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recombinant mouse fgf23  (R&D Systems)


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    R&D Systems recombinant mouse fgf23
    ( a ) Treatment of neonatal rat ventricular myocyte cardiobundles with fibroblast growth factor (FGF) 23 for 20 minutes significantly increased contractile force, whereas 7 days of chronic treatment led to a significant reduction in contractile force that could be rescued by coapplication of BLU9931, a selective FGFR4 inhibitor. ( b ) Electrophysiological function was evaluated by pacing of cardiobundles and application of Di-4-ANEPPS (6-[2-(N,N-Dibutylamino)naphthyl]ethenyl-4′-pyridinium propanesulfonate) as voltage-sensitive dye. Chronic exposure of cardiobundles to <t>FGF23</t> lead to significantly longer action potential durations. ( c ) FGF23-treated bundles exhibited significantly lower conduction velocity that was normalized after coapplication of BLU9931. Besides functional changes, chronic FGF23 treatment also led to cardiobundle hypertrophy, indicated by the ( d,g ) significant increase in cross-section and ( e ) increased expression of hypertrophic mRNA markers Rcan1 and Trpc6 . Increased expression of Rcan1 and Trpc6 was blocked by parallel treatment with BLU9931. ( f ) Metabolic transcription factors that were increased in chronic kidney disease mice also increased in cardiobundles after FGF23 treatment. ( g ) Representative images of cardiobundles indicate cellular hypertrophy after FGF23 treatment by increased myocyte cross-sections. Bars = 10 μm. ( h ) Gene set enrichment analysis of control and FGF23-treated cardiobundles showed an enrichment of metabolic pathways, particularly fatty acid metabolism, adipogenesis, and cholesterol homeostasis. ( i ) Additional enrichment was detected in pathways related to mitochondrial function, such as oxidative phosphorylation, respiratory chain, organelle fission, and organelle inner membrane. Downregulated pathways after FGF23 treatment include angiogenesis, vascular development, tumor necrosis factor (TNF)-α signaling, and P53. Bar graphs represent mean ± SEM with individual values included in the graph. n ≥ 3 for all experiments. * P < 0.05, ** P < 0.005, **** P < 0.0001. APD, action potential duration; DAPI, 4′,6-diamidino-2-phenylindole; ES, enrichment score; FDR, false discovery rate; NES, normalized enrichment score. To optimize viewing of this image, please see the online version of this article at www.kidney-international.org .
    Recombinant Mouse Fgf23, supplied by R&D Systems, used in various techniques. Bioz Stars score: 93/100, based on 21 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
    https://www.bioz.com/product/recombinant+mouse+fgf23/Recombinant+Mouse+FGF-23+Protein%2C+CF/pmc12755233-21-1-7
    Average 93 stars, based on 21 article reviews
    recombinant mouse fgf23 - by Bioz Stars, 2026-09
    93/100 stars

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    1) Product Images from "Fibroblast growth factor 23 and fibroblast growth factor receptor 4 promote cardiac metabolic remodeling in chronic kidney disease"

    Article Title: Fibroblast growth factor 23 and fibroblast growth factor receptor 4 promote cardiac metabolic remodeling in chronic kidney disease

    Journal: Kidney international

    doi: 10.1016/j.kint.2025.01.024

    ( a ) Treatment of neonatal rat ventricular myocyte cardiobundles with fibroblast growth factor (FGF) 23 for 20 minutes significantly increased contractile force, whereas 7 days of chronic treatment led to a significant reduction in contractile force that could be rescued by coapplication of BLU9931, a selective FGFR4 inhibitor. ( b ) Electrophysiological function was evaluated by pacing of cardiobundles and application of Di-4-ANEPPS (6-[2-(N,N-Dibutylamino)naphthyl]ethenyl-4′-pyridinium propanesulfonate) as voltage-sensitive dye. Chronic exposure of cardiobundles to FGF23 lead to significantly longer action potential durations. ( c ) FGF23-treated bundles exhibited significantly lower conduction velocity that was normalized after coapplication of BLU9931. Besides functional changes, chronic FGF23 treatment also led to cardiobundle hypertrophy, indicated by the ( d,g ) significant increase in cross-section and ( e ) increased expression of hypertrophic mRNA markers Rcan1 and Trpc6 . Increased expression of Rcan1 and Trpc6 was blocked by parallel treatment with BLU9931. ( f ) Metabolic transcription factors that were increased in chronic kidney disease mice also increased in cardiobundles after FGF23 treatment. ( g ) Representative images of cardiobundles indicate cellular hypertrophy after FGF23 treatment by increased myocyte cross-sections. Bars = 10 μm. ( h ) Gene set enrichment analysis of control and FGF23-treated cardiobundles showed an enrichment of metabolic pathways, particularly fatty acid metabolism, adipogenesis, and cholesterol homeostasis. ( i ) Additional enrichment was detected in pathways related to mitochondrial function, such as oxidative phosphorylation, respiratory chain, organelle fission, and organelle inner membrane. Downregulated pathways after FGF23 treatment include angiogenesis, vascular development, tumor necrosis factor (TNF)-α signaling, and P53. Bar graphs represent mean ± SEM with individual values included in the graph. n ≥ 3 for all experiments. * P < 0.05, ** P < 0.005, **** P < 0.0001. APD, action potential duration; DAPI, 4′,6-diamidino-2-phenylindole; ES, enrichment score; FDR, false discovery rate; NES, normalized enrichment score. To optimize viewing of this image, please see the online version of this article at www.kidney-international.org .
    Figure Legend Snippet: ( a ) Treatment of neonatal rat ventricular myocyte cardiobundles with fibroblast growth factor (FGF) 23 for 20 minutes significantly increased contractile force, whereas 7 days of chronic treatment led to a significant reduction in contractile force that could be rescued by coapplication of BLU9931, a selective FGFR4 inhibitor. ( b ) Electrophysiological function was evaluated by pacing of cardiobundles and application of Di-4-ANEPPS (6-[2-(N,N-Dibutylamino)naphthyl]ethenyl-4′-pyridinium propanesulfonate) as voltage-sensitive dye. Chronic exposure of cardiobundles to FGF23 lead to significantly longer action potential durations. ( c ) FGF23-treated bundles exhibited significantly lower conduction velocity that was normalized after coapplication of BLU9931. Besides functional changes, chronic FGF23 treatment also led to cardiobundle hypertrophy, indicated by the ( d,g ) significant increase in cross-section and ( e ) increased expression of hypertrophic mRNA markers Rcan1 and Trpc6 . Increased expression of Rcan1 and Trpc6 was blocked by parallel treatment with BLU9931. ( f ) Metabolic transcription factors that were increased in chronic kidney disease mice also increased in cardiobundles after FGF23 treatment. ( g ) Representative images of cardiobundles indicate cellular hypertrophy after FGF23 treatment by increased myocyte cross-sections. Bars = 10 μm. ( h ) Gene set enrichment analysis of control and FGF23-treated cardiobundles showed an enrichment of metabolic pathways, particularly fatty acid metabolism, adipogenesis, and cholesterol homeostasis. ( i ) Additional enrichment was detected in pathways related to mitochondrial function, such as oxidative phosphorylation, respiratory chain, organelle fission, and organelle inner membrane. Downregulated pathways after FGF23 treatment include angiogenesis, vascular development, tumor necrosis factor (TNF)-α signaling, and P53. Bar graphs represent mean ± SEM with individual values included in the graph. n ≥ 3 for all experiments. * P < 0.05, ** P < 0.005, **** P < 0.0001. APD, action potential duration; DAPI, 4′,6-diamidino-2-phenylindole; ES, enrichment score; FDR, false discovery rate; NES, normalized enrichment score. To optimize viewing of this image, please see the online version of this article at www.kidney-international.org .

