to blood pressure. However,FGF23 expression levels in serum were positively correlated withphosphorous and calcium- phosphorous. The mentioned laboratoryparameters had no significant correlation with 24 hours bloodpressure changes. Meanwhile, the minimum diastolic pressureand intact parathyroid hormone (iPTH) level showed a significantdirect linear correlation. CONCLUSION:We suggest that understanding relationship betweenphosphate, FGF23 and cardiovascular disease can be applied intargeted phosphate-based treatment. Kidney failure and the nondippercondition may be highly related to one another and leadto ESRD. Therefore, a special investment in controlling bloodpressure and examining it with a tool such as ABPM can greatlyhelp patients to progress effectively.
    A G protein-coupled, IP3/protein kinase C pathway controlling the synthesis of phosphaturic hormone FGF23. He Qing,Shumate Lauren T,Matthias Julia,Aydin Cumhur,Wein Marc N,Spatz Jordan M,Goetz Regina,Mohammadi Moosa,Plagge Antonius,Divieti Pajevic Paola,Bastepe Murat JCI insight Dysregulated actions of bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) result in several inherited diseases, such as X-linked hypophosphatemia (XLH), and contribute substantially to the mortality in kidney failure. Mechanisms governing FGF23 production are poorly defined. We herein found that ablation of the Gq/11α-like, extralarge Gα subunit (XLαs), a product of GNAS, exhibits FGF23 deficiency and hyperphosphatemia in early postnatal mice (XLKO). FGF23 elevation in response to parathyroid hormone, a stimulator of FGF23 production via cAMP, was intact in XLKO mice, while skeletal levels of protein kinase C isoforms α and δ (PKCα and PKCδ) were diminished. XLαs ablation in osteocyte-like Ocy454 cells suppressed the levels of FGF23 mRNA, inositol 1,4,5-trisphosphate (IP3), and PKCα/PKCδ proteins. PKC activation in vivo via injecting phorbol myristate acetate (PMA) or by constitutively active Gqα-Q209L in osteocytes and osteoblasts promoted FGF23 production. Molecular studies showed that the PKC activation-induced FGF23 elevation was dependent on MAPK signaling. The baseline PKC activity was elevated in bones of Hyp mice, a model of XLH. XLαs ablation significantly, but modestly, reduced serum FGF23 and elevated serum phosphate in Hyp mice. These findings reveal a potentially hitherto-unknown mechanism of FGF23 synthesis involving a G protein-coupled IP3/PKC pathway, which may be targeted to fine-tune FGF23 levels. 10.1172/jci.insight.125007
    FGF23 and Associated Disorders of Phosphate Wasting. Gohil Anisha,Imel Erik A Pediatric endocrinology reviews : PER Fibroblast growth factor 23 (FGF23), one of the endocrine fibroblast growth factors, is a principal regulator in the maintenance of serum phosphorus concentration. Binding to its cofactor αKlotho and a fibroblast growth factor receptor is essential for its activity. Its regulation and interaction with other factors in the bone-parathyroid-kidney axis is complex. FGF23 reduces serum phosphorus concentration through decreased reabsorption of phosphorus in the kidney and by decreasing 1,25 dihydroxyvitamin D (1,25(OH)2D) concentrations. Various FGF23-mediated disorders of renal phosphate wasting share similar clinical and biochemical features. The most common of these is X-linked hypophosphatemia (XLH). Additional disorders of FGF23 excess include autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia, and tumor-induced osteomalacia. Treatment is challenging, requiring careful monitoring and titration of dosages to optimize effectiveness and to balance side effects. Conventional therapy for XLH and other disorders of FGF23-mediated hypophosphatemia involves multiple daily doses of oral phosphate salts and active vitamin D analogs, such as calcitriol or alfacalcidol. Additional treatments may be used to help address side effects of conventional therapy such as thiazides to address hypercalciuria or nephrocalcinosis, and calcimimetics to manage hyperparathyroidism. The recent development and approval of an anti-FGF23 antibody, burosumab, for use in XLH provides a novel treatment option. 10.17458/per.vol17.2019.gi.fgf23anddisordersphosphate
    Vitamin D sterols increase FGF23 expression by stimulating osteoblast and osteocyte maturation in CKD bone. Pereira Renata C,Salusky Isidro B,Bowen Richard E,Freymiller Earl G,Wesseling-Perry Katherine Bone Impaired osteoblast and osteocyte maturation contribute to mineralization defects and excess FGF23 expression in CKD bone. Vitamin D sterols decrease osteoid accumulation and increase FGF23 expression; these agents also increase osteoblast maturation in vitro but a link between changes in bone cell maturation, bone mineralization, and FGF23 expression in response to vitamin D sterols has not been established. We evaluated unmineralized osteoid accumulation, osteocyte maturity markers (FGF23: early osteocytes; sclerostin: late osteocytes), and osteocyte apoptosis in iliac crest of 11 pediatric dialysis patients before and after 8 months of doxercalciferol therapy. We then evaluated the effect of 1,25(OH)vitamin D on in vitro maturation and mineralization of primary osteoblasts from dialysis patients. Unmineralized osteoid accumulation decreased while numbers of early (FGF23-expressing) increased in response to doxercalciferol. Osteocyte apoptosis was low but increased with doxercalciferol. Bone FGF23 expression correlated with numbers of early, FGF23-expressing, osteocytes (r = 0.83, p < 0.001). In vitro, 1,25(OH)vitamin D increased expression of the mature osteoblast marker osteocalcin (BGLAP) but only very high (100 nM) concentrations affected in vitro osteoblast mineralization. High doses (10 and 100 nM) of 1,25(OH)vitamin D also increased the ratio of RANKL/OPG expression in CKD osteoblasts. Vitamin D sterols directly stimulate osteoblast maturation. They also increase osteocyte turnover and increase osteoblast expression of osteoclast differentiation factors, thus likely modulating osteoblast/osteoclast/osteocyte coupling. By increasing numbers of early osteocytes, vitamin D sterols increase FGF23 expression in CKD bone. 10.1016/j.bone.2019.07.026
    Notch signaling is involved in Fgf23 upregulation in osteocytes. Tamamura Yoshihiro,Sakamoto Kei,Katsube Ken-Ichi,Yamaguchi Akira Biochemical and biophysical research communications Fgf23 acts as a phosphaturic factor secreted from osteocytes in bone, but the mechanism regulating Fgf23 is not fully understood. Here, we showed the colocalization of Fgf23, Notch, and Hes1, a downstream target of Notch signaling, in numerous osteocytes in cortical bone of femur in wild-type mice. We generated NICD (Notch intracellular domain)-transgenic mice driven by a 2.3 kb collagenα1 (I) (Col1a1) promoter fragment. Western blot and RT-PCR analyses revealed upregulation of Notch protein and mRNA levels in the bones of transgenic mice compared with those in wild-type mice. In the transgenic mice, immunohistochemical studies demonstrated that numerous osteocytes and osteoblasts express Notch in the rib, whereas only osteoblasts exhibit Notch in the femur. NICD-transgenic mice were characterized by upregulation of Fgf23 mRNA levels in the rib but not in the femur compared with that in wild type mice. These mice exhibited dwarfism associated with an osteomalacia phenotype. The expression of Alpl, Col1a1, and Bglap decreased in NICD-transgenic mice compared with wild-type mice. UMR-106 cells cultured on Jagged1-immobilized wells significantly increased Fgf23 expressions associating with upregulation of Hes1 and Hey1. These results imply that Notch signaling is a positive regulator for Fgf23 expression in osteocytes. 10.1016/j.bbrc.2019.08.038
    Dietary Phosphorus and FGF23: Is More Restriction Better? Hill Gallant Kathleen M Clinical journal of the American Society of Nephrology : CJASN 10.2215/CJN.09640819
    FGF23 and inflammation-a vicious coalition in CKD. Czaya Brian,Faul Christian Kidney international High serum concentrations of the phosphaturic hormone, fibroblast growth factor 23 (FGF23), contribute to various tissue injuries. In chronic kidney disease, the sources of FGF23 and the stimuli that control FGF23 production differ from those in the physiologic scenario. Mediators of inflammation are intensively studied as potential factors that contribute to FGF23 elevations and thereby might function as drug targets to lower FGF23 levels. The present study focuses on tumor necrosis factor. 10.1016/j.kint.2019.05.018
    Changes in serum FGF23 and Klotho levels and calcification scores of the abdominal aorta after parathyroidectomy for secondary hyperparathyroidism. Chou Fong-Fu,Chen Jin-Bor,Huang Shun-Cheng,Chan Yi-Chai,Chi Shun-Yu,Chen Wei-Ting American journal of surgery BACKGROUND:Changes of calcification scores of the abdominal aorta (CSAA) after total parathyroidectomy plus autotransplantation (TPX + AT) for symptomatic secondary hyperparathyroidism (SSHP) have never been reported. METHODS:Forty-nine patients who successfully underwent TPX + AT for SSHP were enrolled; 13 patients who had regular hemodialysis were enrolled as controls. Preoperatively, patients' age, gender, and duration of dialysis were recorded. Serum Ca, P, alkaline phosphatase (Alk-ptase), intact parathyroid hormone (iPTH), vitamin D, FGF23, and Klotho levels, and CSAA were measured. One year postoperatively, these data were measured again. In the control group, these data were recorded and measured before and one year later. RESULTS:Serum iPTH, Alk-ptase and FGF23 levels and CSAA of the study group were significantly higher than those of the control group. One year postoperatively, serum Ca, P, Alk-ptase, iPTH, and FGF23 levels and CSAA were significantly lower than those before surgery. Except for FGF23 levels, other items of the control group did not change significantly one year later, whereas the study group decreased CSAA more than the control group. CONCLUSION:One year postoperatively, CSAA decreased. 10.1016/j.amjsurg.2018.12.026
    FGF23-Mediated Activation of Local RAAS Promotes Cardiac Hypertrophy and Fibrosis. Böckmann Ineke,Lischka Jonas,Richter Beatrice,Deppe Jennifer,Rahn Anja,Fischer Dagmar-Christiane,Heineke Jörg,Haffner Dieter,Leifheit-Nestler Maren International journal of molecular sciences Patients with chronic kidney disease (CKD) are prone to developing cardiac hypertrophy and fibrosis, which is associated with increased fibroblast growth factor 23 (FGF23) serum levels. Elevated circulating FGF23 was shown to induce left ventricular hypertrophy (LVH) via the calcineurin/NFAT pathway and contributed to cardiac fibrosis by stimulation of profibrotic factors. We hypothesized that FGF23 may also stimulate the local renin-angiotensin-aldosterone system (RAAS) in the heart, thereby further promoting the progression of FGF23-mediated cardiac pathologies. We evaluated LVH and fibrosis in association with cardiac FGF23 and activation of RAAS in heart tissue of 5/6 nephrectomized (5/6Nx) rats compared to sham-operated animals followed by in vitro studies with isolated neonatal rat ventricular myocytes and fibroblast (NRVM, NRCF), respectively. Uremic rats showed enhanced cardiomyocyte size and cardiac fibrosis compared with sham. The cardiac expression of and RAAS genes were increased in 5/6Nx rats and correlated with the degree of cardiac fibrosis. In NRVM and NRCF, FGF23 stimulated the expression of RAAS genes and induced indicating mineralocorticoid receptor activation. The FGF23-mediated hypertrophic growth of NRVM and induction of NFAT target genes were attenuated by cyclosporine A, losartan and spironolactone. In NRCF, FGF23 induced and , which were suppressed by losartan and spironolactone, only. Our data suggest that FGF23-mediated activation of local RAAS in the heart promotes cardiac hypertrophy and fibrosis. 10.3390/ijms20184634
    Cardiac FGF23: a new player in myocardial infarction. Schumacher David,Schuh Alexander Discoveries (Craiova, Romania) Fibroblast Growth Factor 23 (FGF23) is a hormone involved in phosphate metabolism. It is known that FGF23 is increased in different pathologies including chronic kidney disease, heart failure or X-linked hypophosphatemia and directly correlates with negative outcome and mortality in severe diseases. However, the role of FGF23 in cardiovascular pathologies is still under debate. This review summarizes the current knowledge about the role of FGF23 in ischemic heart diseases, such as myocardial infarction. 10.15190/d.2019.10
    FGF23 regulates atrial fibrosis in atrial fibrillation by mediating the STAT3 and SMAD3 pathways. Dong Quanbin,Li Shaochuan,Wang Weixue,Han Lu,Xia Zirong,Wu Yanqing,Tang Yanhua,Li Juxiang,Cheng Xiaoshu Journal of cellular physiology High fibroblast growth factor 23 (FGF23) concentrations are a strong predictor of atrial fibrillation (AF), but researchers have not clearly determined the mechanism by which FGF23 causes atrial fibrosis in patients with AF. This study aims to elucidate the mechanism by which FGF23 induces atrial fibrosis in patients with AF. Immunohistochemistry was used to study the expression of FGF23, FGFR4, and fibrotic factors in patients with a normal sinus rhythm (SR) and patients with AF. Cardiac fibroblasts (CFs) were cocultured with different concentrations of the recombinant FGF23 protein. Compared with the SR group, the levels of FGF23, FGFR4, α-smooth muscle actin (α-SMA), and collagen-1 were significantly increased in the AF group. Exposure to high concentrations of the recombinant FGF23 protein increased the accumulation of reactive oxygen species (ROS) and activated α-SMA, collagen-1, signal transducer and activator of transcription 3 (STAT3) and SMAD3 signaling in cultured CFs. The levels of fibrotic proteins in CFs stimulated with high concentrations of the recombinant FGF23 protein were reversed by N-acetylcysteine (NAC, a ROS inhibitor), ship information system 3 (a SMAD3 inhibitor), and Stattic (a STAT3 inhibitor). Furthermore, compared to untreated CFs, CFs treated with the recombinant FGF23 protein were characterized by an increased interaction between STAT3 and SMAD3. Based on these results, FGF23 induces atrial fibrosis in patients with AF by increasing ROS production and subsequently activating STAT3 and SMAD3 signaling. 10.1002/jcp.28548
    αKlotho-FGF23 interactions and their role in kidney disease: a molecular insight. Smith Edward R,Holt Stephen G,Hewitson Tim D Cellular and molecular life sciences : CMLS Following the serendipitous discovery of the ageing suppressor, αKlotho (αKl), several decades ago, a growing body of evidence has defined a pivotal role for its various forms in multiple aspects of vertebrate physiology and pathology. The transmembrane form of αKl serves as a co-receptor for the osteocyte-derived mineral regulator, fibroblast growth factor (FGF)23, principally in the renal tubules. However, compelling data also suggest that circulating soluble forms of αKl, derived from the same source, may have independent homeostatic functions either as a hormone, glycan-cleaving enzyme or lectin. Chronic kidney disease (CKD) is of particular interest as disruption of the FGF23-αKl axis is an early and common feature of disease manifesting in markedly deficient αKl expression, but FGF23 excess. Here we critically discuss recent findings in αKl biology that conflict with the view that soluble αKl has substantive functions independent of FGF23 signalling. Although the issue of whether soluble αKl can act without FGF23 has yet to be resolved, we explore the potential significance of these contrary findings in the context of CKD and highlight how this endocrine pathway represents a promising target for novel anti-ageing therapeutics. 10.1007/s00018-019-03241-y
    FGF23 and Phosphate-Cardiovascular Toxins in CKD. Vogt Isabel,Haffner Dieter,Leifheit-Nestler Maren Toxins Elevated levels of fibroblast growth factor 23 (FGF23) and phosphate are highly associated with increased cardiovascular disease and mortality in patients suffering from chronic kidney disease (CKD). As the kidney function declines, serum phosphate levels rise and subsequently induce the secretion of the phosphaturic hormone FGF23. In early stages of CKD, FGF23 prevents the increase of serum phosphate levels and thereby attenuates phosphate-induced vascular calcification, whereas in end-stage kidney disease, FGF23 fails to maintain phosphate homeostasis. Both hyperphosphatemia and elevated FGF23 levels promote the development of hypertension, vascular calcification, and left ventricular hypertrophy by distinct mechanisms. Therefore, FGF23 and phosphate are considered promising therapeutic targets to improve the cardiovascular outcome in CKD patients. Previous therapeutic strategies are based on dietary and pharmacological reduction of serum phosphate, and consequently FGF23 levels. However, clinical trials proving the effects on the cardiovascular outcome are lacking. Recent publications provide evidence for new promising therapeutic interventions, such as magnesium supplementation and direct targeting of phosphate and FGF receptors to prevent toxicity of FGF23 and hyperphosphatemia in CKD patients. 10.3390/toxins11110647
    Influence of the Klotho/FGF23/Egr1 signaling pathway on calcium-phosphorus metabolism in diabetic nephropathy and the intervention of Shenyuan granules. Zou X R,Zhan L R,Chen L,Long Q H,Yuan J,Wang L,Wang X Q Journal of biological regulators and homeostatic agents This study aimed to explore the effects of Shenyuan granules on the Klotho/FGFR23/Egr1 signaling pathway and calcium-phosphorus metabolism in diabetic mice models with impairment of renal function. Streptozotocin-induced diabetic nephropathy (DN) mice models were randomly divided into three groups: Shenyuan granules group (n=10), model control group (n=10), and blank control group (n=10). Corresponding drugs were given by gavage for 8 weeks. Blood glucose and serum creatinine (SCr), urea nitrogen (BUN), calcium (Ca), phosphorus (P) and mLAB were detected before and after administration. Moreover, RT-qPCR was performed to detect the expression of CYP24 and CYP27 mRNA in kidney tissue. Blood FGF23 was detected by ELISA. Western-blot and immunohistochemistry were performed to detect the expressions of Klotho, FGFR1, Egr1, CYP24, CYP27, ERK1/2 and p-ERK1/2. Compared with the blank control group, in the model control group serum FGF23,P, SCr and 24-hour proteinuria levels increased (P<0.05), serum Ca significantly decreased (P<0.05), expressionss of Egr1, CYP24, CYP27 and p-ERK1/2 were up-regulated (P<0.05), and the expressions of Klotho and FGFR1 were down-regulated (P<0.05). After treatment, compared with the model control group, in the Shenyuan granule group serum FGF23, P, SCr levels decreased (P<0.05), serum Ca increased (P<0.05), expressions of Egr-1, CYP24, CYP27 and p-ERK1/2 were down-regulated (P<0.05), and the expressions of Klotho and FGFR1 were up-regulated (P<0.05). Shenyuan granules may partly intervene in the expressions of CYP24 and CYP27 through the Klotho/FGF23/Egr1 signaling pathway, thereby improving calcium and phosphorus metabolism and alleviating renal injury in diabetic nephropathy. 10.23812/19-207-A
    FGF23-Klotho axis in patients with rheumatoid arthritis. Alvarez-Cienfuegos Antonio,Cantero-Nieto Lucia,Garcia-Gomez Jose Alberto,Robledo Gema,González-Gay Miguel Angel,Ortego-Centeno Norberto Clinical and experimental rheumatology OBJECTIVES:We aimed to compare serum Klotho and fibroblast growth factor-23 (FGF-23) levels between rheumatoid arthritis (RA) patients and healthy controls. Possible association between FGF-23 and soluble Klotho with different characteristic of the disease as well as their potential role as surrogate markers of cardiovascular disease (CVD) were studied. METHODS:Sixty-three patients with RA recruited at Vega-Baja Hospital, Orihuela (Spain) from November 2016 to May 2018 and sixty-five age- and sex-matched healthy controls were included in this study. Serum Klotho and FGF-23 were analysed using ELISA. RESULTS:Patients had higher serum levels of Klotho than healthy controls (p˂0.0001). They were positively associated with the presence of anticitrullinated peptide antibody and rheumatic factor (p<0.05). Klotho serum levels were higher in RA patients treated with biologic agents than in those undergoing conventional therapy (p=0.008). However, no association with carotid intima media thickness was found. Although no significant differences in serum FGF-23 levels between patients and controls were found (p=0.43), FGF-23 levels were positively associated with low-density lipoprotein (LDL-c) level (p<0.05) and smoking (p=0.008) in patients with RA. CONCLUSIONS:The increased serum Klotho levels in RA patients, especially in those undergoing biologic therapy, may indicate a potential implication in the pathogenesis of the disease. Although levels of FGF-23 were related to LDL-c levels, the FGF-23-Klotho axis does not seem to be related to subclinical arteriosclerosis in RA.
