Parathyroid hormone receptor signaling in osteocytes increases the expression of fibroblast growth factor-23 in vitro and in vivo

ObjectiveFibroblast growth factor-23 (FGF23) is a circulating factor involved in phosphate (Pi) and vitamin D metabolism. Serum FGF23 is increased at later stages of chronic kidney disease due to chronic hyperphosphatemia and decreased renal clearance. Recent studies also indicate that FGF23 may directly regulate the expression of parathyroid hormone (PTH) in vitro. Therefore, the objective of the current study was to determine the relationship between FGF23, PTH, and other biochemistries in vivo in subjects with no history of renal disease.DesignSerum biochemistries were measured in a subsample of the population-based Swedish part of the MrOS study. In total, 1000 Caucasian men aged 70–80 years were randomly selected from the population.MethodsIntact FGF23, Pi, calcium, albumin, estimated glomerular filtration rate (eGFR, calculated from cystatin C), PTH, and 25(OH)D3 were measured. Association studies were performed using linear univariate and multivariate regression analyses.ResultsThe median FGF23 level was 36.6 pg/ml, ranging from 0.63 to 957 pg/ml. There was a significant correlation between log FGF23 and eGFR (r=−0.21; P<0.00001) and log PTH (r=0.13; P<0.001). These variables remained as independent predictors of FGF23 in multivariate analysis. In addition, log PTH (β=0.082; P<0.05) and eGFR (β=−0.090; P<0.05) were associated with log FGF23 in subjects with eGFR>60 ml/min. Only eGFR (β=−0.35; P<0.0001) remained as a predictor of log FGF23 in subjects with eGFR<60 ml/min.ConclusionsSerum FGF23 and PTH are associated in vivo, supporting recent findings that FGF23 directly regulates PTH expression in vitro. Additionally, eGFR is associated with FGF23 in subjects with normal or mildly impaired renal function, indicating that GFR may modulate FGF23 levels independent of serum Pi.

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Direct and indirect effects of parathyroid hormone on circulating levels of fibroblast growth factor 23 in vivo

Kidney International ◽

10.1038/ki.2011.107 ◽

2011 ◽

Vol 80 (5) ◽

pp. 475-482 ◽

Cited By ~ 91

Author(s):

Ignacio López ◽

M. Encarnación Rodríguez-Ortiz ◽

Yolanda Almadén ◽

Fátima Guerrero ◽

A. Montes de Oca ◽

...

Keyword(s):

Parathyroid Hormone ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Indirect Effects ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Direct And Indirect Effects ◽

Circulating Levels

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Fibroblast growth factor-23 regulates parathyroid hormone and 1α-hydroxylase expression in cultured bovine parathyroid cells

Journal of Endocrinology ◽

10.1677/joe-07-0267 ◽

2007 ◽

Vol 195 (1) ◽

pp. 125-131 ◽

Cited By ~ 345

Author(s):

Tijana Krajisnik ◽

Peyman Björklund ◽

Richard Marsell ◽

Östen Ljunggren ◽

Göran Åkerström ◽

...

Keyword(s):

Vitamin D ◽

Parathyroid Hormone ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Mrna Level ◽

Serum Levels ◽

Negative Regulator ◽

Fibroblast Growth

Fibroblast growth factor-23 (FGF23) is a circulating factor that decreases serum levels of inorganic phosphate (Pi) as well as 1,25-dihydroxyvitamin D3. Recent studies also suggest a correlation between serum levels of FGF23 and parathyroid hormone (PTH) in patients with chronic kidney disease. It is, however, unknown whether FGF23 directly modulates PTH expression, or whether the correlation is secondary to abnormalities in Pi and vitamin D metabolism. The objective of the current study was therefore to elucidate possible direct effects of FGF23 on bovine parathyroid cells in vitro. Treatment of parathyroid cells with a stabilized form of recombinant FGF23 (FGF23(R176Q)) induced a rise in early response gene-1 mRNA transcripts, a marker of FGF23 signaling. FGF23(R176Q) potently and dose-dependently decreased the PTH mRNA level within 12 h. In agreement, FGF23(R176Q) also decreased PTH secretion into conditioned media. In contrast, FGF23(R176Q) dose-dependently increased 1α-hydroxylase expression within 3 h. FGF23 (R176Q) did not affect cell viability nor induce apoptosis, whereas a small but significant increase in cell proliferation was found. We conclude that FGF23 is a negative regulator of PTH mRNA expression and secretion in vitro. Our data suggest that FGF23 may be a physiologically relevant regulator of PTH. This defines a novel function of FGF23 in addition to the previously established roles in controlling vitamin D and Pi metabolism.