    Techniques Used: Functional Assay, Expressing, Control, Phospho-proteomics, Membrane

    ( a,b ) Cultured neonatal rat ventricular myocytes (NRVMs) responded to 48 hours of fibroblast growth factor (FGF) 23 treatment with significant hypertrophy, indicated by increased cross-sectional area and expression of prohypertrophic markers. Prohypertrophic mRNA expression and cellular hypertrophy could be mitigated by parallel treatment with the FGFR4-specific inhibitor BLU9931. ( a ) Bar = 30 μm. ( c ) NRVMs treated with FGF23 for 1 hour, before observable hypertrophy takes place, were analyzed in a Seahorse XF analyzer for extracellular acidification rate (ECAR), elevated total proton efflux rates (PERs), and glycolysis-specific PER (GlycoPER). ECAR was significantly higher in FGF23-treated cells, which could be reduced to control levels by BLU9931. PER showed elevated basal and compensatory glycolysis on FGF23 treatment; glycolysis-specific proton efflux was also increased. These FGF23-mediated effects were blocked by BLU9931 application. ( c ) Graphs represent 3 independent experiments. ( d ) Seahorse mitochondrial stress test assay showed increased basal and maximal mitochondrial respiration after FGF23 treatment of NRVMs. Adenosine triphosphate (ATP) production-linked, spare respiratory capacity and nonmitochondrial oxygen consumption rate increased in parallel after FGF23 treatment. The significant decrease in coupling efficiency and the increased proton leak indicate uncoupling of substrate oxidation and ATP synthesis after 1 hour of FGF23 treatment. Application of BLU9931 or the calcineurin inhibitor, cyclosporin A, prevented the changes to mitochondrial function caused by FGF23. Bar graphs represent mean ± SEM and individual values included in the graph. n ≥ 9 for all experiments. * P < 0.05, ** P < 0.005, **** P < 0.0001. DMSO, dimethylsulfoxide; Max, maximum; NS, not significant; PBS, phosphate-buffered saline. To optimize viewing of this image, please see the online version of this article at www.kidney-international.org .
    Figure Legend Snippet: ( a,b ) Cultured neonatal rat ventricular myocytes (NRVMs) responded to 48 hours of fibroblast growth factor (FGF) 23 treatment with significant hypertrophy, indicated by increased cross-sectional area and expression of prohypertrophic markers. Prohypertrophic mRNA expression and cellular hypertrophy could be mitigated by parallel treatment with the FGFR4-specific inhibitor BLU9931. ( a ) Bar = 30 μm. ( c ) NRVMs treated with FGF23 for 1 hour, before observable hypertrophy takes place, were analyzed in a Seahorse XF analyzer for extracellular acidification rate (ECAR), elevated total proton efflux rates (PERs), and glycolysis-specific PER (GlycoPER). ECAR was significantly higher in FGF23-treated cells, which could be reduced to control levels by BLU9931. PER showed elevated basal and compensatory glycolysis on FGF23 treatment; glycolysis-specific proton efflux was also increased. These FGF23-mediated effects were blocked by BLU9931 application. ( c ) Graphs represent 3 independent experiments. ( d ) Seahorse mitochondrial stress test assay showed increased basal and maximal mitochondrial respiration after FGF23 treatment of NRVMs. Adenosine triphosphate (ATP) production-linked, spare respiratory capacity and nonmitochondrial oxygen consumption rate increased in parallel after FGF23 treatment. The significant decrease in coupling efficiency and the increased proton leak indicate uncoupling of substrate oxidation and ATP synthesis after 1 hour of FGF23 treatment. Application of BLU9931 or the calcineurin inhibitor, cyclosporin A, prevented the changes to mitochondrial function caused by FGF23. Bar graphs represent mean ± SEM and individual values included in the graph. n ≥ 9 for all experiments. * P < 0.05, ** P < 0.005, **** P < 0.0001. DMSO, dimethylsulfoxide; Max, maximum; NS, not significant; PBS, phosphate-buffered saline. To optimize viewing of this image, please see the online version of this article at www.kidney-international.org .

    Techniques Used: Cell Culture, Expressing, Control, Saline

    Related Articles

    Recombinant:

    Article Title: Fibroblast growth factor 23 and fibroblast growth factor receptor 4 promote cardiac metabolic remodeling in chronic kidney disease
    Article Snippet: .. Carrier-free recombinant mouse FGF23 (catalog number 2629-FG025/CF, R&D Systems) was used at 25 and 100 ng/ml. .. The isoform-specific FGFR4 small-molecule inhibitor BLU9931 (catalog number S7819, Selleck Chemicals) was used at 10 ng/ml.

    Article Title: Renal FGF23 signaling depends on redox protein Memo1 and promotes orthovanadate-sensitive protein phosphotyrosyl phosphatase activity
    Article Snippet: .. For FGF23 treatments, mice aged 6.5 weeks were starved for 6 h and intraperitoneally injected with 220 ng/g body weight of recombinant mouse FGF23 (2629-FG-025 R&D Systems, Minneapolis, MN, USA) in PBS-BSA 0.1% or PBS-BSA 0.1% vehicle with injection volume of 4 μL/g body weight. ..

    Article Title: Indoxyl sulfate induces left ventricular hypertrophy via the AhR-FGF23-FGFR4 signaling pathway
    Article Snippet: .. The cells were incubated with 0, 0.25, or 1.0 mM IS or 0, 50, or 100 ng/mL recombinant mouse FGF23 (2629-FG; R&D Systems, Minneapolis, MN) diluted in normal saline (NS) and collected after 24 and 72 h for real-time reverse transcription-polymerase chain reaction and western blotting, respectively. .. To perform small interfering RNA (siRNA) knockdown, the cells were transfected with On-TARGETplus SMARTpool siRNA [non-targeting control, aryl hydrocarbon receptor (AhR), and FGF23; Horizon Discovery, Cambridge, UK] using Dharmafect 1 reagent (Horizon Discovery) in accordance with the manufacturer’s instructions.

    Article Title: Fibroblast Growth Factor 23 Exacerbates Cardiac Fibrosis in Deoxycorticosterone Acetate-Salt Mice With Hypertension.
    Article Snippet: At this time, a microinfusion pump (iPRECIO model SMP-300; Primetech Corp), which permits quantitative pharmacology in the right jugular vein using a catheter in single animals, was implanted into the DOCA-salt mice to allow continuous intravenous (CIV) infusion of reagents. .. The mice were infused with phosphate-buffered saline for 4 days after implantation, followed by CIV infusion of phosphatebuffered saline (group V), recombinant mouse FGF23 (80 mg/kg/ d; R&D Systems, Inc; group F), or recombinant FGF23 and calcitriol (0.4 mg/kg/d intraperitoneally 3 times per week) (group C) for 10 days. ..

    Article Title: Fibroblast growth factor 23 and fibroblast growth factor receptor 4 promote cardiac metabolic remodeling in chronic kidney disease.
    Article Snippet: .. METHODS Antibodies, recombinant proteins, and heparin Carrier-free recombinant mouse FGF23 (catalog number 2629-FG025/CF, R&D Systems) was used at 25 and 100 ng/ ml. .. The isoform-specific FGFR4 small-molecule inhibitor BLU9931 (catalog number S7819, Selleck Chemicals) was used at 10 ng/ml.