    FGF23-klotho axis as predictive factors of fractures in type 2 diabetics with early chronic kidney disease. Ribeiro Ana Luísa,Mendes Filipa,Carias Eduarda,Rato Fátima,Santos Nélio,Neves Pedro Leão,Silva Ana Paula Journal of diabetes and its complications BACKGROUND:The aim of our study was to evaluate the relevance of FGF23-klotho axis in the predisposition for bone fractures in type 2 diabetic patients with early chronic kidney disease. METHODS:In a prospective study we included 126 type 2 diabetic patients with CKD stages 2-3 (from 2010 to 2017). We used descriptive statistics, ANOVA and chi-square test. Our population was divided into two groups according to the occurrence of a bone fracture event or not, and the groups were compared considering several biological and laboratorial parameters. We employed a multiple regression model to identify risk factors for bone fracture events and hazard ratios (HR) were calculated using a backward stepwise likelihood ratio (LR) Cox regression. RESULTS:Patients with a fracture event displayed higher levels of FGF-23, Phosphorus, PTH, TNF-α, OxLDL, HOMA-IR, calcium × phosphorus product and ACR and lower levels of Osteocalcin, α-Klotho, 25(OH)D3 and eGFR compared with patients without a fracture event (p < 0.001). The number of patients with a fracture event was higher than expected within inclining CKD stages (χ2, p = 0.06). The occurrence of fracture and the levels of TNF- α, klotho, 25(OH)D3 and OxLDL were found to predict patient entry into RRT (p < 0.05). Age, osteocalcin, α-Klotho and FGF-23 independently influenced the occurrence of bone fracture (p < 0.05). CONCLUSIONS:α-Klotho and FGF-23 levels may have a good clinical use as biomarkers to predict the occurrence of fracture events. 10.1016/j.jdiacomp.2019.107476
    FGF23 induced left ventricular hypertrophy mediated by FGFR4 signaling in the myocardium is attenuated by soluble Klotho in mice. Han Xiaobin,Cai Chun,Xiao Zhousheng,Quarles L Darryl Journal of molecular and cellular cardiology There is controversy regarding whether excess FGF23 causes left ventricular hypertrophy (LVH) directly through activation of fibroblast growth factor receptor 4 (FGFR4) in cardiomyocytes or indirectly through reductions in soluble Klotho (sK). We investigated the respective roles of myocardial FGFR4 and sKL in mediating FGF23-induced LVH using mouse genetic and pharmacological approaches. To investigate a direct role of myocardial FGFR4 in mediating the cardiotoxic effects of excess circulating FGF23, we administered rFGF23 to mice with cardiac-specific loss of FGFR4 (FGFR4 heart-cKO). We tested a model of sKL deficiency, hypertension and LVH created by the conditional deletion of FGFR1 in the renal distal tubule (FGFR1DT cKO mice). The cardioprotective effects of sKL in both mouse models was assessed by the systemic administration of recombinant sKL. We confirmed that FGF23 treatment activates PLCγ in the heart and induces LVH in the absence of membrane α-Klotho. Conditional deletion of FGFR4 in the myocardium prevented rFGF23-induced LVH in mice, establishing direct cardiotoxicity of FGF23 through activation of FGFR4. Recombinant sKL administration prevented LVH, but not HTN, in FGFR1DT cKO mice, consistent with direct cardioprotective effects. Co-administration of recombinant sKL with FGF23 in culture inhibited rFGF23-induced p-PLCγ signaling. Thus, FGF23 ability to include LVH represents a balance between FGF23 direct cardiac activation of FGFR4 and the modulating effects of circulating sKL to alter FGF23-dependent myocardial signaling pathways. 10.1016/j.yjmcc.2019.11.149
    FGF23 and Bone and Mineral Metabolism. Fukumoto Seiji Handbook of experimental pharmacology FGF23 is a phosphotropic hormone produced by the bone. FGF23 works by binding to the FGF receptor-Klotho complex. Klotho is expressed in several limited tissues including the kidney and parathyroid glands. This tissue-restricted expression of Klotho is believed to determine the target organs of FGF23. FGF23 reduces serum phosphate by suppressing the expression of type 2a and 2c sodium-phosphate cotransporters in renal proximal tubules. FGF23 also decreases 1,25-dihydroxyvitamin D levels by regulating the expression of vitamin D-metabolizing enzymes, which results in reduced intestinal phosphate absorption. Excessive actions of FGF23 cause several types of hypophosphatemic rickets/osteomalacia characterized by impaired mineralization of bone matrix. In contrast, deficient actions of FGF23 result in hyperphosphatemic tumoral calcinosis with high 1,25-dihydroxyvitamin D levels. These results indicate that FGF23 is a physiological regulator of phosphate and vitamin D metabolism and indispensable for the maintenance of serum phosphate levels. 10.1007/164_2019_330
    Physiology of FGF23 and overview of genetic diseases associated with renal phosphate wasting. Bacchetta Justine,Bardet Claire,Prié Dominique Metabolism: clinical and experimental Phosphate is a cornerstone of several physiological pathways including skeletal development, bone mineralization, membrane composition, nucleotide structure, maintenance of plasma pH, and cellular signaling. The kidneys have a key role in phosphate homeostasis with three hormones having important functions in renal phosphate handling or intestinal absorption: parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1-25-dihydroxyvitamin D (1,25(OH)2D). FGF23 is mainly synthesized by osteocytes; it is a direct phosphaturic factor that also inhibits 1,25(OH)2D and PTH. In addition to crucial effects on phosphate and calcium metabolism, FGF23 also has 'off-target' effects notably on the cardiovascular, immune and central nervous systems. Genetic diseases may affect the FGF23 pathway, resulting in either increased FGF23 levels leading to hypophosphatemia (such as in X-linked hypophosphatemia) or defective secretion/action of intact FGF23 inducing hyperphosphatemia (such as in familial tumoral calcinosis). The aim of this review is to provide an overview of FGF23 physiology and pathophysiology in X-linked hypophosphatemia, with a focus on FGF23-associated genetic diseases. 10.1016/j.metabol.2019.01.006
    Regulation and Effects of FGF23 in Chronic Kidney Disease. Musgrove John,Wolf Myles Annual review of physiology Chronic kidney disease (CKD) is a global health epidemic that accelerates cardiovascular disease, increases risk of infection, and causes anemia and bone disease, among other complications that collectively increase risk of premature death. Alterations in calcium and phosphate homeostasis have long been considered nontraditional risk factors for many of the most morbid outcomes of CKD. The discovery of fibroblast growth factor 23 (FGF23), which revolutionized the diagnosis and treatment of rare hereditary disorders of FGF23 excess that cause hypophosphatemic rickets, has also driven major paradigm shifts in our understanding of the pathophysiology and downstream end-organ complications of disordered mineral metabolism in CKD. As research of FGF23 in CKD has rapidly advanced, major new questions about its regulation and effects continuously emerge. These are promoting exciting innovations in laboratory, patient-oriented, and epidemiological research and stimulating clinical trials of new therapies and repurposing of existing ones to target FGF23. 10.1146/annurev-physiol-021119-034650
    Circulating FGF23 is not associated with cardiac dysfunction, atherosclerosis, infection or inflammation in hemodialysis patients. Takashi Yuichi,Wakino Shu,Minakuchi Hitoshi,Ishizu Masashi,Kuroda Akio,Shima Hisato,Tashiro Manabu,Miya Keiko,Okada Kazuyoshi,Minakuchi Jun,Kawashima Shu,Matsuhisa Munehide,Matsumoto Toshio,Fukumoto Seiji Journal of bone and mineral metabolism Fibroblast growth factor (FGF) 23 is a bone-derived hormone regulating serum inorganic phosphate (Pi) concentration. FGF23 is also involved in the development of chronic kidney disease (CKD)-mineral and bone disorder. Serum FGF23 concentration begins to increase early in the progression of CKD and can be remarkably high in hemodialysis patients with end-stage renal disease. It has been reported that high FGF23 concentration is a risk factor for cardiac dysfunction, atherosclerosis, infection or systemic inflammation in CKD patients. FGF23 was also shown to induce cardiac hypertrophy directly acting on cardiomyocytes. However, it is still controversial whether high FGF23 is causing cardiac dysfunction, atherosclerosis, infection or systemic inflammation in CKD patients. In the current study, we investigated whether FGF23 concentration is associated with cardiac dysfunction, atherosclerosis, infection or systemic inflammation in Japanese hemodialysis patients. We recruited 119 hemodialysis patients and examined the association between serum FGF23 concentration and several parameters concerning mineral metabolism, cardiac dysfunction, atherosclerosis, infection, and systemic inflammation. Serum FGF23 concentration was independently associated with serum calcium and Pi concentration (β = 0.276, p < 0.001; β = 0.689, p < 0.001). However, serum FGF23 concentration was not associated with parameters of cardiac dysfunction, atherosclerosis, infection, and systemic inflammation, either. Our results do not support the hypothesis that high FGF23 in dialysis patients is the cause of cardiac dysfunction, atherosclerosis, infection or systemic inflammation. 10.1007/s00774-019-01027-7
    FGF23 at the crossroads of phosphate, iron economy and erythropoiesis. Edmonston Daniel,Wolf Myles Nature reviews. Nephrology Fibroblast growth factor 23 (FGF23) was initially characterized as an important regulator of phosphate and calcium homeostasis. New research advances demonstrate that FGF23 is also linked to iron economy, inflammation and erythropoiesis. These advances have been fuelled, in part, by the serendipitous development of two distinct FGF23 assays that can substitute for invasive bone biopsies to infer the activity of the three main steps of FGF23 regulation in bone: transcription, post-translational modification and peptide cleavage. This 'liquid bone biopsy for FGF23 dynamics' enables large-scale longitudinal studies of FGF23 regulation that would otherwise be impossible in humans. The balance between FGF23 production, post-translational modification and cleavage is maintained or perturbed in different hereditary monogenic conditions and in acquired conditions that mimic these genetic disorders, including iron deficiency, inflammation, treatment with ferric carboxymaltose and chronic kidney disease. Looking ahead, a deeper understanding of the relationships between FGF23 regulation, iron homeostasis and erythropoiesis can be leveraged to devise novel therapeutic targets for treatment of anaemia and states of FGF23 excess, including chronic kidney disease. 10.1038/s41581-019-0189-5
    FGF23 and inflammation. Sharaf El Din Usama A A,Salem Mona M,Abdulazim Dina O World journal of nephrology Systemic inflammation is a recognized feature in chronic kidney disease (CKD). The role of systemic inflammation in the pathogenesis of vascular calcification was recently settled. FGF23 was recently accused as a direct stimulus of systemic inflammation. This finding explains the strong association of FGF23 to vascular calcification and increased mortality among CKD. 10.5527/wjn.v6.i1.57
    Effect of Calcitriol on FGF23 Level in Healthy Adults and its Dependence on Phosphate Level. Georgiadou Effrosyni,Marketou Helen,Trovas George,Dontas Ismene,Papaioannou Nikolaos,Makris Konstantinos,Galanos Antonios,Papavassiliou Athanasios In vivo (Athens, Greece) AIM: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. PATIENTS AND METHODS: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. RESULTS: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. CONCLUSION: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. 10.21873/invivo.11038
    PTH Regulation of FGF23 Fragments: A Tail in Two Acts Suva Larry J,Friedman Peter A Endocrinology 10.1210/en.2017-00185
    Low serum iron is associated with high serum intact FGF23 in elderly men: The Swedish MrOS study. Lewerin Catharina,Ljunggren Östen,Nilsson-Ehle Herman,Karlsson Magnus K,Herlitz Hans,Lorentzon Mattias,Ohlsson Claes,Mellström Dan Bone BACKGROUND:Fibroblast growth factor (FGF23) is a protein that is produced by osteoblasts and osteocytes. Increased serum levels of FGF23 have been associated with increased risks of osteoporotic fractures and cardiovascular disease, particularly in participants with poor renal function. Serum iron (Fe) has been suggested as a regulator of FGF23 homeostasis. OBJECTIVE:To determine whether Fe and iron status are determinants of the levels of intact FGF23 (iFGF23) in elderly men. METHODS:The MrOS study is a population-based study of elderly men (N=1010; mean age, 75.3years; range, 69-81years). The levels of Fe, transferrin saturation (TS), and ferritin were evaluated in relation to the serum concentrations of iFGF23 before and after adjustments for confounders. RESULTS:TS <15% was found in 3.5% (34/977) of the participants, who had a higher median level iFGF23 compared with the remaining subjects (47.4μmol/L vs. 41.9μmol/L, p=0.008). The levels of iFGF23 correlated negatively (un-adjusted) with the levels of Fe (r=-0.17, p<0.001), TS (r=-0.16, p<0.001) and serum ferritin (r=-0.07, p=0.022). In addition, in participants with estimated glomerular filtration rate eGFRCystatin C>60mL/min, the levels of iFGF23 correlated (age-adjusted) negatively with the levels of Fe (r=-0.15, p<0.001) and TS (r=-0.17, p<0.001). The level of iFGF23 correlated positively (un-adjusted) with lumbar spine bone mineral density (BMD) (r=0.14, p<0.001), total body BMD (r=0.11, p=0.001), and total hip BMD (r=0.09, p=0.004). The corresponding correlations, when adjusted for age, weight, and height were: r=0.08, p=0.018; r=0.05, p=0.120; and r=0.02, p=0.624, respectively. No associations were found between BMD and the levels of Fe or TS. Multiple step-wise linear regression analyses [adjusting for age, body mass index (BMI), comorbidity index, cystatin C, C-reactive protein (hs-CRP), serum vitamin D 25-OH (25OHD), phosphate, calcium, parathyroid hormone (PTH), erythropoietin, hemoglobin, lumbar spine BMD, apolipoprotein B/A1 ratio] were performed in three separate models with Fe, TS or ferritin as potential explanatory variables. Fe and TS, but not ferritin, were independent predictors of iFGF23 level (standardized β-values: -0.10, p<0.001; -0.10, p<0.001; and -0.05, p=0.062, respectively). CONCLUSION:Low levels of Fe in elderly men are associated with high levels of iFGF23, independently of markers of inflammation and renal function, suggesting an iron-related pathway for FGF23 regulation. 10.1016/j.bone.2017.02.005