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Identification of novel small molecules that elevate Klotho expression

Biochemical Journal ◽

10.1042/bj20101909 ◽

2011 ◽

Vol 441 (1) ◽

pp. 453-461 ◽

Cited By ~ 35

Author(s):

Gwendalyn D. King ◽

CiDi Chen ◽

Mickey M. Huang ◽

Ella Zeldich ◽

Patricia L. Brazee ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Functional Change ◽

In Vivo Studies ◽

Luciferase Expression ◽

Fibroblast Growth ◽

Opossum Kidney

The absence of Klotho (KL) from mice causes the development of disorders associated with human aging and decreased longevity, whereas increased expression prolongs lifespan. With age, KL protein levels decrease, and keeping levels consistent may promote healthier aging and be disease-modifying. Using the KL promoter to drive expression of luciferase, we conducted a high-throughput screen to identify compounds that activate KL transcription. Hits were identified as compounds that elevated luciferase expression at least 30%. Following validation for dose-dependent activation and lack of cytotoxicity, hit compounds were evaluated further in vitro by incubation with opossum kidney and Z310 rat choroid plexus cells, which express KL endogenously. All compounds elevated KL protein compared with control. To determine whether increased protein resulted in an in vitro functional change, we assayed FGF23 (fibroblast growth factor 23) signalling. Compounds G–I augmented ERK (extracellular-signal-regulated kinase) phosphorylation in FGFR (fibroblast growth factor receptor)-transfected cells, whereas co-transfection with KL siRNA (small interfering RNA) blocked the effect. These compounds will be useful tools to allow insight into the mechanisms of KL regulation. Further optimization will provide pharmacological tools for in vivo studies of KL.

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Faculty Opinions recommendation of Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1120416.576608 ◽

2008 ◽

Author(s):

Eleanor Lederer

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Osteoblast Differentiation ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Matrix Mineralization

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Faculty Opinions recommendation of Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13323976.14688082 ◽

2011 ◽

Author(s):

Albert Ong ◽

Tim Ellam

Keyword(s):

Chronic Kidney Disease ◽

Parathyroid Hormone ◽

Growth Factor ◽

Kidney Disease ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth

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Faculty Opinions recommendation of Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718084603.793512405 ◽

2015 ◽

Author(s):

Mariano Rodriguez

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth ◽

Calcium And Phosphorus

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Dynamic changes of podocytes caused by fibroblast growth factor 2 in culture

Cell and Tissue Research ◽

10.1007/s00441-021-03511-x ◽

2021 ◽

Author(s):

Eishin Yaoita ◽

Masaaki Nameta ◽

Yutaka Yoshida ◽

Hidehiko Fujinaka

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 2 ◽

Quiescent State ◽

Fibroblast Growth ◽

Gene Expressions ◽

Dynamic Changes ◽

Ki 67

AbstractFibroblast growth factor 2 (FGF2) augments podocyte injury, which induces glomerulosclerosis, although the mechanisms remain obscure. In this study, we investigated the effects of FGF2 on cultured podocytes with interdigitating cell processes in rats. After 48 h incubation with FGF2 dynamic changes in the shape of primary processes and cell bodies of podocytes resulted in the loss of interdigitation, which was clearly shown by time-lapse photography. FGF2 reduced the gene expressions of constituents of the slit diaphragm, inflections of intercellular junctions positive for nephrin, and the width of the intercellular space. Immunostaining for the proliferation marker Ki-67 was rarely seen and weakly stained in the control without FGF2, whereas intensely stained cells were frequently found in the presence of FGF2. Binucleation and cell division were also observed, although no significant increase in cell number was shown. An in vitro scratch assay revealed that FGF2 enhanced migration of podocytes. These findings show that FGF2 makes podocytes to transition from the quiescent state into the cell cycle and change their morphology due to enhanced motility, and that the culture system in this study is useful for analyzing the pathological changes of podocytes in vivo.

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