    Article Title: Renal FGF23 signaling depends on redox protein Memo1 and promotes orthovanadate-sensitive protein phosphotyrosyl phosphatase activity.
    Article Snippet: .. For FGF23 treatments, mice aged 6.5 weeks were starved for 6 h and intraperitoneally injected with 220 ng/g body weight of recombinant mouse FGF23 (2629-FG-025 R&D Systems, Minneapolis, MN, USA) in PBS-BSA 0.1% or PBS-BSA 0.1% vehicle with injection volume of 4 μL/g body weight. ..

    Injection:

    Article Title: Renal FGF23 signaling depends on redox protein Memo1 and promotes orthovanadate-sensitive protein phosphotyrosyl phosphatase activity
    Article Snippet: .. For FGF23 treatments, mice aged 6.5 weeks were starved for 6 h and intraperitoneally injected with 220 ng/g body weight of recombinant mouse FGF23 (2629-FG-025 R&D Systems, Minneapolis, MN, USA) in PBS-BSA 0.1% or PBS-BSA 0.1% vehicle with injection volume of 4 μL/g body weight. ..

    Article Title: Renal FGF23 signaling depends on redox protein Memo1 and promotes orthovanadate-sensitive protein phosphotyrosyl phosphatase activity.
    Article Snippet: .. For FGF23 treatments, mice aged 6.5 weeks were starved for 6 h and intraperitoneally injected with 220 ng/g body weight of recombinant mouse FGF23 (2629-FG-025 R&D Systems, Minneapolis, MN, USA) in PBS-BSA 0.1% or PBS-BSA 0.1% vehicle with injection volume of 4 μL/g body weight. ..

    Incubation:

    Article Title: Indoxyl sulfate induces left ventricular hypertrophy via the AhR-FGF23-FGFR4 signaling pathway
    Article Snippet: .. The cells were incubated with 0, 0.25, or 1.0 mM IS or 0, 50, or 100 ng/mL recombinant mouse FGF23 (2629-FG; R&D Systems, Minneapolis, MN) diluted in normal saline (NS) and collected after 24 and 72 h for real-time reverse transcription-polymerase chain reaction and western blotting, respectively. .. To perform small interfering RNA (siRNA) knockdown, the cells were transfected with On-TARGETplus SMARTpool siRNA [non-targeting control, aryl hydrocarbon receptor (AhR), and FGF23; Horizon Discovery, Cambridge, UK] using Dharmafect 1 reagent (Horizon Discovery) in accordance with the manufacturer’s instructions.

    Article Title: Indoxyl sulfate induces left ventricular hypertrophy via the AhR-FGF23-FGFR4 signaling pathway.
    Article Snippet: .. The cells were incubated with 0, 0.25, or 1.0 mM IS or 0, 50, or 100 ng/mL recombinant mouse FGF23 (2629-FG; R&D Systems, Minneapolis, MN) diluted in normal saline (NS) and collected after 24 and 72 h for real-time reverse transcription-polymerase chain reaction and western blotting, respectively. .. To perform small interfering RNA (siRNA) knockdown, the cells were transfected with On-TARGETplus SMARTpool siRNA [non-targeting control, aryl hydrocarbon receptor (AhR), and FGF23; Horizon Discovery, Cambridge, UK] using Dharmafect 1 reagent (Horizon Discovery) in accordance with the manufacturer’s instructions.

    Saline:

    Article Title: Indoxyl sulfate induces left ventricular hypertrophy via the AhR-FGF23-FGFR4 signaling pathway
    Article Snippet: .. The cells were incubated with 0, 0.25, or 1.0 mM IS or 0, 50, or 100 ng/mL recombinant mouse FGF23 (2629-FG; R&D Systems, Minneapolis, MN) diluted in normal saline (NS) and collected after 24 and 72 h for real-time reverse transcription-polymerase chain reaction and western blotting, respectively. .. To perform small interfering RNA (siRNA) knockdown, the cells were transfected with On-TARGETplus SMARTpool siRNA [non-targeting control, aryl hydrocarbon receptor (AhR), and FGF23; Horizon Discovery, Cambridge, UK] using Dharmafect 1 reagent (Horizon Discovery) in accordance with the manufacturer’s instructions.

    Article Title: Fibroblast Growth Factor 23 Exacerbates Cardiac Fibrosis in Deoxycorticosterone Acetate-Salt Mice With Hypertension.
    Article Snippet: At this time, a microinfusion pump (iPRECIO model SMP-300; Primetech Corp), which permits quantitative pharmacology in the right jugular vein using a catheter in single animals, was implanted into the DOCA-salt mice to allow continuous intravenous (CIV) infusion of reagents. .. The mice were infused with phosphate-buffered saline for 4 days after implantation, followed by CIV infusion of phosphatebuffered saline (group V), recombinant mouse FGF23 (80 mg/kg/ d; R&D Systems, Inc; group F), or recombinant FGF23 and calcitriol (0.4 mg/kg/d intraperitoneally 3 times per week) (group C) for 10 days. ..

    Reverse Transcription Polymerase Chain Reaction:

    Article Title: Indoxyl sulfate induces left ventricular hypertrophy via the AhR-FGF23-FGFR4 signaling pathway
    Article Snippet: .. The cells were incubated with 0, 0.25, or 1.0 mM IS or 0, 50, or 100 ng/mL recombinant mouse FGF23 (2629-FG; R&D Systems, Minneapolis, MN) diluted in normal saline (NS) and collected after 24 and 72 h for real-time reverse transcription-polymerase chain reaction and western blotting, respectively. .. To perform small interfering RNA (siRNA) knockdown, the cells were transfected with On-TARGETplus SMARTpool siRNA [non-targeting control, aryl hydrocarbon receptor (AhR), and FGF23; Horizon Discovery, Cambridge, UK] using Dharmafect 1 reagent (Horizon Discovery) in accordance with the manufacturer’s instructions.

    Article Title: Indoxyl sulfate induces left ventricular hypertrophy via the AhR-FGF23-FGFR4 signaling pathway.
    Article Snippet: .. The cells were incubated with 0, 0.25, or 1.0 mM IS or 0, 50, or 100 ng/mL recombinant mouse FGF23 (2629-FG; R&D Systems, Minneapolis, MN) diluted in normal saline (NS) and collected after 24 and 72 h for real-time reverse transcription-polymerase chain reaction and western blotting, respectively. .. To perform small interfering RNA (siRNA) knockdown, the cells were transfected with On-TARGETplus SMARTpool siRNA [non-targeting control, aryl hydrocarbon receptor (AhR), and FGF23; Horizon Discovery, Cambridge, UK] using Dharmafect 1 reagent (Horizon Discovery) in accordance with the manufacturer’s instructions.

    Western Blot:

    Article Title: Indoxyl sulfate induces left ventricular hypertrophy via the AhR-FGF23-FGFR4 signaling pathway
    Article Snippet: .. The cells were incubated with 0, 0.25, or 1.0 mM IS or 0, 50, or 100 ng/mL recombinant mouse FGF23 (2629-FG; R&D Systems, Minneapolis, MN) diluted in normal saline (NS) and collected after 24 and 72 h for real-time reverse transcription-polymerase chain reaction and western blotting, respectively. .. To perform small interfering RNA (siRNA) knockdown, the cells were transfected with On-TARGETplus SMARTpool siRNA [non-targeting control, aryl hydrocarbon receptor (AhR), and FGF23; Horizon Discovery, Cambridge, UK] using Dharmafect 1 reagent (Horizon Discovery) in accordance with the manufacturer’s instructions.