    FGF23/FGFR4-mediated left ventricular hypertrophy is reversible. Grabner Alexander,Schramm Karla,Silswal Neerupma,Hendrix Matt,Yanucil Christopher,Czaya Brian,Singh Saurav,Wolf Myles,Hermann Sven,Stypmann Jörg,Di Marco Giovana Seno,Brand Marcus,Wacker Michael J,Faul Christian Scientific reports Fibroblast growth factor (FGF) 23 is a phosphaturic hormone that directly targets cardiac myocytes via FGF receptor (FGFR) 4 thereby inducing hypertrophic myocyte growth and the development of left ventricular hypertrophy (LVH) in rodents. Serum FGF23 levels are highly elevated in patients with chronic kidney disease (CKD), and it is likely that FGF23 directly contributes to the high rates of LVH and cardiac death in CKD. It is currently unknown if the cardiac effects of FGF23 are solely pathological, or if they potentially can be reversed. Here, we report that FGF23-induced cardiac hypertrophy is reversible in vitro and in vivo upon removal of the hypertrophic stimulus. Specific blockade of FGFR4 attenuates established LVH in the 5/6 nephrectomy rat model of CKD. Since CKD mimics a form of accelerated cardiovascular aging, we also studied age-related cardiac remodeling. We show that aging mice lacking FGFR4 are protected from LVH. Finally, FGF23 increases cardiac contractility via FGFR4, while known effects of FGF23 on aortic relaxation do not require FGFR4. Taken together, our data highlight a role of FGF23/FGFR4 signaling in the regulation of cardiac remodeling and function, and indicate that pharmacological interference with cardiac FGF23/FGFR4 signaling might protect from CKD- and age-related LVH. 10.1038/s41598-017-02068-6
    Intact FGF23 and α-klotho during acute inflammation/sepsis in CKD patients. Dounousi Evangelia,Torino Claudia,Pizzini Patrizia,Cutrupi Sebastiano,Panuccio Vincenzo,D'Arrigo Graziella,Abd ElHafeez Samar,Tripepi Giovanni,Mallamaci Francesca,Zoccali Carmine European journal of clinical investigation 10.1111/eci.12765
    FGF23 is synthesised locally by renal tubules and activates injury-primed fibroblasts. Smith Edward R,Tan Sven-Jean,Holt Stephen G,Hewitson Tim D Scientific reports In kidney disease, higher circulating levels of the mineral-regulating hormone fibroblast growth factor (FGF)-23 are predictive of disease progression but direct pathogenic effects on the kidney are unknown. We sought evidence of local renal synthesis in response to unilateral ureteric obstruction in the mouse, and pro-fibrotic actions of FGF23 on the fibroblast in vitro. Acute tubulointerstitial injury due to unilateral ureteric obstruction stimulated renal FGF23 synthesis by tubules, and downregulated inactivating proprotein convertases, without effects on systemic mineral metabolism. In vitro, FGF23 had divergent effects on fibroblast activation in cells derived from normal and obstructed kidneys. While FGF23 failed to stimulate fibrogenesis in normal fibroblasts, in those primed by injury, FGF23 induced pro-fibrotic signalling cascades via activation of TGF-β pathways. Effects were independent of α-klotho. Tubule-derived FGF23 may amplify myofibroblast activation in acute renal injury, and might provide a novel therapeutic target in renal fibrosis. 10.1038/s41598-017-02709-w
    Effect of additive calcium administration on FGF23 levels in patients with mild chronic kidney disease treated with calcitriol: a randomized, open-labeled clinical trial. Han Nayoung,Hong Su Hyun,Kim Yon Su,Kim Dong Ki,Kim In-Wha,Ji Eunhee,Oh Jung Mi Therapeutics and clinical risk management BACKGROUND:The purpose of the present study was to determine the effect of additional calcium carbonate treatment on fibroblast growth factor 23 (FGF23) levels in patients treated with calcitriol. METHODS:In this randomized, open-labeled, and parallel-group study, a total of 30 patients with early chronic kidney disease (CKD) and vitamin D deficiency were randomly assigned to two groups and received interventions for 8 weeks: 1) a combination of calcium carbonate and calcitriol group; and 2) calcitriol only group. The primary outcome was the difference in percentage change of serum FGF23 levels from baseline between the two groups. Secondary end points included the changes in serum levels of calcium, phosphate, parathyroid hormone (PTH), and 25-hydroxyvitamin D (25(OH)D) from baseline. RESULTS:Serum FGF23 levels were more elevated in the combination group than in the calcitriol-alone group. However, both mean change and percentage change in the serum FGF23 levels during the 8-week period were not significantly different between the two groups. Serum calcium level was increased significantly only in the combination treatment group. There was no significant difference in percentage change of serum calcium levels between the two groups. In addition, changes in serum levels of phosphate, 25(OH)D, or PTH were not significantly different between the two groups. In correlation analysis, changes in serum FGF23 levels were positively correlated with changes in serum calcium and phosphate levels, but not with changes in 25(OH)D or PTH levels. No serious adverse events were observed, however, there was one case of mild gastrointestinal discomfort. CONCLUSION:This study revealed that additional calcium carbonate treatment significantly increased serum FGF23 levels in patients treated with calcitriol, with their synergistic effect in promoting intestinal calcium absorption. This suggests that serum FGF23 levels should be monitored regularly, especially in those who use combination of vitamin D and calcium carbonate from the early stages of CKD. 10.2147/TCRM.S142564
    Heritable and acquired disorders of phosphate metabolism: Etiologies involving FGF23 and current therapeutics. Clinkenbeard Erica L,White Kenneth E Bone Phosphate is critical for many cellular processes and structural functions, including as a key molecule for nucleic acid synthesis and energy metabolism, as well as hydroxyapatite formation in bone. Therefore it is critical to maintain tight regulation of systemic phosphate levels. Based upon its broad biological importance, disruption of normal phosphate homeostasis has detrimental effects on skeletal integrity and overall health. Investigating heritable diseases of altered phosphate metabolism has led to key discoveries underlying the regulation and systemic actions of the phosphaturic hormone Fibroblast growth factor-23 (FGF23). Both molecular and clinical studies have revealed novel targets for the development and optimization of therapies for disorders of phosphate handling. This review will focus upon the bridge between genetic discoveries involving disorders of altered FGF23 bioactivity, as well as describe how these findings have translated into pharmacologic application. 10.1016/j.bone.2017.01.034
    Vitamin D treatment attenuates cardiac FGF23/FGFR4 signaling and hypertrophy in uremic rats. Leifheit-Nestler Maren,Grabner Alexander,Hermann Laura,Richter Beatrice,Schmitz Karin,Fischer Dagmar-Christiane,Yanucil Christopher,Faul Christian,Haffner Dieter Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Background:Vitamin D deficiency and excess of circulating fibroblast growth factor 23 (FGF23) contribute to cardiovascular mortality in patients with chronic kidney disease (CKD). FGF23 activates FGF receptor 4 and (FGFR4) calcineurin/nuclear factor of activated T cells (NFAT) signaling in cardiac myocytes, thereby causing left ventricular hypertrophy (LVH). Here, we determined if 1,25-dihydroxyvitamin D (calcitriol) inhibits FGF23-induced cardiac signaling and LVH. Methods:5/6 nephrectomized (5/6 Nx) rats were treated with different doses of calcitriol for 4 or 10 weeks and cardiac expression of FGF23/FGFR4 and activation of calcineurin/NFAT as well as LVH were analyzed. FGFR4 activation and hypertrophic cell growth were studied in cultured cardiac myocytes that were co-treated with FGF23 and calcitriol. Results:In 5/6Nx rats with LVH, we detected elevated FGF23 expression in bone and myocardium, increased cardiac expression of FGFR4 and elevated cardiac activation of calcineurin/NFAT signaling. Cardiac expression levels of FGF23 and FGFR4 significantly correlated with the presence of LVH in uremic rats. Treatment with calcitriol reduced LVH as well as cardiac FGFR4 expression and calcineurin/NFAT activation. Bone and cardiac FGF23 expression were further stimulated by calcitriol in a dose-dependent manner, but levels of intact cardiac FGF23 protein were suppressed by high-dose calcitriol. In cultured cardiac myocytes, co-treatment with calcitriol blocked FGF23-induced activation of FGFR4 and hypertrophic cell growth. Conclusions:Our data suggest that in CKD, cardioprotective effects of calcitriol stem from its inhibitory actions on the cardiac FGF23/FGFR4 system, and based on their counterbalancing effects on cardiac myocytes, high FGF23 and low calcitriol synergistically contribute to cardiac hypertrophy. 10.1093/ndt/gfw454
    Genetic Ablation of Fgf23 or Klotho Does not Modulate Experimental Heart Hypertrophy Induced by Pressure Overload. Slavic Svetlana,Ford Kristopher,Modert Magalie,Becirovic Amarela,Handschuh Stephan,Baierl Andreas,Katica Nejla,Zeitz Ute,Erben Reinhold G,Andrukhova Olena Scientific reports Left ventricular hypertrophy (LVH) ultimately leads to heart failure in conditions of increased cardiac pre- or afterload. The bone-derived phosphaturic and sodium-conserving hormone fibroblast growth factor-23 (FGF23) and its co-receptor Klotho have been implicated in the development of uremic LVH. Using transverse aortic constriction (TAC) in gene-targeted mouse models, we examine the role of Fgf23 and Klotho in cardiac hypertrophy and dysfunction induced by pressure overload. TAC profoundly increases serum intact Fgf23 due to increased cardiac and bony Fgf23 transcription and downregulation of Fgf23 cleavage. Aldosterone receptor blocker spironolactone normalizes serum intact Fgf23 levels after TAC by reducing bony Fgf23 transcription. Notably, genetic Fgf23 or Klotho deficiency does not influence TAC-induced hypertrophic remodelling, LV functional impairment, or LV fibrosis. Despite the profound, aldosterone-mediated increase in circulating intact Fgf23 after TAC, our data do not support an essential role of Fgf23 or Klotho in the pathophysiology of pressure overload-induced cardiac hypertrophy. 10.1038/s41598-017-10140-4
    PAI-1 is a critical regulator of FGF23 homeostasis. Eren Mesut,Place Aaron T,Thomas Paul M,Flevaris Panagiotis,Miyata Toshio,Vaughan Douglas E Science advances Elevated levels of fibroblast growth factor 23 (FGF23), a bone-derived phosphaturic hormone, are associated with a number of pathologic conditions including chronic kidney disease, cardiac hypertrophy, and congestive heart failure. Currently, there are no specific treatments available to lower plasma FGF23 levels. We have recently reported that genetic plasminogen activator inhibitor-1 (PAI-1) deficiency provided a significant reduction in circulating FGF23 levels while simultaneously prolonging the life span of -deficient mice. We extend our investigations into the effect of PAI-1 on FGF23 homeostasis. Transgenic overexpression of PAI-1 resulted in threefold increase in FGF23 levels compared to wild-type littermates. Moreover, pharmacological modulation of PAI-1 activity with the small-molecule PAI-1 antagonist TM5441 significantly reduced FGF23 levels in PAI-1 transgenic and -deficient mice. In addition, TM5441 treatment or PAI-1 deficiency significantly accelerated the clearance of endogenous FGF23 and recombinant human FGF23 from circulation in mice with acute kidney injury. On the basis of these observations, we studied the effects of plasminogen activators (PAs), tissue-type PA (tPA) and urokinase-type PA (uPA), on FGF23. We demonstrate that both PAs directly cleave FGF23; however, it is not known whether the PA-generated FGF23 peptides retain or acquire functions that affect binding and/or signaling properties of intact FGF23. PAI-1 inhibits the PA-dependent cleavage of FGF23, and TM5441 inhibition of PAI-1 restores the proteolysis of FGF23. Furthermore, top-down proteomic analysis indicates that tPA cleaves FGF23 at multiple arginines including the proconvertase sensitive site R176. In summary, our results indicate that PAI-1 prevents the PA-driven proteolysis of FGF23 and PAI-1 inhibition provides a novel therapeutic approach to prevent the pathologic consequences of increased FGF23. 10.1126/sciadv.1603259
    FGF23 and Nutritional Metabolism. Pool Lindsay R,Wolf Myles Annual review of nutrition The discovery of fibroblast growth factor 23 (FGF23) has provided a more complete understanding of the regulation of phosphate and mineral homeostasis in health and in chronic kidney disease. It has also offered new insights into stratification of risk of cardiovascular events and death among patients with chronic kidney disease and the general population. In this review, we provide an overview of FGF23 biology and physiology, summarize clinical outcomes that have been associated with FGF23, discuss potential mechanisms for these observations and their public health implications, and explore clinical and population health interventions that aim to reduce FGF23 levels and improve public health. 10.1146/annurev-nutr-071816-064620
    Pleiotropic Actions of FGF23. Erben Reinhold G Toxicologic pathology Fibroblast growth factor-23 (FGF23) is a bone-derived hormone, mainly produced by osteoblasts and osteocytes in response to increased extracellular phosphate and circulating vitamin D hormone. Endocrine FGF23 signaling requires co-expression of the ubiquitously expressed FGF receptor 1 (FGFR1) and the co-receptor α-Klotho (Klotho). In proximal renal tubules, FGF23 suppresses the membrane expression of the sodium-phosphate cotransporters Npt2a and Npt2c which mediate urinary reabsorption of filtered phosphate. In addition, FGF23 suppresses proximal tubular expression of 1α-hydroxylase, the key enzyme responsible for vitamin D hormone production. In distal renal tubules, FGF23 signaling activates with-no-lysine kinase 4, leading to increased renal tubular reabsorption of calcium and sodium. Therefore, FGF23 is not only a phosphaturic but also a calcium- and sodium-conserving hormone, a finding that may have important implications for the pathophysiology of chronic kidney disease. Besides these endocrine, Klotho-dependent functions of FGF23, FGF23 is also an auto-/paracrine suppressor of tissue-nonspecific alkaline phosphatase transcription via Klotho-independent FGFR3 signaling, leading to local inhibition of mineralization through accumulation of pyrophosphate. In addition, FGF23 may target the heart via an FGFR4-mediated Klotho-independent signaling cascade. Taken together, there is emerging evidence that FGF23 is a pleiotropic hormone, linking bone with several other organ systems. 10.1177/0192623317737469
    [Correlations of FGF23 and Klotho with cardiovascular injury in chronic kidney disease patients]. Gan Lu,Zhou Qiaoling Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences OBJECTIVE:To analyze the levels of serum calcium, phosphate, fibroblast growth factor 23 (FGF23), and Klotho proteins in patients with chronic kidney disease (CKD), and to investigate the correlations of FGF23 and Klotho proteins with cardiac complicates in patients with chronic kidney disease-mineral and bone disorder (CKD-MBD).
 Methods: A total of 180 CKD-MBD patients were enrolled for this study. Among them, 60 patients underwent regular hemodialysis, 60 patients did not undergo renal replacement therapy and 60 patients were diagnosed as second hyperparathyroidism (SHPT). Thirty age and gender-matched health volunteers served as controls. Serum samples were collected and tested, and the demographical, clinical and biochemical data were all recorded. FGF23 and Klotho levels in serum samples were analyzed by enzyme-linked immunosorbent assay. Data of echocardiography and plain abdominal X rays were collected as well. The influential factors for cardiovascular injury, the relationship between biochemical indexes and ectopic calcification, and the correlations of FGF23 and Klotho with cardiac complicates were analyzed
 Results: Patients, who kept hemodialysis, especially those with SHPT, exhibited an increase in serum FGF23 level while a decrease in serum Klotho protein levels (P<0.01). Patients with higher levels of serum FGF23 were more likely to have ectopic calcification (OR=4.667), while patients with lower levels of serum Klotho had high risks to get myocardial hypertrophy (OR=3.496). Receiver operator characteristic (ROC) curve analysis showed that the area under the curve (AUC) for FGF23 was 0.778 (P<0.01) while for Klotho was 0.715 (P<0.01).
 Conclusion: Patients, who kept hemodialysis, especially those with SHPT, have a significant increase in serum FGF23 protein levels and a significant decrease in serum Klotho protein levels. Serum FGF23 and Klotho protein levels are closely correlated with left ventricular enlargement and hypertrophy. Serum FGF23 and Klotho protein are risk factors for heart. 10.11817/j.issn.1672-7347.2017.09.011
    Klotho Lacks an FGF23-Independent Role in Mineral Homeostasis. Andrukhova Olena,Bayer Jessica,Schüler Christiane,Zeitz Ute,Murali Sathish K,Ada Sibel,Alvarez-Pez Jose M,Smorodchenko Alina,Erben Reinhold G Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Fibroblast growth factor-23 (FGF23) is a bone-derived hormone regulating vitamin D hormone production and renal handling of minerals by signaling through an FGF receptor/αKlotho (Klotho) receptor complex. Whether Klotho has FGF23-independent effects on mineral homeostasis is a controversial issue. Here, we aimed to shed more light on this controversy by comparing male and female triple knockout mice with simultaneous deficiency in Fgf23 and Klotho and a nonfunctioning vitamin D receptor (VDR) (Fgf23/Klotho/VDR) with double (Fgf23/VDR, Klotho/VDR, and Fgf23/Klotho) and single Fgf23, Klotho, and VDR mutants. As expected, 4-week-old Fgf23, Klotho, and Fgf23/Klotho knockout mice were hypercalcemic and hyperphosphatemic, whereas VDR, Fgf23/VDR, and Klotho/VDR mice on rescue diet were normocalcemic and normophosphatemic. Serum levels of calcium, phosphate, and sodium did not differ between 4-week-old triple Fgf23/Klotho/VDR and double Fgf23/VDR or Klotho/VDR knockout mice. Notably, 3-month-old Fgf23/Klotho/VDR triple knockout mice were indistinguishable from double Fgf23/VDR and Klotho/VDR compound mutants in terms of serum calcium, serum phosphate, serum sodium, and serum PTH, as well as urinary calcium and sodium excretion. Protein expression analysis revealed increased membrane abundance of sodium-phosphate co-transporter 2a (NaPi-2a), and decreased expression of sodium-chloride co-transporter (NCC) and transient receptor potential cation channel subfamily V member 5 (TRPV5) in Fgf23/Klotho/VDR, Fgf23/VDR, and Klotho/VDR mice, relative to wild-type and VDR mice, but no differences between triple and double knockouts. Further, ex vivo treatment of live kidney slices isolated from wild-type and Klotho/VDR mice with soluble Klotho did not induce changes in intracellular phosphate, calcium or sodium accumulation assessed by two-photon microscopy. In conclusion, our data suggest that the main physiological function of Klotho for mineral homeostasis in vivo is its role as co-receptor mediating Fgf23 action. © 2017 American Society for Bone and Mineral Research. 10.1002/jbmr.3195
    Evaluation of a New Fully Automated Assay for Plasma Intact FGF23. Souberbielle Jean-Claude,Prié Dominique,Piketty Marie-Liesse,Rothenbuhler Anya,Delanaye Pierre,Chanson Philippe,Cavalier Etienne Calcified tissue international Several FGF23 immunoassays are available. However, they are reserved for research purposes as none have been approved for clinical use. We evaluated the performances of a new automated assay for intact FGF23 on the DiaSorin Liaison platform which is approved for clinical use. We established reference values in 908 healthy French subjects aged 18-89 years, and measured iFGF23 in patients with disorders of phosphate metabolism and in patients with chronic kidney disease (CKD). Intra-assay CV was 1.04-2.86% and inter-assay CV was 4.01-6.3%. The limit of quantification was <10 ng/L. Serum iFGF23 concentrations were considerably lower than EDTA values highlighting the importance of using exclusively EDTA plasma. Liaison iFGF23 values were approximately 25% higher than Immutopics values. In the 908 healthy subjects, distribution of the Liaison iFGF23 values was Gaussian with a mean ± 2SD interval of 22.7-93.1 ng/L. Men had a slightly higher level than women (60.3 ± 17.6 and 55.2 ± 17.2 ng/L, respectively). Plasma iFGF23 concentration in 11 patients with tumour-induced osteomalacia, 8 patients with X-linked hypophosphatemic rickets, 43 stage 3a, 43 stage 3b, 43 stage 4, 44 stage 5 CKD patients, and 44 dialysis patients were 217.2 ± 144.0, 150.9 ± 28.6, 98.5 ± 42.0, 130.8 ± 88.6, 130.8 ± 88.6, 331.7 ± 468.2, 788.8 ± 1306.6 and 6103.9 ± 11,178.8 ng/L, respectively. This new iFGF23 assay available on a platform that already allows the measurement of other important parameters of the mineral metabolism is a real improvement for the laboratories and clinicians/researchers involved in this field. 10.1007/s00223-017-0307-y
    FGF23 activates injury-primed renal fibroblasts via FGFR4-dependent signalling and enhancement of TGF-β autoinduction. Smith Edward R,Holt Stephen G,Hewitson Tim D The international journal of biochemistry & cell biology Bone-derived fibroblast growth factor 23 (FGF23) is an important endocrine regulator of mineral homeostasis with effects transduced by cognate FGF receptor (FGFR)1-α-Klotho complexes. Circulating FGF23 levels rise precipitously in patients with kidney disease and portend worse renal and cardiovascular outcomes. De novo expression of FGF23 has been found in the heart and kidney following injury but its significance remains unclear. Studies showing that exposure to chronically high FGF23 concentrations activates hypertrophic gene programs in the cardiomyocyte has spawned intense interest in other pathological off-target effects of FGF23 excess. In the kidney, observational evidence points to a concordance of ectopic renal FGF23 expression and the activation of local transforming growth factor (TGF)-β signalling. Although we have previously shown that FGF23 activates injury-primed renal fibroblasts in vitro, our understanding of the mechanism underpinning these effects was incomplete. Here we show that in the absence of α-Klotho, FGF23 augments pro-fibrotic signalling cascades in injury-primed renal fibroblasts via activation of FGFR4 and upregulation of the calcium transporter, transient receptor potential cation channel 6. The resultant rise in intracellular calcium and production of mitochondrial reactive oxygen species induced expression of NFAT responsive-genes and enhanced TGF-β1 autoinduction through non-canonical JNK-dependent pathways. Reconstitution with transmembrane α-Klotho, or its soluble ectodomain, restored classical Egr signalling and antagonised FGF23-driven myofibroblast differentiation. Thus, renal FGF23 may amplify local myofibroblast activation in injury and perpetuate pro-fibrotic signalling. These findings strengthen the rationale for exploring therapeutic inhibition of FGFR4 or restoration of α-Klotho as upstream regulators of off-target FGF23 effects. 10.1016/j.biocel.2017.09.009
    Klotho-FGF23, Cardiovascular Disease, and Vascular Calcification: Black or White? Cianciolo Giuseppe,Galassi Andrea,Capelli Irene,Schillaci Roberto,La Manna Gaetano,Cozzolino Mario Current vascular pharmacology BACKGROUND:Patients affected by Chronic Kidney Disease and Mineral Bone Disorder (CKD-MBD) have a high risk of cardiovascular (CV) mortality that is poorly explained by traditional risk factors. The newest medical treatments for CKD-MBD have been associated with encouraging, but still inconsistent, improvement in CV disease complications and patient survival. A better understanding of the biomarkers and mechanisms of left ventricular hypertrophy (LVH), atherosclerosis, and vascular calcification (VC) may help with diagnosis and treatment of the organ damage that occurs secondary to CKD-MBD, thus improving survival. Recent insights about fibroblast growth factor-23 (FGF23) and its co-receptor, Klotho, have led to marked advancement in interpreting data on vascular aging and CKDMBD. CONCLUSION:This review will discuss the current experimental and clinical evidence regarding FGF23 and Klotho, with a particular focus on their roles in LVH, atherosclerosis, and VC. 10.2174/1570161115666170310092202
    Fibroblast growth factor 23 (FGF23) gene polymorphisms are associated with essential hypertension risk and blood pressure levels in Chinese Han population. Cai Peng,Peng Yan,Li Li,Chu Wei,Wang Xukai Clinical and experimental hypertension (New York, N.Y. : 1993) In this case-control study, 246 EH patients and 157 healthy controls were selected from Chinese Han population to explore the associations between the fibroblast growth factor 23 (FGF23) gene polymorphisms and essential hypertension (EH).The SequenomMassarray system was used for the genotyping of three FGF23 gene Tag single-nucleotide polymorphisms, namely rs7955866, rs13312756, and rs3812822. The primers were designed by Assay Designer 3.1 software, and then the samples were added to a 384-well plate for the polymerase chain reaction amplification, shrimp alkaline phosphatase reaction, and desalting after extension. The distributions of the alleles, genotypes, and haplotypes were compared between the two groups. Confounding factors (sex, age, BMI, smoking, and drinking) were adjusted in the non-logistic regression, and the results showed that rs7955866 and rs3812822 polymorphisms were independently associated with the risk of developing EH (P < 0.05). The statistical analysis of the haplotype of rs7955866-rs13312756-rs3812822 showed that haplotype ACC could increase the risk of developing EH (P = 0.046; OR = 1.513, 95%CI: 1.005-2.278). The analysis of the control group showed that carrying rs7955866 A allele (P = 0.031) and rs3812822 C allele (P = 0.025) was associated with the increase of systolic blood pressure (SBP). The insulin (INS) level in the peripheral blood was significantly different between the case and control groups (P = 0.014). After confounding factors were excluded, the results showed that the serum INS level was also an independent risk factor of developing EH (P = 0.044; OR = 1.604, 95%CI: 1.014-2.539). In summary, our results suggest that FGF23 gene polymorphisms are associated with the risk of developing EH in Chinese Han population. 10.1080/10641963.2018.1425417
    Associations Between Intravenous Iron, Inflammation and FGF23 in Non-Dialysis Patients with Chronic Kidney Disease Stages 3-5. Muras-Szwedziak Katarzyna,Nowicki Michal Kidney & blood pressure research BACKGROUND/AIMS:Both iron deficiency and chronic inflammation are highly prevalent in patients with chronic kidney disease (CKD). The effect of intravenous iron infusion on mineral metabolism in CKD may be modified by inflammation. Intravenous iron theraphy may reduce peripheral degradation, secretion, clearence of iFGF23 and lead to hypophosphatemia. The aim of the study was to evaluate the effect of intravenous iron on mineral metabolism in CKD patients. METHODS:35 non-dialysis patients with CKD stages 3-5. received 100 mg/24h of ferric oxide saccharated solution for 5 days. Serum calcium (Ca), phosphorus (P), parathormone (PTH), intact-FGF23 (iFGF23), C-terminal-FGF23 (cFGF23), bone alkaline phosphatase (BAP) and high-sensitive CRP were assessed on day 1 and 3 at baseline and 2 hours after each dose administration and once on day 6. Plasma iFGF23 and cFGF23, as well as serum BAP were measured with ELISA and other parameters with standard automated laboratory methods. RESULTS:Serum iFGF23 increased after iv iron on day 1 and 6 (from 268.9±446.5 to 326.3±529.9 on day 1; p=0.05 and to 451.4±601 pg/mL on day 6; p=0.03). cFGF23 was reduced only on day 1 (from 654.3±441.3 to 473.6±414 RU/mL; p=0.016). P concentration decreased significantly two hours after the first iron infusion (from 1.69±0.5 to 1.54±0.35 mmol/l; p=0.003). In following days the changes of cFGF23, P and of other calcium-phosphate metabolism were not significant. Serum CRP correlated neither with iFGF-23 nor cFGF-23. CONCLUSION:Intravenous iron supplementation may only transiently affect the production and degradation of FGF23 resulting in hypophosphatemia at the commencement of iron therapy. Chronic low-grade inflammation does not seem to play a role in that mechanism. 10.1159/000487368
    Continued Search for Therapies to Favorably Modify Phosphate and FGF23 Levels in CKD. Mehta Rupal,Isakova Tamara Clinical journal of the American Society of Nephrology : CJASN 10.2215/CJN.11011017
    α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling. Chen Gaozhi,Liu Yang,Goetz Regina,Fu Lili,Jayaraman Seetharaman,Hu Ming-Chang,Moe Orson W,Liang Guang,Li Xiaokun,Mohammadi Moosa Nature The ageing suppressor α-klotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion and vitamin D homeostasis. The role and mechanism of this co-receptor are unknown. Here we present the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of α-klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, α-klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23-FGFR1c proximity and conferring stability. Dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signalling. The structure of α-klotho is incompatible with its purported glycosidase activity. Thus, shed α-klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signalling. 10.1038/nature25451
    Technical and diagnostic performance of a new fully automated immunoassay for the determination of intact fibroblast growth factor 23 (FGF23). van Helden Josef,Weiskirchen Ralf Scandinavian journal of clinical and laboratory investigation There is growing interest in measuring plasma fibroblast growth factor 23 (FGF23) concentrations in a number of clinical settings. However, a reliable assay with acceptable performance is lacking. Plasma samples of healthy adults and patients with different stages of chronic kidney disease (CKD) were used to compare the precision, recovery, linearity and the pre-analytical stability characteristics of a new fully automated FGF23 (intact) assay with a commercially available FGF23 (intact) ELISA. Method agreement was evaluated, reference and stage-specific ranges for kidney disease were established. Other biomarkers relevant for CKD were measured and compared with the FGF23 assays. The fully automated FGF23 (intact) assay demonstrated superior performance compared with the ELISA. A marked positive proportional bias was detected relative to the ELISA assay readout, especially in samples of higher concentration of patients undergoing hemodialysis. Overall, the method comparison revealed a poor degree of correlation. A significant inverse correlation was found between the glomerular filtration rate and both FGF23 assays (both p < .001). Regression analysis revealed that both assays are suitable to predict progression of CKD. A positive correlation was found between FGF23 and phosphate, parathyroid hormone (PTH) and vitamin D, 25(OH)D and 1,25(OH)D-total assays, respectively. Cutoff points between different stages of CKD were calculated by receiver operator characteristic analysis. The fully automated assay displayed an improved discrimination compared with the ELISA, especially in mild to moderate kidney disease. The new fully automated FGF23 (intact) assay demonstrates excellent analytical performance data and represents a robust, fast and precise alternative to manual FGF23 testing. 10.1080/00365513.2018.1526411