    Article Title: Indoxyl sulfate induces left ventricular hypertrophy via the AhR-FGF23-FGFR4 signaling pathway.
    Article Snippet: .. The cells were incubated with 0, 0.25, or 1.0 mM IS or 0, 50, or 100 ng/mL recombinant mouse FGF23 (2629-FG; R&D Systems, Minneapolis, MN) diluted in normal saline (NS) and collected after 24 and 72 h for real-time reverse transcription-polymerase chain reaction and western blotting, respectively. .. To perform small interfering RNA (siRNA) knockdown, the cells were transfected with On-TARGETplus SMARTpool siRNA [non-targeting control, aryl hydrocarbon receptor (AhR), and FGF23; Horizon Discovery, Cambridge, UK] using Dharmafect 1 reagent (Horizon Discovery) in accordance with the manufacturer’s instructions.



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    ( a ) Treatment of neonatal rat ventricular myocyte cardiobundles with fibroblast growth factor (FGF) 23 for 20 minutes significantly increased contractile force, whereas 7 days of chronic treatment led to a significant reduction in contractile force that could be rescued by coapplication of BLU9931, a selective FGFR4 inhibitor. ( b ) Electrophysiological function was evaluated by pacing of cardiobundles and application of Di-4-ANEPPS (6-[2-(N,N-Dibutylamino)naphthyl]ethenyl-4′-pyridinium propanesulfonate) as voltage-sensitive dye. Chronic exposure of cardiobundles to FGF23 lead to significantly longer action potential durations. ( c ) FGF23-treated bundles exhibited significantly lower conduction velocity that was normalized after coapplication of BLU9931. Besides functional changes, chronic FGF23 treatment also led to cardiobundle hypertrophy, indicated by the ( d,g ) significant increase in cross-section and ( e ) increased expression of hypertrophic mRNA markers Rcan1 and Trpc6 . Increased expression of Rcan1 and Trpc6 was blocked by parallel treatment with BLU9931. ( f ) Metabolic transcription factors that were increased in chronic kidney disease mice also increased in cardiobundles after FGF23 treatment. ( g ) Representative images of cardiobundles indicate cellular hypertrophy after FGF23 treatment by increased myocyte cross-sections. Bars = 10 μm. ( h ) Gene set enrichment analysis of control and FGF23-treated cardiobundles showed an enrichment of metabolic pathways, particularly fatty acid metabolism, adipogenesis, and cholesterol homeostasis. ( i ) Additional enrichment was detected in pathways related to mitochondrial function, such as oxidative phosphorylation, respiratory chain, organelle fission, and organelle inner membrane. Downregulated pathways after FGF23 treatment include angiogenesis, vascular development, tumor necrosis factor (TNF)-α signaling, and P53. Bar graphs represent mean ± SEM with individual values included in the graph. n ≥ 3 for all experiments. * P < 0.05, ** P < 0.005, **** P < 0.0001. APD, action potential duration; DAPI, 4′,6-diamidino-2-phenylindole; ES, enrichment score; FDR, false discovery rate; NES, normalized enrichment score. To optimize viewing of this image, please see the online version of this article at www.kidney-international.org .

    Journal: Kidney international

    Article Title: Fibroblast growth factor 23 and fibroblast growth factor receptor 4 promote cardiac metabolic remodeling in chronic kidney disease

    doi: 10.1016/j.kint.2025.01.024

    Figure Lengend Snippet: ( a ) Treatment of neonatal rat ventricular myocyte cardiobundles with fibroblast growth factor (FGF) 23 for 20 minutes significantly increased contractile force, whereas 7 days of chronic treatment led to a significant reduction in contractile force that could be rescued by coapplication of BLU9931, a selective FGFR4 inhibitor. ( b ) Electrophysiological function was evaluated by pacing of cardiobundles and application of Di-4-ANEPPS (6-[2-(N,N-Dibutylamino)naphthyl]ethenyl-4′-pyridinium propanesulfonate) as voltage-sensitive dye. Chronic exposure of cardiobundles to FGF23 lead to significantly longer action potential durations. ( c ) FGF23-treated bundles exhibited significantly lower conduction velocity that was normalized after coapplication of BLU9931. Besides functional changes, chronic FGF23 treatment also led to cardiobundle hypertrophy, indicated by the ( d,g ) significant increase in cross-section and ( e ) increased expression of hypertrophic mRNA markers Rcan1 and Trpc6 . Increased expression of Rcan1 and Trpc6 was blocked by parallel treatment with BLU9931. ( f ) Metabolic transcription factors that were increased in chronic kidney disease mice also increased in cardiobundles after FGF23 treatment. ( g ) Representative images of cardiobundles indicate cellular hypertrophy after FGF23 treatment by increased myocyte cross-sections. Bars = 10 μm. ( h ) Gene set enrichment analysis of control and FGF23-treated cardiobundles showed an enrichment of metabolic pathways, particularly fatty acid metabolism, adipogenesis, and cholesterol homeostasis. ( i ) Additional enrichment was detected in pathways related to mitochondrial function, such as oxidative phosphorylation, respiratory chain, organelle fission, and organelle inner membrane. Downregulated pathways after FGF23 treatment include angiogenesis, vascular development, tumor necrosis factor (TNF)-α signaling, and P53. Bar graphs represent mean ± SEM with individual values included in the graph. n ≥ 3 for all experiments. * P < 0.05, ** P < 0.005, **** P < 0.0001. APD, action potential duration; DAPI, 4′,6-diamidino-2-phenylindole; ES, enrichment score; FDR, false discovery rate; NES, normalized enrichment score. To optimize viewing of this image, please see the online version of this article at www.kidney-international.org .

    Article Snippet: Carrier-free recombinant mouse FGF23 (catalog number 2629-FG025/CF, R&D Systems) was used at 25 and 100 ng/ml.

    Techniques: Functional Assay, Expressing, Control, Phospho-proteomics, Membrane

    ( a,b ) Cultured neonatal rat ventricular myocytes (NRVMs) responded to 48 hours of fibroblast growth factor (FGF) 23 treatment with significant hypertrophy, indicated by increased cross-sectional area and expression of prohypertrophic markers. Prohypertrophic mRNA expression and cellular hypertrophy could be mitigated by parallel treatment with the FGFR4-specific inhibitor BLU9931. ( a ) Bar = 30 μm. ( c ) NRVMs treated with FGF23 for 1 hour, before observable hypertrophy takes place, were analyzed in a Seahorse XF analyzer for extracellular acidification rate (ECAR), elevated total proton efflux rates (PERs), and glycolysis-specific PER (GlycoPER). ECAR was significantly higher in FGF23-treated cells, which could be reduced to control levels by BLU9931. PER showed elevated basal and compensatory glycolysis on FGF23 treatment; glycolysis-specific proton efflux was also increased. These FGF23-mediated effects were blocked by BLU9931 application. ( c ) Graphs represent 3 independent experiments. ( d ) Seahorse mitochondrial stress test assay showed increased basal and maximal mitochondrial respiration after FGF23 treatment of NRVMs. Adenosine triphosphate (ATP) production-linked, spare respiratory capacity and nonmitochondrial oxygen consumption rate increased in parallel after FGF23 treatment. The significant decrease in coupling efficiency and the increased proton leak indicate uncoupling of substrate oxidation and ATP synthesis after 1 hour of FGF23 treatment. Application of BLU9931 or the calcineurin inhibitor, cyclosporin A, prevented the changes to mitochondrial function caused by FGF23. Bar graphs represent mean ± SEM and individual values included in the graph. n ≥ 9 for all experiments. * P < 0.05, ** P < 0.005, **** P < 0.0001. DMSO, dimethylsulfoxide; Max, maximum; NS, not significant; PBS, phosphate-buffered saline. To optimize viewing of this image, please see the online version of this article at www.kidney-international.org .