    FGF23, NGAL, and Endostatin: the Predictors of Allograft Function in Renal Transplant Recipients. Gürlek Demirci Bahar,Sezer Siren,Uyanık Yıldırım Saliha,Kaynar Erdoğan Meltem,Tutal Emre,Özdemir Özlem,Orazbayev Gani,Haberal Mehmet Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation OBJECTIVES:Increased circulating levels of fibroblast growth factor 23, neutrophil gelatinase-associated lipocalin, and endostatin are independent risk factors for cardiovascular disease. Here, we evaluated correlations among these parameters and graft dysfunction and their relation with arterial stiffness. MATERIALS AND METHODS:This prospective study included 73 maintenance kidney transplant patients with stable allograft function who had received the transplant at least 36 months previously. We calculated the estimated glomerular filtration rate (eGFR). Pulsewave velocity was determined. Serum levels of fibroblast growth factor 23, neutrophil gelatinaseassociated lipocalin, and endostatin were measured by enzyme-linked immunosorbent assay. RESULTS:Demographic characteristics and pulse-wave velocity values were similar in groups 1 and 2 (GFR < 60 and > 60 mL/min, respectively). Mean levels of fibroblast growth factor 23 (P = .036), neutrophil gelatinaseassociated lipocalin (P = .018), and endostatin were significantly higher in group 1. Fibroblast growth factor 23 was negatively correlated with eGFR (r = -0.267, P = .023) and positively correlated with neutrophil gelatinase-associated lipocalin (r = 0.258, P = .036) and endostatin (r = 0.321, P = .006). Serum endostatin levels were positively correlated with pulse-wave velocity (r = 0.276, P = .019). In linear regression analysis, eGFR was detected as the unique predictor of neutrophil gelatinase-associated lipocalin (P = .001). In addition, each 1 mL/min decrease in eGFR resulted in a 0.281 pg/mL increase in fibroblast growth factor 23 (P = .023) and a 0.04 ng/mL increase in neutrophil gelatinase-associated lipocalin (P = .007); each 1 cm/s increase in pulse-wave velocity resulted in a 3648.7 U/L increase of endostatin (P = .019). CONCLUSIONS:All 3 parameters were associated with loss of graft function in kidney transplant recipients. Moreover, endostatin can be used as an independent predictor for cardiovascular morbidity in this population. 10.6002/ect.TOND-TDTD2017.P29
    Impact of serum FGF23 levels on blood pressure of patients with chronic kidney disease. Li J-X,Yu G-Q,Zhuang Y-Z European review for medical and pharmacological sciences OBJECTIVE:To investigate the impact of serum FGF23 levels on blood pressure of patients with chronic kidney disease (CKD). PATIENTS AND METHODS:128 patients with chronic kidney disease were selected from February 2013 to January 2016. Using CKD staging method, all the patients were divided into 1 to 5 stages according to the glomerular filtration rate. Enzyme-Linked ImmunoSorbent Assay (ELISA) was used to detect serum FGF23 levels of CKD patients and healthy control subjects. 24 h blood pressure monitoring method was used to monitor the mean arterial pressure of patients. Spearman-related analysis method was used to statistically analyze serum FGF23 level, mean arterial pressure and glomerular filtration rate. RESULTS:The serum FGF23 levels of CKD patients were significantly higher than those of the healthy control subjects (p<0.05). Also, FGF23 expression levels in serum were positively correlated with mean arterial pressure based on the results of the Spearman-related analysis. On the other hand, FGF23 expression levels in serum were negatively correlated with glomerular filtration rate. The FGF23 expression levels in serum of the patients were significantly decreased along with the decrease of mean arterial pressure. CONCLUSIONS:Serum FGF23 level is positively correlated with mean arterial pressure and negatively correlated with glomerular filtration rate. So, FGF23 has an important clinical significance that can reflect blood pressure and treatment effect of dialysis of CKD patients. 10.26355/eurrev_201802_14299
    [Relationship between FGF23/FGFR4 expression in atrial tissue and atrial fibrosis in patients with atrial fibrillation]. Dong Q B,Tang Y H,Wang W X,Wu Y B,Han L,Li J X,Hong K,Wu Y Q,Wu Q H,Cheng X S Zhonghua yi xue za zhi To observe the expression of fibroblast growth factor 23 (FGF23) and FGFR4 in patients with atrial fibrillation (AF) and its relationship with atrial fibrosis. Fifty-one patients with rheumatic heart disease undergoing cardiac surgery at the Second Affiliated Hospital of Nanchang University from October 2016 to April 2017 were divided into two groups according to whether they were complicated with atrial fibrillation: 39 patients with persistent AF(AF group), and 12 patients with sinus rhythm (SR group). The right atrial appendage was cut out during cardiac surgery. The expression of FGF23 and FGFR4 mRNA was detected by quantitative real-time PCR. The expression of FGFR4 protein was detected by Western blot. Atrial structure was evaluated by echocardiography. Masson staining was used to evaluate the degree of atrial fibrosis. The expression of FGF23 and FGFR4 was compared between the two groups.Additionally, the relationship between FGF23 and FGFR4 expression and atrial fibrosis was evaluated. AF group had significantly higher right and left atrial diameter than SR group((40.1±1.6 )mm vs (34.1±1.5)mm, (52.4±2.9)mm vs (41.3±2.4)mm, all <0.05) . There were no statistically significant differences in age, gender, ejection fraction between the two groups. The expression of FGF23 and FGFR4 mRNA in AF group were significantly higher than those in SR group (1.93±0.32 vs 0.93±0.14, 1.89±0.17 vs 0.91±0.11, both <0.05). Compared with the SR group, the protein expression of FGFR4 in the AF group was significantly higher(1.76±0.21 vs 0.84±0.12). In AF group, there was no correlation between FGF23 mRNA and atrial diameter (=0.274 (left atrial), =0.238 (right atrium), both >0.05). Meanwhile, FGFR4 mRNA and protein expression had no correlation with atrial diameter either. There was positive correlation between FGF23 mRNA and atrial collagen volume fraction in AF group (=0.42, <0.05). The expression of FGFR4 mRNA and protein were positively correlated with the atrial collagen volume fraction (=0.573, =0.478, all <0.05). The expression of FGF23 and FGFR4 in atrial fibrillation patients is increased, which is positively correlated with atrial fibrosis, suggesting that FGF23/FGFR4 pathway may play an important role in atrial fibrillation by promoting atrial fibrosis. 10.3760/cma.j.issn.0376-2491.2018.13.010
    Comment on Chan et al. FGF23 Concentration and Genotype Are Novel Predictors of Mortality in African Americans With Type 2 Diabetes. Diabetes Care 2018;41:178-186. Zheng Ying,Wang Zhen Diabetes care 10.2337/dc18-0031
    Response to Comment on Chan et al. FGF23 Concentration and Genotype Are Novel Predictors of Mortality in African Americans With Type 2 Diabetes. Diabetes Care 2018;41:178-186. Divers Jasmin,Freedman Barry I Diabetes care 10.2337/dci18-0005
    Insulin suppresses the production of fibroblast growth factor 23 (FGF23). Bär Ludmilla,Feger Martina,Fajol Abul,Klotz Lars-Oliver,Zeng Shufei,Lang Florian,Hocher Berthold,Föller Michael Proceedings of the National Academy of Sciences of the United States of America 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. 10.1073/pnas.1800160115
    Paracrine Effects of FGF23 on the Heart. Leifheit-Nestler Maren,Haffner Dieter Frontiers in endocrinology Fibroblast growth factor (FGF) 23 is a phosphaturic hormone primarily secreted by osteocytes to maintain phosphate and mineral homeostasis. In patients with and without chronic kidney disease, enhanced circulating FGF23 levels associate with pathologic cardiac remodeling, i.e., left ventricular hypertrophy (LVH) and myocardial fibrosis and increased cardiovascular mortality. Experimental studies demonstrate that FGF23 promotes hypertrophic growth of cardiac myocytes FGF receptor 4-dependent activation of phospholipase Cγ/calcineurin/nuclear factor of activated T cell signaling independent of its co-receptor klotho. Recent studies indicate that FGF23 is also expressed in the heart, and markedly enhanced in various clinical and experimental settings of cardiac remodeling and heart failure independent of preserved or reduced renal function. On a cellular level, FGF23 is expressed in cardiac myocytes and in other non-cardiac myocytes, including cardiac fibroblasts, vascular smooth muscle and endothelial cells in coronary arteries, and in inflammatory macrophages. Current data suggest that secreted by cardiac myocytes, FGF23 can stimulate pro-fibrotic factors in myocytes to induce fibrosis-related pathways in fibroblasts and consequently cardiac fibrosis in a paracrine manner. While acting on cardiac myocytes, FGF23 directly induces pro-hypertrophic genes and promotes the progression of LVH in an autocrine and paracrine fashion. Thus, enhanced FGF23 may promote cardiac injury in various clinical settings not only by endocrine but also paracrine/autocrine mechanisms. In this review, we discuss recent clinical and experimental data regarding molecular mechanisms of FGF23's paracrine action on the heart with respect to pathological cardiac remodeling. 10.3389/fendo.2018.00278
    Molecular Mechanisms Underlying Accelerated Aging by Defects in the FGF23-Klotho System. Kuro-O Makoto International journal of nephrology The basic research of aging has been primarily focused on elucidating mechanisms of aging and longevity that are evolutionarily conserved from yeasts to primates. Such efforts have culminated in the notion that (1) senescence at the cellular level is associated with aging at the organismal level and that (2) calorie restriction and growth suppression decelerate aging. However, these important findings in the basic research have not necessarily been linked to improvement of daily medical practice in the aging society. It has become increasingly important to investigate mechanisms of aging unique to mammals or humans and apply the research fruits for the treatment of major age-related disorders to extend the health span. Seminal studies on the mouse, a mutant exhibiting a premature aging syndrome, have identified phosphate as a proaging factor in mammals. In this review, mechanisms of phosphate-induced premature aging and potential therapeutic targets will be discussed, which may be directly applicable for developing novel strategies for the treatment of chronic kidney disease and its complications. 10.1155/2018/9679841
    The association of serum FGF23 and non-alcoholic fatty liver disease is independent of vitamin D in type 2 diabetes patients. He Xingxing,Shen Yun,Ma Xiaojing,Ying Lingwen,Peng Jiahui,Pan Xiaoping,Bao Yuqian,Zhou Jian Clinical and experimental pharmacology & physiology Recent studies have shown that circulating fibroblast growth factor (FGF) 23 and vitamin D levels are closely correlated with insulin resistance. The aim of this study was to investigate the relationship among serum FGF 23 levels, serum 25-hydroxyvitamin D [25(OH)D] levels, and non-alcoholic fatty liver disease (NAFLD) in Chinese patients with type 2 diabetes mellitus (T2DM). This study enrolled 331 hospitalized T2DM patients (209 patients with NAFLD and 122 patients without NAFLD). Serum FGF23 levels were measured using a sandwich enzyme-linked immunosorbent assay. Serum 25(OH)D levels were determined by an electrochemiluminescence immunoassay. NAFLD was diagnosed by hepatic ultrasound, and the fatty liver index (FLI) was calculated to quantify hepatic steatosis. Results showed that T2DM patients with NAFLD had significantly higher serum FGF23 levels (44.17 [37.92-51.30] pg/mL vs 40.21 [34.07-48.33] pg/mL, P = .002), but lower serum 25(OH)D levels (16.43 [12.70-21.37] ng/mL vs 19.59 [13.78-26.26] ng/mL, P = .002) than those without NAFLD. Moreover, the incidence rate of NAFLD increased with increasing serum FGF23 levels and decreased with increasing 25(OH)D levels (both P < .05). Logistic regression analysis showed that both serum FGF23 and 25(OH)D levels were independent factors for NAFLD (both P < .05). Furthermore, a multiple stepwise regression analysis also revealed that both serum FGF23 and 25(OH)D levels were independently correlated with FLI (both P < .01). In conclusion, both high FGF23 and low vitamin D levels showed an independent relationship with NAFLD in Chinese T2DM patients, indicating that FGF23 and vitamin D function via different regulatory pathways in the liver. 10.1111/1440-1681.12933
    FGF23 effects on the heart-levels, time, source, and context matter. Faul Christian Kidney international Fibroblast growth factor 23 (FGF23) has appeared as a hormone that is massively elevated in patients with chronic kidney disease. Whether FGF23 is a risk factor that associates with cardiac pathologies and cardiovascular mortality, as suggested by a variety of clinical studies, or additionally acts as a causative factor that induces cardiac injury, as more recently indicated by cell culture and animal studies, is under debate and the center of many ongoing experimental studies. 10.1016/j.kint.2018.03.024
    Serum and urine FGF23 and IGFBP-7 for the prediction of acute kidney injury in critically ill children. Bai Zhenjiang,Fang Fang,Xu Zhong,Lu Chunjiu,Wang Xueqin,Chen Jiao,Pan Jian,Wang Jian,Li Yanhong BMC pediatrics BACKGROUND:Fibroblast growth factor 23 (FGF23) and insulin-like growth factor binding protein 7 (IGFBP-7) are suggested to be biomarkers for predicting acute kidney injury (AKI). We compared them with proposed AKI biomarker of cystatin C (CysC), and aimed (1) to examine whether concentrations of these biomarkers vary with age, body weight, illness severity assessed by pediatric risk of mortality III score, and kidney function assessed by estimated glomerular filtration rate (eGFR), (2) to determine the association between these biomarkers and AKI, and (3) to evaluate whether these biomarkers could serve as early independent predictors of AKI in critically ill children. METHODS:This prospective single center study included 144 critically ill patients admitted to the pediatric intensive care unit (PICU) regardless of diagnosis. Serum and spot urine samples were collected during the first 24 h after PICU admission. AKI was diagnosed based on the AKI network (AKIN) criteria. RESULTS:Twenty-one patients developed AKI within 120 h of sample collection, including 11 with severe AKI defined as AKIN stages 2 and 3. Serum FGF23 levels were independently associated with eGFR after adjustment in a multivariate linear analysis (P < 0.001). Urinary IGFBP-7 (Adjusted OR = 2.94 per 1000 ng/mg increase, P = 0.035), serum CysC (Adjusted OR = 5.28, P = 0.005), and urinary CysC (Adjusted OR = 1.13 per 1000 ng/mg increase, P = 0.022) remained significantly associated with severe AKI after adjustment for body weight and illness severity, respectively. Urinary IGFBP-7 level was predictive of severe AKI and achieved the AUC of 0.79 (P = 0.001), but was not better than serum (AUC = 0.89, P < 0.001) and urinary (AUC = 0.88, P < 0.001) CysC in predicting severe AKI. CONCLUSIONS:Serum FGF23 levels were inversely related to measures of eGFR. In contrast to serum and urinary FGF23 which are not associated with AKI in a general and heterogeneous PICU population, an increased urinary IGFBP-7 level was independently associated with the increased risk of severe AKI diagnosed within the next 5 days after sampling, but not superior to serum or urinary CysC in predicting severe AKI in critically ill children. 10.1186/s12887-018-1175-y