    Journal: Kidney international

    Article Title: Fibroblast growth factor 23 and fibroblast growth factor receptor 4 promote cardiac metabolic remodeling in chronic kidney disease

    doi: 10.1016/j.kint.2025.01.024

    Figure Lengend Snippet: ( a,b ) Cultured neonatal rat ventricular myocytes (NRVMs) responded to 48 hours of fibroblast growth factor (FGF) 23 treatment with significant hypertrophy, indicated by increased cross-sectional area and expression of prohypertrophic markers. Prohypertrophic mRNA expression and cellular hypertrophy could be mitigated by parallel treatment with the FGFR4-specific inhibitor BLU9931. ( a ) Bar = 30 μm. ( c ) NRVMs treated with FGF23 for 1 hour, before observable hypertrophy takes place, were analyzed in a Seahorse XF analyzer for extracellular acidification rate (ECAR), elevated total proton efflux rates (PERs), and glycolysis-specific PER (GlycoPER). ECAR was significantly higher in FGF23-treated cells, which could be reduced to control levels by BLU9931. PER showed elevated basal and compensatory glycolysis on FGF23 treatment; glycolysis-specific proton efflux was also increased. These FGF23-mediated effects were blocked by BLU9931 application. ( c ) Graphs represent 3 independent experiments. ( d ) Seahorse mitochondrial stress test assay showed increased basal and maximal mitochondrial respiration after FGF23 treatment of NRVMs. Adenosine triphosphate (ATP) production-linked, spare respiratory capacity and nonmitochondrial oxygen consumption rate increased in parallel after FGF23 treatment. The significant decrease in coupling efficiency and the increased proton leak indicate uncoupling of substrate oxidation and ATP synthesis after 1 hour of FGF23 treatment. Application of BLU9931 or the calcineurin inhibitor, cyclosporin A, prevented the changes to mitochondrial function caused by FGF23. Bar graphs represent mean ± SEM and individual values included in the graph. n ≥ 9 for all experiments. * P < 0.05, ** P < 0.005, **** P < 0.0001. DMSO, dimethylsulfoxide; Max, maximum; NS, not significant; PBS, phosphate-buffered saline. To optimize viewing of this image, please see the online version of this article at www.kidney-international.org .

    Article Snippet: Carrier-free recombinant mouse FGF23 (catalog number 2629-FG025/CF, R&D Systems) was used at 25 and 100 ng/ml.

    Techniques: Cell Culture, Expressing, Control, Saline

    Mouse primer sequences. The following oligonucleotides shown in 5′ to 3′ orientation were used as primers in quantitative real-time PCR analyses.

    Journal: Journal of Cardiovascular Development and Disease

    Article Title: FGFR4 Is Required for Concentric Growth of Cardiac Myocytes during Physiologic Cardiac Hypertrophy

    doi: 10.3390/jcdd11100320

    Figure Lengend Snippet: Mouse primer sequences. The following oligonucleotides shown in 5′ to 3′ orientation were used as primers in quantitative real-time PCR analyses.

    Article Snippet: We used recombinant murine FGF2 (3139-FB) and FGF23 (2629-FG/CF) proteins from R&D Systems.

    Techniques: Real-time Polymerase Chain Reaction, Sequencing

    Serum FGF23 levels are elevated in mice during late pregnancy. Wild-type and global FGFR4 knockout (FGFR4 −/− ) mice were investigated during late pregnancy (LP; 18 days post-mating) and compared to non-pregnant virgin littermates (NP). Serum FGF23 concentrations were measured via ELISA. Both ( A ) total FGF23 and ( B ) intact FGF23 were significantly elevated in the serum of wild-type (total **** p < 0.0001; intact ** p = 0.0014) and FGFR4 −/− mice (total **** p < 0.0001; intact **** p < 0.0001) when compared to their respective NP controls (n = 8–12 mice per genotype and timepoint). FGFR4 −/− LP mice exhibit significantly higher intact FGF23 compared to wild-type LP mice (** p = 0.0055). ( C ) The ratios of intact FGF23 over total FGF23 show no significant differences between groups (n = 8–12 mice per genotype and timepoint). ( D ) Cardiac tissue from LP mice showed significant decreases in Klotho expression in wild-type mice (* p = 0.0398) compared to wild-type NP mice, but there were no significant differences between NP and LP in FGFR4 −/− mice (n = 4–6 mice per genotype and timepoint). Cardiac tissue from wild-type mice in LP showed a significant decline in Fgfr1 mRNA levels (** p = 0.0026), while FGFR4 −/− mice had no significant change in expression when compared to their respective NP control mice (n = 6–9 mice per genotype and timepoint). Fgfr4 expression in cardiac tissue from wild-type mice in LP remained unaltered, compared to wild-type mice in LP (n = 7–8 mice per genotype and timepoint). RTqPCR analysis of tissue was conducted using Gapdh as a housekeeping gene. All values are shown as ±SD.

    Journal: Journal of Cardiovascular Development and Disease

    Article Title: FGFR4 Is Required for Concentric Growth of Cardiac Myocytes during Physiologic Cardiac Hypertrophy

    doi: 10.3390/jcdd11100320

    Figure Lengend Snippet: Serum FGF23 levels are elevated in mice during late pregnancy. Wild-type and global FGFR4 knockout (FGFR4 −/− ) mice were investigated during late pregnancy (LP; 18 days post-mating) and compared to non-pregnant virgin littermates (NP). Serum FGF23 concentrations were measured via ELISA. Both ( A ) total FGF23 and ( B ) intact FGF23 were significantly elevated in the serum of wild-type (total **** p < 0.0001; intact ** p = 0.0014) and FGFR4 −/− mice (total **** p < 0.0001; intact **** p < 0.0001) when compared to their respective NP controls (n = 8–12 mice per genotype and timepoint). FGFR4 −/− LP mice exhibit significantly higher intact FGF23 compared to wild-type LP mice (** p = 0.0055). ( C ) The ratios of intact FGF23 over total FGF23 show no significant differences between groups (n = 8–12 mice per genotype and timepoint). ( D ) Cardiac tissue from LP mice showed significant decreases in Klotho expression in wild-type mice (* p = 0.0398) compared to wild-type NP mice, but there were no significant differences between NP and LP in FGFR4 −/− mice (n = 4–6 mice per genotype and timepoint). Cardiac tissue from wild-type mice in LP showed a significant decline in Fgfr1 mRNA levels (** p = 0.0026), while FGFR4 −/− mice had no significant change in expression when compared to their respective NP control mice (n = 6–9 mice per genotype and timepoint). Fgfr4 expression in cardiac tissue from wild-type mice in LP remained unaltered, compared to wild-type mice in LP (n = 7–8 mice per genotype and timepoint). RTqPCR analysis of tissue was conducted using Gapdh as a housekeeping gene. All values are shown as ±SD.

    Article Snippet: We used recombinant murine FGF2 (3139-FB) and FGF23 (2629-FG/CF) proteins from R&D Systems.