    Phosphate control in reducing FGF23 levels in hemodialysis patients. Rodelo-Haad Cristian,Rodríguez-Ortiz Maria E,Martin-Malo Alejandro,Pendon-Ruiz de Mier M Victoria,Agüera M Luisa,Muñoz-Castañeda Juan R,Soriano Sagrario,Caravaca Francisco,Alvarez-Lara M Antonia,Felsenfeld Arnold,Aljama Pedro,Rodriguez Mariano PloS one BACKGROUND:In hemodialysis patients, high levels of Fibroblast Growth Factor 23 (FGF23) predict mortality. Our study was designed to test whether the control of serum phosphate is associated with a reduction in serum FGF23 levels. Additionally other variables with a potential effect on FGF23 levels were evaluated. MATERIAL AND METHODS:The effect of sustained (40-weeks) control of serum phosphate on FGF23 levels (intact and c-terminal) was evaluated in 21 stable hemodialysis patients that were not receiving calcimimetics or active vitamin D. Patients received non-calcium phosphate binders to maintain serum phosphate below 4.5 mg/dl. In an additional analysis, values of intact-FGF23 (iFGF23) and c-terminal FGF23 (cFGF23) from 150 hemodialysis patients were correlated with parameters of mineral metabolism and inflammation. Linear mixed models and linear regression were performed to evaluate longitudinal trajectories of variables and the association between FGF23 and the other variables examined. RESULTS:During the 40-week treatment, 12 of 21 patients achieved the target of serum phosphate <4.5 mg/dl. In these 12 patients, iFGF23 decreased to less than half whereas cFGF23 did not reduce significantly. In patients with serum phosphate >4.5 mg, iFGF23 and cFGF23 increased two and four-fold respectively as compared with baseline. Furthermore, changes in serum phosphate correlated with changes in C-reactive protein (hs-CRP). In our 150 hemodialysis patients, those in the higher tertile of serum phosphate also showed increased hs-CRP, iPTH, iFGF23 and cFGF23. Multiple regression analysis revealed that iFGF23 levels directly correlated with both serum phosphate and calcium, whereas cFGF23 correlated with serum phosphate and hs-CRP but not with calcium. CONCLUSIONS:The control of serum phosphate reduced iFGF23. This reduction was also associated with a decreased in inflammatory parameters. Considering the entire cohort of hemodialysis patients, iFGF23 levels correlated directly with serum phosphate levels and also correlated inversely with serum calcium concentration. The levels of cFGF23 were closely related to serum phosphate and parameters of inflammation. 10.1371/journal.pone.0201537
    FGF23 (Fibroblast Growth Factor-23) and Incident Hypertension in Young and Middle-Aged Adults: The CARDIA Study. Akhabue Ehimare,Montag Samantha,Reis Jared P,Pool Lindsay R,Mehta Rupal,Yancy Clyde W,Zhao Lihui,Wolf Myles,Gutierrez Orlando M,Carnethon Mercedes R,Isakova Tamara Hypertension (Dallas, Tex. : 1979) Blacks have the highest prevalence of hypertension in the United States. Higher levels of FGF23 (fibroblast growth factor-23) have been associated with worse cardiovascular outcomes. Whether FGF23 is associated with rising blood pressure (BP) and racial differences in incident hypertension is unclear. We studied 1758 adults (45.0±3.7 years; 57.8% female; 36.9% black) without hypertension or cardiovascular disease who participated in the year 20 (2005-2006) follow-up examination of the CARDIA study (Coronary Artery Risk Development in Young Adults). We investigated the associations of baseline (year 20) cFGF23 (C-terminal FGF23) levels with longitudinal BP patterns and incident hypertension (defined as being on antihypertensive medication, systolic BP ≥130 or diastolic BP ≥80 mm Hg) during 2 follow-up visits (years 25 and 30). During follow-up, 35.2% of participants developed hypertension. In multivariable linear mixed models, there were greater increases in systolic BP from year 20 to 25 and year 25 to 30 in the highest FGF23 quartile relative to the lowest quartile (+2.1 mm Hg, =0.0057 and +2.2 mm Hg, =0.0108, respectively for each time period), whereas there were greater increases in diastolic BP from year 20 to 25 in the highest quartile relative to the lowest (+1.6 mm Hg; =0.0024). In multivariable modified Poisson regression analyses, the highest FGF23 quartile was associated with a 45% greater risk of developing hypertension during follow-up compared with the lowest quartile (relative risk, 1.45 [1.18-1.77]). Results did not vary by race (=0.1523). Higher FGF23 levels are independently associated with rising BP over time and an increased risk of incident hypertension but not racial differences in hypertension. 10.1161/HYPERTENSIONAHA.118.11060
    The interrelation between FGF23 and glucose metabolism in humans. Ursem Stan R,Vervloet Marc G,Büttler Rahel M,Ackermans Mariëtte T,Oosterwerff Mirjam M,Eekhoff Elisabeth M V,Lips Paul,Serlie Mireille J,la Fleur Susanne E,Heijboer Annemieke C Journal of diabetes and its complications AIMS:Different studies point to a link between glucose metabolism and Fibroblast Growth Factor 23 (FGF23), an osteocyte-derived phosphaturic hormone. We aimed to investigate in humans the effect of (I) a glucose load and (II) a hyperinsulinemic-euglycemic clamp on FGF23 concentrations and conversely (III) the effect of a diet-induced increase in FGF23 concentration on glucose and insulin concentrations. METHODS:Plasma cFGF23 concentrations were measured during: I. an oral glucose tolerance test in eight adults with impaired glucose tolerance and vitamin D deficiency and II. a hyperinsulinemic-euglycemic clamp in nine healthy adults. III. Serum glucose and insulin concentrations were measured in nine healthy adults receiving a single-day phosphate-enriched or -restricted diet. RESULTS:I. A glucose load decreased FGF23 and phosphate concentrations. II. The hyperinsulinemic-euglycemic clamp decreased phosphate concentrations, but did not affect FGF23 concentrations. III. Fasting insulin and glucose concentrations remained unchanged after a diet-induced increase in FGF23 concentration. CONCLUSIONS:An oral glucose load in vitamin D deficient patients with impaired glucose metabolism decreased FGF23 concentrations, which cannot be attributed to changes in insulin concentration. Thus, bone may react rapidly after glucose loading by alternating FGF23 secretion. A diet-induced increase in FGF23 concentrations did not affect fasting glucose or insulin levels. 10.1016/j.jdiacomp.2018.06.013
    Energy sensor as a new regulator of FGF23 synthesis. Komaba Hirotaka Kidney international Phosphate plays an important role in biological energy cycle, but the interaction of cellular energy metabolism with fibroblast growth factor 23 production has been less well characterized. Glosse and colleagues now demonstrate that AMP-activated protein kinase, a cellular energy sensor, regulates fibroblast growth factor 23 production. Interestingly, AMP-activated protein kinase-deficient mice show high fibroblast growth factor 23 levels, normal phosphate levels, and cardiac hypertrophy, which resemble those seen in patients with moderate chronic kidney disease. 10.1016/j.kint.2018.05.008
    In vivo evidence for an interplay of FGF23/Klotho/PTH axis on the phosphate handling in renal proximal tubules. Ide Noriko,Ye Rui,Courbebaisse Marie,Olauson Hannes,Densmore Michael J,Larsson Tobias E,Hanai Jun-Ichi,Lanske Beate American journal of physiology. Renal physiology 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)D, 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)D 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. 10.1152/ajprenal.00650.2017
    FGF23 beyond Phosphotropic Hormone. Takashi Yuichi,Fukumoto Seiji Trends in endocrinology and metabolism: TEM Fibroblast growth factor (FGF) 23 is a bone-derived phosphotropic hormone that regulates phosphate and vitamin D metabolism. FGF23 mainly affects kidney function via the FGF receptor (FGFR)/α-Klotho complex. The physiological roles of FGF23 and α-Klotho in the regulation of mineral homeostasis have been well established. In addition, recent studies have reported that FGF23 has various effects on many other tissues, sometimes in an α-Klotho-independent manner, especially under pathological conditions. However, how FGF23 works in these tissues without α-Klotho is not entirely clear. Here we review the recent reports concerning the actions of FGF23 on various tissues and discuss the remaining questions about FGF23. 10.1016/j.tem.2018.08.006
    FGF23 blockade coming to clinical practice. Emma Francesco,Haffner Dieter Kidney international 10.1016/j.kint.2018.08.022
    FGF23 Concentration and Genotype Are Novel Predictors of Mortality in African Americans With Type 2 Diabetes. Chan Gary C,Divers Jasmin,Russell Gregory B,Langefeld Carl D,Wagenknecht Lynne E,Hsu Fang-Chi,Xu Jianzhao,Smith S Carrie,Palmer Nicholette D,Hicks Pamela J,Bowden Donald W,Register Thomas C,Ma Lijun,Carr J Jeffrey,Freedman Barry I Diabetes care OBJECTIVE:Cardiovascular and renal complications contribute to higher mortality in patients with diabetes. We assessed novel and conventional predictors of mortality in African American-Diabetes Heart Study (AA-DHS) participants. RESEARCH DESIGN AND METHODS:Associations between mortality and subclinical atherosclerosis, urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), plasma fibroblast growth factor 23 (FGF23) concentration, African ancestry proportion, and apolipoprotein L1 genotypes () were assessed in 513 African Americans with type 2 diabetes; analyses were performed using Cox proportional hazards models. RESULTS:At baseline, participants were 55.6% female with median (25th, 75th percentile) age 55 years (49.0, 62.0), diabetes duration 8 years (5.0, 13.0), glycosylated hemoglobin 60.7 mmol/mol (48.6, 76.0), eGFR 91.3 mL/min/1.73 m (76.4, 111.3), UACR 12.5 mg/mmol (4.2, 51.2), and coronary artery calcium 28.5 mg Ca (1.0, 348.6); 11.5% had two renal-risk variants. After 6.6-year follow-up (5.8, 7.5), 54 deaths were recorded. Higher levels of coronary artery calcified plaque, carotid artery calcified plaque, albuminuria, and FGF23 were associated with higher mortality after adjustment for age, sex, and African ancestry proportion. A penalized Cox regression that included all covariates and predictors associated with mortality identified male sex (hazard ratio [HR] 4.17 [95% CI 1.96-9.09]), higher FGF23 (HR 2.10 [95% CI 1.59-2.78]), and absence of renal-risk genotypes (HR 0.07 [95% CI 0.01-0.69]) as the strongest predictors of mortality. CONCLUSIONS:Accounting for conventional risk factors, higher FGF23 concentrations and non-renal-risk genotypes associated with higher mortality in African Americans with diabetes. These data add to growing evidence supporting FGF23 association with mortality; mechanisms whereby these novel predictors impact survival remain to be determined. 10.2337/dc17-0820
    FGF23 Level and Intima-Media Thickness Are Elevated From Early Stages of Chronic Kidney Disease. Figurek Andreja,Spasovski Goce,Popovic-Pejicic Snjezana Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy Considering high cardiovascular (CV) risk in chronic kidney disease (CKD), the aim of this cross-sectional study was to assess the association between carotid intima-media thickness (IMT) and fibroblast growth factor (FGF) 23 as important players in CV pathophysiology. Eighty-seven patients with mean estimated glomerular filtration rate 40.1 mL/min per 1.73 m were involved. FGF23 and IMT were elevated from early stages of CKD. Mean IMT value was 1.10 ± 0.20 mm, being significantly elevated starting from early CKD, showing no correlation with FGF23 (r = -0.01, P = -0.91). Unlike the FGF23 level that followed worsening of kidney function, IMT was increasing only in the initial CKD stages, with no further increase from CKD stage 3 on. Although we found no direct association between current use of vitamin D and statin therapy, this may be associated with the sustained reference values of lipid and vitamin D status under treatment that further preclude worsening of IMT in patients with advanced CKD. 10.1111/1744-9987.12592
    Crosstalk between FGF23- and angiotensin II-mediated Ca signaling in pathological cardiac hypertrophy. Mhatre Ketaki N,Wakula Paulina,Klein Oliver,Bisping Egbert,Völkl Jakob,Pieske Burkert,Heinzel Frank R Cellular and molecular life sciences : CMLS Heart failure (HF) manifestation and progression are driven by systemic activation of neuroendocrine signaling cascades, such as the renin-angiotensin aldosterone system (RAAS). Fibroblast growth factor 23 (FGF23), an endocrine hormone, is linked to HF and cardiovascular mortality. It is also a mediator of left-ventricular hypertrophy (LVH). In vivo, high circulating levels of FGF23 are associated with an altered systemic RAAS response. FGF23 is proposed to trigger pathological signaling mediated by Ca-regulated transcriptional pathways. In the present study, we investigated Ca-dependent signaling of FGF23 in ventricular cardiomyocytes and its association with angiotensin II (ATII). In neonatal rat ventricular myocytes (NRVMs), both ATII and FGF23 induced hypertrophy as observed by an increase in cell area and hypertrophic gene expression. Furthermore, FGF23 activates nuclear Ca-regulated CaMKII-HDAC4 pathway, similar to ATII. In addition to a global increase in cytoplasmic Ca, FGF23, like ATII, induced inositol 1, 4, 5-triphosphate (IP3)-induced Ca release from the nucleoplasmic Ca store, associated with cellular hypertrophy. Interestingly, ATII receptor antagonist, losartan, significantly attenuated FGF23-induced changes in Ca homeostasis and cellular hypertrophy suggesting an involvement of ATII receptor-mediated signaling. In addition, application of FGF23 increased intracellular expression of ATII peptide and its secretion in NRVMs, confirming the participation of ATII. In conclusion, FGF23 and ATII share a common mechanism of IP3-nuclear Ca-dependent cardiomyocyte hypertrophy. FGF23-mediated cellular hypertrophy is associated with increased production and secretion of ATII by cardiomyocytes. These findings indicate a pathophysiological role of the cellular angiotensin system in FGF23-induced hypertrophy in ventricular cardiomyocytes. 10.1007/s00018-018-2885-x
    Pre-operative level of FGF23 predicts severe acute kidney injury after heart surgery in children. Volovelsky Oded,Terrell Tara C,Swain Hayley,Bennett Michael R,Cooper David S,Goldstein Stuart L Pediatric nephrology (Berlin, Germany) BACKGROUND:Early detection of acute kidney injury (AKI) after cardiac surgery has improved recently with the discovery and validation of novel urinary biomarkers. However, objective tools to predict the risk of AKI before the insult are still missing. We tested the hypothesis that pre-operative serum fibroblast growth factor 23 (FGF23) concentrations would be elevated in children who develop AKI after heart surgery with cardiopulmonary bypass (CPB). We also compared post-operative FGF23 concentrations to other biomarkers for early detection of AKI. METHODS:Blood and urine samples were collected in a prospective observational study from 83 children with congenital heart disease. Severe AKI (sAKI) development (KDIGO stages II-III) in the first seven days after surgery was the primary outcome. RESULTS:Thirty of 76 (39.5%) and 11/76 (14.5%) of patients developed AKI and sAKI, respectively. Pre-operative serum creatinine, cystatin C, and urine biomarker concentrations did not differ between sAKI patients and controls. Pre-operative serum FGF23 levels were higher in patients who developed sAKI (median [IQR] value of 819 RU/ml [397.7, 1196.8] vs. 324.3 RU/ml [124.6, 679.8] (p = 0.02). FGF23 12-24 h after the termination of CPB was also associated with sAKI in the first week after surgery (498 RU/ml [226, 928] vs. 1435 RU/ml [831, 12,996]). CONCLUSIONS:Pre- and post-operative FGF23 levels are higher in children who develop sAKI after cardiac surgery. We suggest FGF23 may be able to detect sub-clinical kidney injury and can be used with demographic AKI risk factors to enhance post-operative sAKI risk prediction. 10.1007/s00467-018-4024-1