    Techniques: Knock-Out, Enzyme-linked Immunosorbent Assay, Expressing, Control

    FGF23 is expressed in the heart during late pregnancy in mice. ( A ) In wild-type mice during late pregnancy (LP; 18 days post-mating), Fgf23 mRNA levels were not altered in bone or liver tissue compared to non-pregnancy (NP) (n = 5–6 mice per timepoint). ( B ) Cardiac tissue from LP mice showed significant increases in Fgf23 expression in both wild-type (* p = 0.0213) and FGFR4 knockout (FGFR4 −/− ) (* p = 0.0246) mice when compared to respective NP controls (n = 4–8 mice per genotype and timepoint). ( C ) In cardiac tissue of wild-type mice, no differences in the mRNA levels of the FGF23 regulatory genes Galnt3 , Furin , or Fam20c were observed between NP and LP (n = 7–8 mice per timepoint). ( D ) Bone tissue from wild-type mice showed no differences in mRNA levels of Galnt3 , Furin , or Fam20c (n = 5–6 mice per timepoint) in NP versus LP. RTqPCR analysis of tissue was conducted using Gapdh as a housekeeping gene. All values are shown as mean ± SD.

    Journal: Journal of Cardiovascular Development and Disease

    Article Title: FGFR4 Is Required for Concentric Growth of Cardiac Myocytes during Physiologic Cardiac Hypertrophy

    doi: 10.3390/jcdd11100320

    Figure Lengend Snippet: FGF23 is expressed in the heart during late pregnancy in mice. ( A ) In wild-type mice during late pregnancy (LP; 18 days post-mating), Fgf23 mRNA levels were not altered in bone or liver tissue compared to non-pregnancy (NP) (n = 5–6 mice per timepoint). ( B ) Cardiac tissue from LP mice showed significant increases in Fgf23 expression in both wild-type (* p = 0.0213) and FGFR4 knockout (FGFR4 −/− ) (* p = 0.0246) mice when compared to respective NP controls (n = 4–8 mice per genotype and timepoint). ( C ) In cardiac tissue of wild-type mice, no differences in the mRNA levels of the FGF23 regulatory genes Galnt3 , Furin , or Fam20c were observed between NP and LP (n = 7–8 mice per timepoint). ( D ) Bone tissue from wild-type mice showed no differences in mRNA levels of Galnt3 , Furin , or Fam20c (n = 5–6 mice per timepoint) in NP versus LP. RTqPCR analysis of tissue was conducted using Gapdh as a housekeeping gene. All values are shown as mean ± SD.

    Article Snippet: We used recombinant murine FGF2 (3139-FB) and FGF23 (2629-FG/CF) proteins from R&D Systems.

    Techniques: Expressing, Knock-Out

    Pregnant mice have increased serum phosphorus and calcium despite FGF23 elevations. ( A ) Serum phosphorus was significantly elevated during late pregnancy (LP; 18 days post-mating) in wild-type mice (* p = 0.0196; n = 14–19 mice per timepoint) and FGFR4 knockout (FGFR4 −/− ) mice (**** p < 0.0001; n = 8–11) when compared to non-pregnant (NP) mice. FGFR4 −/− LP mice have significantly higher serum phosphorus compared to wild-type LP mice (** p = 0.0093; n = 8–14). ( B ) Serum calcium was also significantly elevated in pregnant wild-type (*** p = 0.0001; n = 14–19) and FGFR4 −/− mice (** p = 0.0026; n = 9–12), compared to NP controls. FGFR4 −/− LP mice have significantly higher serum calcium compared to wild-type LP mice (* p = 0.0364; n = 9–14). Renal tissue from wild-type mice in LP exhibited no alterations in the mRNA levels of ( C ) sodium-dependent phosphate transporters Slc34a1 and Slc34a3 or of ( D ) Klotho , Fgfr1 , or Fgfr4 (n = 8 mice per timepoint). RTqPCR analysis of tissue was conducted using Gapdh as a housekeeping gene. All values are shown as mean ± SD.

    Journal: Journal of Cardiovascular Development and Disease

    Article Title: FGFR4 Is Required for Concentric Growth of Cardiac Myocytes during Physiologic Cardiac Hypertrophy

    doi: 10.3390/jcdd11100320

    Figure Lengend Snippet: Pregnant mice have increased serum phosphorus and calcium despite FGF23 elevations. ( A ) Serum phosphorus was significantly elevated during late pregnancy (LP; 18 days post-mating) in wild-type mice (* p = 0.0196; n = 14–19 mice per timepoint) and FGFR4 knockout (FGFR4 −/− ) mice (**** p < 0.0001; n = 8–11) when compared to non-pregnant (NP) mice. FGFR4 −/− LP mice have significantly higher serum phosphorus compared to wild-type LP mice (** p = 0.0093; n = 8–14). ( B ) Serum calcium was also significantly elevated in pregnant wild-type (*** p = 0.0001; n = 14–19) and FGFR4 −/− mice (** p = 0.0026; n = 9–12), compared to NP controls. FGFR4 −/− LP mice have significantly higher serum calcium compared to wild-type LP mice (* p = 0.0364; n = 9–14). Renal tissue from wild-type mice in LP exhibited no alterations in the mRNA levels of ( C ) sodium-dependent phosphate transporters Slc34a1 and Slc34a3 or of ( D ) Klotho , Fgfr1 , or Fgfr4 (n = 8 mice per timepoint). RTqPCR analysis of tissue was conducted using Gapdh as a housekeeping gene. All values are shown as mean ± SD.

    Article Snippet: We used recombinant murine FGF2 (3139-FB) and FGF23 (2629-FG/CF) proteins from R&D Systems.

    Techniques: Knock-Out

    FGFR4 inhibition abrogates cardiac myocyte hypertrophy induced by serum from fed pythons. Neonatal rat ventricular myocytes (NRVMs) were treated with media containing either vehicle, FGF2 (25 ng/mL), FGF23 (25 ng/mL), or serum from fasted or fed snakes (diluted to 2% of the total media volume), without or in combination with a small molecule inhibitor of FGFR4 (iFGFR4; BLU9931, 10 ng/mL), for 48 h. Compared to vehicle-treated NRVMs (Ctrl) or to NRVMs treated with serum from fasted pythons, serum collected from pythons twelve hours post-feeding (Python 12HPF; #### p < 0.0001) and three days post-feeding (Python 3DPF; #### p < 0.0001) induced a significant increase in myocyte area. When co-treated with iFGFR4 (textured bars), both Python 12HPF (**** p < 0.0001) and Python 3DPF (*** p = 0.0003) did not induce a significant increase in NRVM area when compared to the same treatment without iFGFR4. Python 12HPF ( $$$ p = 0.0003)- and Python 3DPF ( $$ p = 0.0016)-treated NRVMs had significantly increased myocyte area when compared to Python Fasted serum treatments. Treatment with recombinant FGF23 significantly increased myocyte area compared to Ctrl ( #### p < 0.0001), fasted python serum treatments ( $$$$ p < 0.0001), and FGF23 + iFGFR4 treatment (**** p < 0.0001) NRVMs. Treatment with recombinant FGF2 protein served as a positive control for hypertrophy ( ## p = 0.003). Treatment with serum from fasted and two-days-post-feeding water snakes (Water Snake Fasted, Water Snake 2DPF) served as negative controls Each individual color corresponds with the treatment indicated below the bars. # = versus Ctrl; * = versus same treatment + iFGFR4; $ = versus Python Fasted; 150 cells per condition; n = 3–4 independent isolations of NRVMs. All values are shown as mean ± SD.

    Journal: Journal of Cardiovascular Development and Disease

    Article Title: FGFR4 Is Required for Concentric Growth of Cardiac Myocytes during Physiologic Cardiac Hypertrophy

    doi: 10.3390/jcdd11100320

    Figure Lengend Snippet: FGFR4 inhibition abrogates cardiac myocyte hypertrophy induced by serum from fed pythons. Neonatal rat ventricular myocytes (NRVMs) were treated with media containing either vehicle, FGF2 (25 ng/mL), FGF23 (25 ng/mL), or serum from fasted or fed snakes (diluted to 2% of the total media volume), without or in combination with a small molecule inhibitor of FGFR4 (iFGFR4; BLU9931, 10 ng/mL), for 48 h. Compared to vehicle-treated NRVMs (Ctrl) or to NRVMs treated with serum from fasted pythons, serum collected from pythons twelve hours post-feeding (Python 12HPF; #### p < 0.0001) and three days post-feeding (Python 3DPF; #### p < 0.0001) induced a significant increase in myocyte area. When co-treated with iFGFR4 (textured bars), both Python 12HPF (**** p < 0.0001) and Python 3DPF (*** p = 0.0003) did not induce a significant increase in NRVM area when compared to the same treatment without iFGFR4. Python 12HPF ( $$$ p = 0.0003)- and Python 3DPF ( $$ p = 0.0016)-treated NRVMs had significantly increased myocyte area when compared to Python Fasted serum treatments. Treatment with recombinant FGF23 significantly increased myocyte area compared to Ctrl ( #### p < 0.0001), fasted python serum treatments ( $$$$ p < 0.0001), and FGF23 + iFGFR4 treatment (**** p < 0.0001) NRVMs. Treatment with recombinant FGF2 protein served as a positive control for hypertrophy ( ## p = 0.003). Treatment with serum from fasted and two-days-post-feeding water snakes (Water Snake Fasted, Water Snake 2DPF) served as negative controls Each individual color corresponds with the treatment indicated below the bars. # = versus Ctrl; * = versus same treatment + iFGFR4; $ = versus Python Fasted; 150 cells per condition; n = 3–4 independent isolations of NRVMs. All values are shown as mean ± SD.

    Article Snippet: We used recombinant murine FGF2 (3139-FB) and FGF23 (2629-FG/CF) proteins from R&D Systems.

    Techniques: Inhibition, Recombinant, Positive Control

    Figure 1. Dietary phosphate supplementation aggravates FGF23 excess and bone microarchitecture in Dmp1KO mice. Serum levels of (A) total FGF23 (cFGF23), (B) intact FGF23 (iFGF23), (C) intact to total FGF23 ratio (i/c FGF23), (D) parathyroid hormone (PTH), (E) 1,25-dihydroxyvitamin D [1,25(OH)2D], (F) calcium (Ca2+), and (G) phosphate (Pi); (H) fractional excretion of Pi (FePi); (I) body weight, (J) tail length, and (K) femur length; 3D-μCT scan reconstruction of (L) distal femur trabecular metaphysis (scale bar = 200 μm); (M) midshaft femur cortical diaphysis (scale bar = 500 μm); (N) 2D μCT analysis of cortical bone porosity (scale bar = 100 μm); (O) red fluorescence microscopy imaging of alizarin red S–stained (ARS-stained) mineralization fronts; (P) bright-field microscopy imaging of modified trichrome Goldner staining; and (Q) tartrate-resistant acidic phosphatase (TRAcP) staining of longitudinal histology sections of distal femur (scale bar = 100 μm for ARS, 500 μm for Goldner and TRAcP). All analyses were performed in 12-week-old WT (n ≥ 5) and Dmp1KO (n ≥ 5) mice fed a diet containing 0.7% Pi (normal Pi, NP) or 2% Pi (high Pi, HP) from 6 to 12 weeks of age. Values are expressed as mean ± SEM; P < 0.05 vs. aNP-WT, bHP-WT, cNP-Dmp1KO; P < 0.1 vs. dNP-WT, eHP-WT. Statistical tests were ANOVA test followed by post hoc t tests and multiple-testing correction using Holm-Bonferroni method.

    Journal: JCI insight

    Article Title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

    doi: 10.1172/jci.insight.156850

    Figure Lengend Snippet: Figure 1. Dietary phosphate supplementation aggravates FGF23 excess and bone microarchitecture in Dmp1KO mice. Serum levels of (A) total FGF23 (cFGF23), (B) intact FGF23 (iFGF23), (C) intact to total FGF23 ratio (i/c FGF23), (D) parathyroid hormone (PTH), (E) 1,25-dihydroxyvitamin D [1,25(OH)2D], (F) calcium (Ca2+), and (G) phosphate (Pi); (H) fractional excretion of Pi (FePi); (I) body weight, (J) tail length, and (K) femur length; 3D-μCT scan reconstruction of (L) distal femur trabecular metaphysis (scale bar = 200 μm); (M) midshaft femur cortical diaphysis (scale bar = 500 μm); (N) 2D μCT analysis of cortical bone porosity (scale bar = 100 μm); (O) red fluorescence microscopy imaging of alizarin red S–stained (ARS-stained) mineralization fronts; (P) bright-field microscopy imaging of modified trichrome Goldner staining; and (Q) tartrate-resistant acidic phosphatase (TRAcP) staining of longitudinal histology sections of distal femur (scale bar = 100 μm for ARS, 500 μm for Goldner and TRAcP). All analyses were performed in 12-week-old WT (n ≥ 5) and Dmp1KO (n ≥ 5) mice fed a diet containing 0.7% Pi (normal Pi, NP) or 2% Pi (high Pi, HP) from 6 to 12 weeks of age. Values are expressed as mean ± SEM; P < 0.05 vs. aNP-WT, bHP-WT, cNP-Dmp1KO; P < 0.1 vs. dNP-WT, eHP-WT. Statistical tests were ANOVA test followed by post hoc t tests and multiple-testing correction using Holm-Bonferroni method.

    Article Snippet: We cultured MC3T3-E1 (Subclone 4, CRL-2593, ATCC) osteoblasts for 21 days in osteoblast differentiation medium of similar composition containing 10 mmol/L bGP and 0/25/50 ng/mL of mouse recombinant FGF23 (R&D Systems).

    Techniques: Fluorescence, Microscopy, Imaging, Staining, Modification

    Figure 2. Osteocyte-specific deletion of Fgf23 fully corrects hypophosphatemia in Dmp1KO mice. Serum levels of (A) total FGF23 (cFGF23), (B) intact FGF23 (iFGF23), (C) intact to total FGF23 ratio (i/c FGF23), (D) parathyroid hormone (PTH), (E) 1,25-dihydroxyvitamin D [1,25(OH)2D], (F) calcium (Ca2+), and (G) phosphate (Pi); (H) fractional excretion of Pi (FePi); and kidney mRNA expression of (I) NaPi2a, (J) Cyp27b1, and (K) Cyp24a1 in 12-week-old WT (n ≥ 5), Fgf23Dmp1-cKO (n ≥ 5), Dmp1KO (n ≥ 3), and Dmp1KO Fgf23Dmp1-cKO (n ≥ 5) mice. Values are expressed as mean ± SEM; P < 0.05 vs. aWT,

    Journal: JCI insight

    Article Title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

    doi: 10.1172/jci.insight.156850

    Figure Lengend Snippet: Figure 2. Osteocyte-specific deletion of Fgf23 fully corrects hypophosphatemia in Dmp1KO mice. Serum levels of (A) total FGF23 (cFGF23), (B) intact FGF23 (iFGF23), (C) intact to total FGF23 ratio (i/c FGF23), (D) parathyroid hormone (PTH), (E) 1,25-dihydroxyvitamin D [1,25(OH)2D], (F) calcium (Ca2+), and (G) phosphate (Pi); (H) fractional excretion of Pi (FePi); and kidney mRNA expression of (I) NaPi2a, (J) Cyp27b1, and (K) Cyp24a1 in 12-week-old WT (n ≥ 5), Fgf23Dmp1-cKO (n ≥ 5), Dmp1KO (n ≥ 3), and Dmp1KO Fgf23Dmp1-cKO (n ≥ 5) mice. Values are expressed as mean ± SEM; P < 0.05 vs. aWT,

    Article Snippet: We cultured MC3T3-E1 (Subclone 4, CRL-2593, ATCC) osteoblasts for 21 days in osteoblast differentiation medium of similar composition containing 10 mmol/L bGP and 0/25/50 ng/mL of mouse recombinant FGF23 (R&D Systems).