    Non-renal-Related Mechanisms of FGF23 Pathophysiology. Hanudel Mark R,Laster Marciana,Salusky Isidro B Current osteoporosis reports PURPOSE OF REVIEW:We will review non-renal-related mechanisms of fibroblast growth factor 23 (FGF23) pathophysiology. RECENT FINDINGS:FGF23 production and metabolism may be affected by many bone, mineral, and kidney factors. However, it has recently been demonstrated that other factors, such as iron status, erythropoietin, and inflammation, also affect FGF23 production and metabolism. As these non-mineral factors are especially relevant in the setting of chronic kidney disease (CKD), they may represent emerging determinants of CKD-associated elevated FGF23 levels. Moreover, FGF23 itself may promote anemia and inflammation, thus contributing to the multifactorial etiologies of these CKD-associated comorbidities. CKD-relevant, non-mineral-related, bidirectional relationships exist between FGF23 and anemia, and between FGF23 and inflammation. Iron deficiency, anemia, and inflammation affect FGF23 production and metabolism, and FGF23 itself may contribute to anemia and inflammation, highlighting complex interactions that may affect aspects of CKD pathogenesis and treatment. 10.1007/s11914-018-0492-2
    FGF23 and Fetuin-A Interaction in the Liver and in the Circulation. Mattinzoli Deborah,Ikehata Masami,Tsugawa Koji,Alfieri Carlo M,Dongiovanni Paola,Trombetta Elena,Valenti Luca,Puliti Aldamaria,Lazzari Lorenza,Messa Piergiorgio International journal of biological sciences Recently it has been demonstrated that Fetuin-A, an anti-inflammatory protein synthesized by the liver, is produced also in bone by an FGF23-regulated pathway. FGF23 has been also demonstrated to induce inflammatory cytokine production in the liver. This study aimed to explore if FGF23 plays a role in the Fetuin-A production in the liver cells too and the possible relationships with FGF23 pro-inflammatory effects. FGF23 and Fetuin-A were studied in liver, kidney and in plasma with immunochemistry, immunoprecipitation, western blot, chromatin immunoprecipitation, duolink, ELISA, qrtPCR methodology. FGF23 is produced, but not secreted by the liver cells. In hepatocytes and circulation, FGF23 was present only strictly linked to Fetuin-A, while Fetuin-A was found also in unbounded form. No link was observed in the kidney. FGF23 up to 600 pg/ml stimulates, while, at higher concentrations, reduces Fetuin-A expression. Notably, overall the range of concentrations, FGF23 stimulates Fetuin-A promoter, TNFα and IL6 expression. In the nucleus, FGF23 seems to act as a direct transcription factor of Fetuin-A promoter. These results suggest that FGF23 played a direct regulatory role in Fetuin-A expression in liver cells with a biphasic effect: Fetuin-A progressively increases when FGF23 increases up to 400-600 pg/mL, and declines at higher FGF23 concentrations. These results lead us to hypothesize: a) a possible epigenetic post-transcriptional regulation; b) a possible counter-regulatory effect of FGF23 induced inflammatory cytokines (TNFα/ NF-κB mechanism). This study could add an additional key for the interpretation of the possible mechanisms linking FGF23, Fetuin-A and inflammation in CKD patients and suggests a role for FGF23 as transcription factor. 10.7150/ijbs.23256
    FGF23 modulates the effects of erythropoietin on gene expression in renal epithelial cells. Yashiro Mitsuru,Ohya Masaki,Mima Toru,Ueda Yumi,Nakashima Yuri,Kawakami Kazuki,Ishizawa Yohei,Yamamoto Shuto,Kobayashi Sou,Yano Takurou,Tanaka Yusuke,Okuda Kouji,Sonou Tomohiro,Shoshihara Tomohiro,Iwashita Yuko,Iwashita Yu,Tatsuta Kouichi,Matoba Ryo,Negi Shigeo,Shigematsu Takashi International journal of nephrology and renovascular disease Background:FGF23 plays an important role in calcium-phosphorus metabolism. Other roles of FGF23 have recently been reported, such as commitment to myocardium enlargement and immunological roles in the spleen. In this study, we aimed to identify the roles of FGF23 in the kidneys other than calcium-phosphorus metabolism. Methods:DNA microarrays and bioinformatics tools were used to analyze gene expression in mIMCD3 mouse renal tubule cells following treatment with FGF23, erythropoietin and/or an inhibitor of ERK. Results:Three protein-coding genes were upregulated and 12 were downregulated in response to FGF23. Following bioinformatics analysis of these genes, PPARγ and STAT3 were identified as candidate transcript factors for mediating their upregulation, and STAT1 as a candidate for mediating their downregulation. Because STAT1 and STAT3 also mediate erythropoietin signaling, we investigated whether FGF23 and erythropoietin might show interactive effects in these cells. Of the 15 genes regulated by FGF23, 11 were upregulated by erythropoietin; 10 of these were downregulated following cotreatment with FGF23. Inhibition of ERK, an intracellular mediator of FGF23, reversed the effects of FGF23. However, FGF23 did not influence STAT1 phosphorylation, suggesting that it impinges on erythropoietin signaling through other mechanisms. Conclusion:Our results suggest cross talk between erythropoietin and FGF23 signaling in the regulation of renal epithelial cells. 10.2147/IJNRD.S158422
    Phosphate-dependent FGF23 secretion is modulated by PiT2/Slc20a2. Bon Nina,Frangi Giulia,Sourice Sophie,Guicheux Jérôme,Beck-Cormier Sarah,Beck Laurent Molecular metabolism OBJECTIVE:The canonical role of the bone-derived fibroblast growth factor 23 (Fgf23) is to regulate the serum inorganic phosphate (Pi) level. As part of a feedback loop, serum Pi levels control Fgf23 secretion through undefined mechanisms. We recently showed in vitro that the two high-affinity Na-Pi co-transporters PiT1/Slc20a1 and PiT2/Slc20a2 were required for mediating Pi-dependent signaling. Here, we addressed the contribution of PiT1 and PiT2 to the regulation of Fgf23 secretion. METHODS:To this aim, we used PiT2 KO and DMP1Cre; PiT1 fed Pi-modified diets, as well as ex vivo isolated long bone shafts. Fgf23 secretion and expression of Pi homeostasis-related genes were assessed. RESULTS:In vivo, PiT2 KO mice responded inappropriately to low-Pi diets, displaying abnormally normal serum levels of intact Fgf23. Despite the high iFgf23 level, serum Pi levels remained unaffected, an effect that may relate to lower αKlotho expression in the kidney. Moreover, consistent with a role of PiT2 as a possible endocrine Pi sensor, the iFGF23/cFGF23 ratios were suppressed in PiT2 KO mice, irrespective of the Pi loads. While deletion of PiT1 in osteocytes using the DMP1-Cre mice was inefficient, adenovirus-mediated deletion of PiT1 in isolated long bone shafts suggested that PiT1 does not contribute to Pi-dependent regulation of Fgf23 secretion. In contrast, using isolated bone shafts from PiT2 KO mice, we showed that PiT2 was necessary for the appropriate Pi-dependent secretion of Fgf23, independently from possible endocrine regulatory loops. CONCLUSIONS:Our data provide initial mechanistic insights underlying the Pi-dependent regulation of Fgf23 secretion in identifying PiT2 as a potential player in this process, at least in high Pi conditions. Targeting PiT2, therefore, could improve excess FGF23 in hyperphosphatemic conditions such as chronic kidney disease. 10.1016/j.molmet.2018.02.007
    The participation of fibroblast growth factor 23 (FGF23) in the progression of osteoporosis via JAK/STAT pathway. Xu Lijun,Zhang Lixia,Zhang Huijuan,Yang Zaigang,Qi Lei,Wang Yurong,Ren Shuxin Journal of cellular biochemistry Osteoporosis (OP) is a major skeletal disorder for the old man. The fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced by osteoblasts and osteocytes. However, the regulatory mechanisms of FGF23 in the progression of osteoporosis remain poorly understood. This study aims to explore the downstream regulating pathway of FGF23 in postmenopausal osteoporosis. The rat model of osteoporosis was established through ovariectomy (OVX). The investigation demonstrated that the serum levels of FGF23 and the phosphorylation levels of JAK2, STAT1, and STAT3 were up-regulated in the OVX + NVP-BGJ398 group while were down-regulated in the OVX + Anti-FGF23 group than that in the OVX group. Moreover, the JAK2/STAT1/3 inhibitor, AG490 promoted the OVX-induced increase in the osteocalcin, ALP, BALP, TRAP, and CTX-I levels. Besides, AG490 enhanced cartilage lesions and increased TUNEL-positive chondrocytes in the OVX group. In addition, higher protein expression of MMP-1 and MMP-13 and lower expression of COX-II were observed in the OVX + AG490 group than that in the OVX group. Our findings suggested that FGF23 was involved in the progression of osteoporosis via the JAK/STAT signaling pathway. 10.1002/jcb.26332
    FGF23 Actions on Target Tissues-With and Without Klotho. Richter Beatrice,Faul Christian Frontiers in endocrinology Fibroblast growth factor (FGF) 23 is a phosphaturic hormone whose physiologic actions on target tissues are mediated by FGF receptors (FGFR) and klotho, which functions as a co-receptor that increases the binding affinity of FGF23 for FGFRs. By stimulating FGFR/klotho complexes in the kidney and parathyroid gland, FGF23 reduces renal phosphate uptake and secretion of parathyroid hormone, respectively, thereby acting as a key regulator of phosphate metabolism. Recently, it has been shown that FGF23 can also target cell types that lack klotho. This unconventional signaling event occurs in an FGFR-dependent manner, but involves other downstream signaling pathways than in "classic" klotho-expressing target organs. It appears that klotho-independent signaling mechanisms are only activated in the presence of high FGF23 concentrations and result in pathologic cellular changes. Therefore, it has been postulated that massive elevations in circulating levels of FGF23, as found in patients with chronic kidney disease, contribute to associated pathologies by targeting cells and tissues that lack klotho. This includes the induction of cardiac hypertrophy and fibrosis, the elevation of inflammatory cytokine expression in the liver, and the inhibition of neutrophil recruitment. Here, we describe the signaling and cellular events that are caused by FGF23 in tissues lacking klotho, and we discuss FGF23's potential role as a hormone with widespread pathologic actions. Since the soluble form of klotho can function as a circulating co-receptor for FGF23, we also discuss the potential inhibitory effects of soluble klotho on FGF23-mediated signaling which might-at least partially-underlie the pleiotropic tissue-protective functions of klotho. 10.3389/fendo.2018.00189
    FGF23 in Cardiovascular Disease: Innocent Bystander or Active Mediator? Stöhr Robert,Schuh Alexander,Heine Gunnar H,Brandenburg Vincent Frontiers in endocrinology Fibroblast growth factor-23 (FGF23) is a mainly osteocytic hormone which increases renal phosphate excretion and reduces calcitriol synthesis. These renal actions are mediated via alpha-klotho as the obligate co-receptor. Beyond these canonical "mineral metabolism" actions, FGF23 has been identified as an independent marker for cardiovascular risk in various patient populations. Previous research has linked elevated FGF23 predominantly to left-ventricular dysfunction and consecutive morbidity and mortality. Moreover, some experimental data suggest FGF23 as a direct and causal stimulator for cardiac hypertrophy via specific myocardial FGF23-receptor activation, independent from alpha-klotho. This hypothesis offers fascinating prospects in terms of therapeutic interventions, specifically in patients with chronic kidney disease (CKD) in whom the FGF23 system is strongly stimulated and in whom left-ventricular dysfunction is a major disease burden. However, novel data challenges the previous stand-alone hypothesis about a one-way road which guides unidirectionally skeletal FGF23 toward cardiotoxic effects. In fact, recent data point toward local myocardial production and release of FGF23 in cases where (acute) myocardial damage occurs. The effects of this local production and the physiological meaning are under current examination. Moreover, epidemiologic studies suggest that high FGF-23 may follow, rather than induce, myocardial disease in certain conditions. In summary, while FGF23 is an interesting link between mineral metabolism and cardiac function underlining the meaning of the bone-heart axis, more research is needed before therapeutic interventions may be considered. 10.3389/fendo.2018.00351
    Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia. Agoro Rafiou,Montagna Anna,Goetz Regina,Aligbe Onyedikachi,Singh Gurinder,Coe Lindsay M,Mohammadi Moosa,Rivella Stefano,Sitara Despina FASEB journal : official publication of the Federation of American Societies for Experimental Biology Severe anemia and iron deficiency are common complications in chronic kidney disease. The cause of renal anemia is multifactorial and includes decreased erythropoietin (Epo) production, iron deficiency, and inflammation, and it is currently treated with injections of synthetic Epo. However, the use of recombinant Epo has several adverse effects. We previously reported that high fibroblast growth factor 23 (FGF23) levels in mice are associated with decreased red blood cell production, whereas genetic inactivation of Fgf23 results in expansion of the erythroid lineage. The present study is the first to show that high FGF23 levels in a mouse model of renal failure contribute to renal anemia, and inhibiting FGF23 signaling stimulates erythropoiesis and abolishes anemia and iron deficiency. Moreover, we show that inhibition of FGF23 signaling significantly decreases erythroid cell apoptosis and influences the commitment of hematopoietic stem cells toward the erythroid linage. Furthermore, we show that blocking FGF23 signaling attenuates inflammation, resulting in increased serum iron and ferritin levels. Our data clearly demonstrate that elevated FGF23 is a causative factor in the development of renal anemia and iron deficiency, and importantly, blocking FGF23 signaling represents a novel approach to stimulate erythropoiesis and possibly improve survival for millions of chronic kidney disease patients worldwide.-Agoro, R., Montagna, A., Goetz, R., Aligbe, O., Singh, G., Coe, L. M., Mohammadi, M., Rivella, S., Sitara, D. Inhibition of fibroblast growth factor 23 (FGF23) signaling rescues renal anemia. 10.1096/fj.201700667R
    Is FGF23 effective on insulin resistance in individuals with metabolic syndrome? Sit Dede,Tanrıverdi Ender,Kayabasi Hasan,Erdem Muslum,Sari Hakan Hormone molecular biology and clinical investigation Purpose Metabolic syndrome (MetS) is a polymetabolic syndrome has high morbidity and mortality rates. Insulin resistance (IR) plays a key role in the increasing frequency of this situation and has been cited as being an important etiologic factor in MetS. In this study, the relationship between IR and fibroblast growth factor-23 (FGF23), was investigated in a population with MetS. Materials and methods Forty patients with diagnosis of MetS and 40 healthy volunteers with an equal number of males and females were included in the study and classified as patient group and control group. Blood samples were obtained after 12-h fasting period to study FGF23 and other parameters. MetS, defined according to the International Diabetes Federation (IDF) guidelines, FGF23 was studied by Enzyme-Linked ImmunoSorbent Assay (ELISA) method and IR was calculated using the homeostatic model assessment-insulin resistance (HOMA-IR) formula. Results There was a statistically significant difference in HOMA-IR between the patient and control group as expected, while levels of FGF23 were similar. According to gender, levels of FGF23 was statistically significantly higher in male patients compared with controls (p = 0.037). A relationship was not detected between HOMA-IR and FGF23 in the correlation analysis. Conclusion Although there are many studies suggesting the correlation between FGF23 and IR in different populations, we did not find any statistically significant relationship between IR and FGF23 levels in MetS in this study. 10.1515/hmbci-2018-0018
    Erythropoietin stimulates fibroblast growth factor 23 (FGF23) in mice and men. Daryadel Arezoo,Bettoni Carla,Haider Thomas,Imenez Silva Pedro H,Schnitzbauer Udo,Pastor-Arroyo Eva Maria,Wenger Roland H,Gassmann Max,Wagner Carsten A Pflugers Archiv : European journal of physiology Fibroblast growth factor 23 (FGF23) is a major endocrine regulator of phosphate and 1,25 (OH) vitamin D metabolism and is mainly produced by osteocytes. Its production is upregulated by a variety of factors including 1,25 (OH) vitamin D, high dietary phosphate intake, and parathyroid hormone (PTH). Recently, iron deficiency and hypoxia have been suggested as additional regulators of FGF23 and a role of erythropoietin (EPO) was shown. However, the regulation of FGF23 by EPO and the impact on phosphate and 1,25(OH) vitamin D are not completely understood. Here, we demonstrate that acute administration of recombinant human EPO (rhEPO) to healthy humans increases the C-terminal fragment of FGF23 (C-terminal FGF23) but not intact FGF23 (iFGF23). In mice, rhEPO stimulates acutely (24 h) C-terminal FGF23 but iFGF23 only after 4 days without effects on PTH and plasma phosphate. 1,25 (OH) D levels and αklotho expression in the kidney decrease after 4 days. rhEPO induced FGF23 mRNA in bone marrow but not in bone, with increased staining of FGF23 in CD71 erythroid precursors in bone marrow. Chronic elevation of EPO in transgenic mice increases iFGF23. Finally, acute injections of recombinant FGF23 reduced renal EPO mRNA expression. Our data demonstrate stimulation of FGF23 levels in mice which impacts mostly on 1,25 (OH) vitamin D levels and metabolism. In humans, EPO is mostly associated with the C-terminal fragment of FGF23; in mice, EPO has a time-dependent effect on both FGF23 forms. EPO and FGF23 may form a feedback loop controlling and linking erythropoiesis and mineral metabolism. 10.1007/s00424-018-2171-7
    FGF23 impairs peripheral microvascular function in renal failure. Verkaik Melissa,Juni Rio P,van Loon Ellen P M,van Poelgeest Erik M,Kwekkeboom Rick F J,Gam Zeineb,Richards William G,Ter Wee Pieter M,Hoenderop Joost G,Eringa Etto C,Vervloet Marc G, American journal of physiology. Heart and circulatory physiology Cardiovascular diseases account for ~50% of mortality in patients with chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF23) is independently associated with endothelial dysfunction and cardiovascular mortality. We hypothesized that CKD impairs microvascular endothelial function and that this can be attributed to FGF23. Mice were subjected to partial nephrectomy (5/6Nx) or sham surgery. To evaluate the functional role of FGF23, non-CKD mice received FGF23 injections and CKD mice received FGF23-blocking antibodies after 5/6Nx surgery. To examine microvascular function, myocardial perfusion in vivo and vascular function of gracilis resistance arteries ex vivo were assessed in mice. 5/6Nx surgery blunted ex vivo vasodilator responses to acetylcholine, whereas responses to sodium nitroprusside or endothelin were normal. In vivo FGF23 injections in non-CKD mice mimicked this endothelial defect, and FGF23 antibodies in 5/6Nx mice prevented endothelial dysfunction. Stimulation of microvascular endothelial cells with FGF23 in vitro did not induce ERK phosphorylation. Increased plasma asymmetric dimethylarginine concentrations were increased by FGF23 and strongly correlated with endothelial dysfunction. Increased FGF23 concentration did not mimic impaired endothelial function in the myocardium of 5/6Nx mice. In conclusion, impaired peripheral endothelium-dependent vasodilatation in 5/6Nx mice is mediated by FGF23 and can be prevented by blocking FGF23. These data corroborate FGF23 as an important target to combat cardiovascular disease in CKD. NEW & NOTEWORTHY In the present study, we provide the first evidence that fibroblast growth factor 23 (FGF23) is a cause of peripheral endothelial dysfunction in a model of early chronic kidney disease (CKD) and that endothelial dysfunction in CKD can be prevented by blockade of FGF23. This pathological effect on endothelial cells was induced by long-term exposure of physiological levels of FGF23. Mechanistically, increased plasma asymmetric dimethylarginine concentrations were strongly associated with this endothelial dysfunction in CKD and were increased by FGF23. 10.1152/ajpheart.00272.2018
    C-terminal and intact FGF23 in critical illness and their associations with acute kidney injury and in-hospital mortality. Rygasiewicz Karolina,Hryszko Tomasz,Siemiatkowski Andrzej,Brzosko Szymon,Rydzewska-Rosolowska Alicja,Naumnik Beata Cytokine BACKGROUND:FGF23 proved its value in prognostication of cardiovascular events and mortality among renal patients and general population. Limited data exist whether FGF23 may have any use in prediction of negative outcomes among critically ill patients admitted to intensive care unit (ICU). METHODS:Single center cohort study performed among patients admitted to ICU. The primary exposure was FGF23 plasma concentration measured within 24 h of ICU admission. The primary outcome was incident Acute Kidney Injury (AKI) and in-hospital mortality during the ICU stay. RESULTS:The study enrolled 79 patients admitted to ICU. C-terminal FGF23 (cFGF23) but not intact FGF23 (iFGF23) concentration was significantly elevated in patients, who acquired AKI and non-survivors (p < .001). ROC analysis of cFGF23 yielded an AUC of 0.81 and 0.85 for prediction of incident AKI and death during ICU stay, respectively. Multivariate analysis showed higher odds for AKI (OR 1.80; 95% CI 1.10-2.96) and in-hospital mortality (OR 2.85; 95% CI 1.60-5.06) for one unit increase of log transformed cFGF23. CONCLUSIONS:cFGF23 measurement may serve as a novel biomarker for incident AKI and death among critically ill patients. 10.1016/j.cyto.2017.12.024
    Effect of Cholecalciferol therapy on serum FGF in vitamin D deficient patients: a randomized clinical trial. Kamelian T,Saki F,Jeddi M,Dabbaghmanesh M H,Omrani G H R Journal of endocrinological investigation INTRODUCTION:Fibroblast growth factor-23 plays an important role in regulating systemic phosphate homeostasis, and vitamin D metabolism. However, the effect of Cholecalciferol therapy on FGF serum level in patients with vitamin D deficiency has not been studied, yet. MATERIALS AND METHODS:This is a double-blind, randomized clinical trial on 119 vitamin D deficient patients in 2016. Biochemical variables of treatment and placebo groups were analyzed after 12 weeks of 50,000 IU of Cholecalciferol vs. placebo therapy once a week, by SPSS18. RESULTS:After Cholecalciferol therapy, delta of serum PTH in treatment group was less than the controls (P < 0.001). However, delta values of serum 25(OH)D, 1,25(OH)D and FGF in vitamin D treated group were more than the placebo-treated ones (P < 0.001, P = 0.002, and P = 0.04, respectively). Moreover, FGF serum level in treatment group was associated with serum calcium (P = 0.005, r = -0.256), and serum 1,25(OH)D (P < 0.001, r = 0.529). CONCLUSIONS:We propose that in these patients 1,25(OH)D has a positive association with serum FGF, and hypostasized that serum calcium might be a down regulator of serum FGF. 10.1007/s40618-017-0739-2
    The FGF23-Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease-a prospective cohort study. Tranæus Lindblad Ylva,Olauson Hannes,Vavilis Georgios,Hammar Ulf,Herthelius Maria,Axelsson Jonas,Bárány Peter Pediatric nephrology (Berlin, Germany) BACKGROUND:Chronic kidney disease-associated mineral bone disorder (CKD-MBD) is common in pediatric kidney disease patients and a risk factor for future cardiovascular disease (CVD). Fibroblast growth factor-23 (FGF23) and Klotho are novel key players in CKD-MBD, and has been suggested to be involved in the development of CVD. METHODS:This prospective cohort study included 74 pediatric patients; 31 with CKD (age range 0.8-18.8 years, glomerular filtration rate (GFR) range 9-68 mL/min/1.73 m) and 43 transplanted patients (CKD-T; age range 3.3-17.7 years, GFR range 10-99 mL/min/1.73 m) examined annually for 3 years. We assessed longitudinal patterns and predictors of FGF23 and soluble Klotho, as well as associations to cardiac remodeling and function using echocardiographic pulse wave Doppler (PWD) and color-coded tissue Doppler imaging (cc-TDI). RESULTS:The prevalence of high FGF23 levels (≥95th percentile) was 60% in CKD and 42% in CKD-T patients, despite a low prevalence of hyperphosphatemia and normal Klotho levels. Low GFR at baseline was a predictor for high mean log FGF23 during follow-up in CKD and CKD-T patients (β = -0.2, p < 0.001). A high log FGF23 z-score longitudinally was borderline significantly associated with elevated left ventricular mass index (LVMI) in CKD patients (β = 1.8, p = 0.06). In addition, high log FGF23 (β = -0.43, p = 0.01) and low log Klotho (β = 0.44, p = 0.006) over time were associated with a worse left ventricular diastolic function (cc-TDI e'/a') in CKD-T patients. CONCLUSIONS:In pediatric CKD and CKD-T patients, the FGF23 level increase and Klotho level decrease with progressing renal failure, despite well-controlled phosphate levels. Following adjustments, both high FGF23 and low Klotho levels were strongly associated with a worse left ventricular diastolic function longitudinally. The potential role of FGF23 and Klotho in cardiac morbidity in pediatric CKD requires further investigation. 10.1007/s00467-017-3766-5
    FGF23 and Left Ventricular Hypertrophy in Children with CKD. Mitsnefes Mark M,Betoko Aisha,Schneider Michael F,Salusky Isidro B,Wolf Myles Selig,Jüppner Harald,Warady Bradley A,Furth Susan L,Portale Anthony A Clinical journal of the American Society of Nephrology : CJASN BACKGROUND AND OBJECTIVES:High plasma concentration of fibroblast growth factor 23 (FGF23) is a risk factor for left ventricular hypertrophy (LVH) in adults with CKD, and induces myocardial hypertrophy in experimental CKD. We hypothesized that high FGF23 levels associate with a higher prevalence of LVH in children with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We performed echocardiograms and measured plasma C-terminal FGF23 concentrations in 587 children with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study. We used linear and logistic regression to analyze the association of plasma FGF23 with left ventricular mass index (LVMI) and LVH (LVMI ≥95th percentile), adjusted for demographics, body mass index, eGFR, and CKD-specific factors. We also examined the relationship between FGF23 and LVH by eGFR level. RESULTS:Median age was 12 years (interquartile range, 8-15) and eGFR was 50 ml/min per 1.73 m (interquartile range, 38-64). Overall prevalence of LVH was 11%. After adjustment for demographics and body mass index, the odds of having LVH was higher by 2.53 (95% confidence interval, 1.28 to 4.97; <0.01) in participants with FGF23 concentrations ≥170 RU/ml compared with those with FGF23<100 RU/ml, but this association was attenuated after full adjustment. Among participants with eGFR≥45 ml/min per 1.73 m, the prevalence of LVH was 5.4%, 11.2%, and 15.3% for those with FGF23 <100 RU/ml, 100-169 RU/ml, and ≥170 RU/ml, respectively (=0.01). When eGFR was ≥45 ml/min per 1.73 m, higher FGF23 concentrations were independently associated with LVH (fully adjusted odds ratio, 3.08 in the highest versus lowest FGF23 category; 95% confidence interval, 1.02 to 9.24; <0.05; fully adjusted odds ratio, 2.02 per doubling of FGF23; 95% confidence interval, 1.29 to 3.17; <0.01). By contrast, in participants with eGFR<45 ml/min per 1.73 m, FGF23 did not associate with LVH. CONCLUSIONS:Plasma FGF23 concentration ≥170 RU/ml is an independent predictor of LVH in children with eGFR≥45 ml/min per 1.73 m. 10.2215/CJN.02110217
    Longitudinal FGF23 Trajectories and Mortality in Patients with CKD. Isakova Tamara,Cai Xuan,Lee Jungwha,Xie Dawei,Wang Xue,Mehta Rupal,Allen Norrina B,Scialla Julia J,Pencina Michael J,Anderson Amanda H,Talierco John,Chen Jing,Fischer Michael J,Steigerwalt Susan P,Leonard Mary B,Hsu Chi-Yuan,de Boer Ian H,Kusek John W,Feldman Harold I,Wolf Myles, Journal of the American Society of Nephrology : JASN 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, =724) and smaller subpopulations with slowly (slope=0.14, 95% CI, 0.12 to 0.16, =486) or rapidly (slope=0.46, 95% CI, 0.38 to 0.54, =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. 10.1681/ASN.2017070772
    Effect of ferric citrate hydrate on FGF23 and PTH levels in patients with non-dialysis-dependent chronic kidney disease with normophosphatemia and iron deficiency. Iguchi Akira,Yamamoto Suguru,Yamazaki Mihoko,Tasaki Kazuyuki,Suzuki Yasushi,Kazama Junichiro James,Narita Ichiei Clinical and experimental nephrology BACKGROUND:In patients with normophosphatemia with chronic kidney disease (CKD), fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) increase urinary phosphate excretion while maintaining serum phosphate within the normal range. Recent reports have shown that, in this stage, phosphate binders do not decrease serum FGF23 and PTH levels. Iron deficiency promotes transcription of FGF23 and iron-supplementation for iron deficiency decreases serum FGF23 levels. We hypothesized that ferric citrate hydrate, an iron-based phosphate binder, will decrease serum FGF23 levels in patients with non-dialysis-dependent CKD with normophosphatemia and iron deficiency. METHODS:This was a single-center, randomized, open-label interventional study. The inclusion criteria were as follows: (1) eGFR < 45 mL/min/1.73 m, (2) normophosphatemia, (3) iron deficiency. Patients were assigned to the following groups: ferric citrate hydrate (FCH)-group, sodium ferrous citrate (SFC)-group, and control-group. After 12 weeks of intervention, we evaluated serum FGF23 levels and CKD-mineral bone disorder markers. RESULTS:There were 17 patients in the FCH-group, 14 in the SFC-group, and 9 in the control-group. The serum ferritin levels increased in the FCH-group and SFC-group compared with baseline. Serum FGF23 levels were unchanged; the change in the FCH-group was from 52.91 RU/mL (42.48-72.91) to 40.00 RU/mL (30.30-58.13) (P = 0.1764). However, in the FCH-group, serum PTH levels significantly decreased compared with baseline, from 68.00 pg/mL (49.00-141.00) to 60.00 pg/mL (44.00-144.00) (P = 0.0101). CONCLUSION:Iron-based phosphate binder did not decrease serum FGF23 levels, but decreased serum PTH levels. 10.1007/s10157-017-1510-x