    Techniques: Expressing

    Figure 3. Osteocyte-specific deletion of Fgf23 partially corrects bone growth in Dmp1KO mice. (A) Mouse gross appearance, (B) body weight, (C) tail length, (D) femur length, (E) femur gross appear- ance, and (F) 3D μCT representation of total femur in sagittal plane (scale bar = 1 mm) in 12-week- old WT (n ≥ 6), Fgf23Dmp1-cKO (n ≥ 5), Dmp1KO (n ≥ 5), and Dmp1KO Fgf23Dmp1-cKO (n ≥ 4) mice. Values are expressed as mean ± SEM; P < 0.05 vs. aWT,

    Journal: JCI insight

    Article Title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

    doi: 10.1172/jci.insight.156850

    Figure Lengend Snippet: Figure 3. Osteocyte-specific deletion of Fgf23 partially corrects bone growth in Dmp1KO mice. (A) Mouse gross appearance, (B) body weight, (C) tail length, (D) femur length, (E) femur gross appear- ance, and (F) 3D μCT representation of total femur in sagittal plane (scale bar = 1 mm) in 12-week- old WT (n ≥ 6), Fgf23Dmp1-cKO (n ≥ 5), Dmp1KO (n ≥ 5), and Dmp1KO Fgf23Dmp1-cKO (n ≥ 4) mice. Values are expressed as mean ± SEM; P < 0.05 vs. aWT,

    Article Snippet: We cultured MC3T3-E1 (Subclone 4, CRL-2593, ATCC) osteoblasts for 21 days in osteoblast differentiation medium of similar composition containing 10 mmol/L bGP and 0/25/50 ng/mL of mouse recombinant FGF23 (R&D Systems).

    Techniques:

    Figure 4. Osteocyte-specific deletion of Fgf23 partially restores bone microarchitecture in Dmp1KO mice. 3D μCT (A) scan reconstruction of distal femur trabecular metaphysis (scale bar = 500 μm) and (B–G) parameters of trabecular bone microarchitecture; (H) scan reconstruction of midshaft femur cortical diaphysis (scale bar = 500 μm) and (I–O) parameters of cortical bone microarchitecture. All analyses were performed in 12-week-old WT (n ≥ 5), Fgf23Dmp1-cKO (n ≥ 5), Dmp1KO (n ≥ 5), and Dmp1KO Fgf23Dmp1-cKO (n ≥ 5) mice. Values are expressed as mean ± SEM; P < 0.05 vs. aWT, bFgf23cKO, cDmp1KO. Statistical tests were ANOVA test followed by post hoc t tests and multiple-testing correction using Holm-Bonferroni method. BV/TV, bone volume to tissue volume ratio; Tb.N, trabecular number; Tb.Th, trabecular thickness; Tb.Sp, trabecular separation; Conn.Dens, connectivity density; SMI, structural model index; mat BMD, material bone mineral density; Ma.Ar, marrow area; CSA, cross-sectional area; Ct.Ar, cortical area; Ct.Th, cortical thickness; Ct.Po, cortical porosity.

    Journal: JCI insight

    Article Title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

    doi: 10.1172/jci.insight.156850

    Figure Lengend Snippet: Figure 4. Osteocyte-specific deletion of Fgf23 partially restores bone microarchitecture in Dmp1KO mice. 3D μCT (A) scan reconstruction of distal femur trabecular metaphysis (scale bar = 500 μm) and (B–G) parameters of trabecular bone microarchitecture; (H) scan reconstruction of midshaft femur cortical diaphysis (scale bar = 500 μm) and (I–O) parameters of cortical bone microarchitecture. All analyses were performed in 12-week-old WT (n ≥ 5), Fgf23Dmp1-cKO (n ≥ 5), Dmp1KO (n ≥ 5), and Dmp1KO Fgf23Dmp1-cKO (n ≥ 5) mice. Values are expressed as mean ± SEM; P < 0.05 vs. aWT, bFgf23cKO, cDmp1KO. Statistical tests were ANOVA test followed by post hoc t tests and multiple-testing correction using Holm-Bonferroni method. BV/TV, bone volume to tissue volume ratio; Tb.N, trabecular number; Tb.Th, trabecular thickness; Tb.Sp, trabecular separation; Conn.Dens, connectivity density; SMI, structural model index; mat BMD, material bone mineral density; Ma.Ar, marrow area; CSA, cross-sectional area; Ct.Ar, cortical area; Ct.Th, cortical thickness; Ct.Po, cortical porosity.

    Article Snippet: We cultured MC3T3-E1 (Subclone 4, CRL-2593, ATCC) osteoblasts for 21 days in osteoblast differentiation medium of similar composition containing 10 mmol/L bGP and 0/25/50 ng/mL of mouse recombinant FGF23 (R&D Systems).

    Techniques:

    Figure 5. Osteocyte-specific deletion of Fgf23 partially restores mineralization and lacuno-canalicular network in Dmp1KO mice. (A and B) High-resolu- tion μCT analysis of cortical bone porosity (scale bar = 100 μm), (C) acid-etched scanning electron microscopy of femur cortical bone (scale bar = 20 μm), (D) red fluorescence microscopy imaging of ARS-stained mineralization fronts (top), and bright-field microscopy imaging of modified trichrome Goldner staining (middle) and tartrate-resistant acidic phosphatase (TRAcP) staining (bottom) of longitudinal histology sections of distal femur (scale bar = 100 μm for ARS, 250 μm for Goldner and TRAcP). For each staining, top (×3.5 original magnification) and bottom (×1.8 original magnification) zoom-in panels represent regions of interest in trabecular and in cortical bone, respectively. All analyses were performed in 12-week-old WT (n ≥ 5), Fgf23Dmp1-cKO (n ≥ 5), Dmp1KO (n ≥ 5), and Dmp1KO Fgf23Dmp1-cKO (n ≥ 5) mice.

    Journal: JCI insight

    Article Title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

    doi: 10.1172/jci.insight.156850

    Figure Lengend Snippet: Figure 5. Osteocyte-specific deletion of Fgf23 partially restores mineralization and lacuno-canalicular network in Dmp1KO mice. (A and B) High-resolu- tion μCT analysis of cortical bone porosity (scale bar = 100 μm), (C) acid-etched scanning electron microscopy of femur cortical bone (scale bar = 20 μm), (D) red fluorescence microscopy imaging of ARS-stained mineralization fronts (top), and bright-field microscopy imaging of modified trichrome Goldner staining (middle) and tartrate-resistant acidic phosphatase (TRAcP) staining (bottom) of longitudinal histology sections of distal femur (scale bar = 100 μm for ARS, 250 μm for Goldner and TRAcP). For each staining, top (×3.5 original magnification) and bottom (×1.8 original magnification) zoom-in panels represent regions of interest in trabecular and in cortical bone, respectively. All analyses were performed in 12-week-old WT (n ≥ 5), Fgf23Dmp1-cKO (n ≥ 5), Dmp1KO (n ≥ 5), and Dmp1KO Fgf23Dmp1-cKO (n ≥ 5) mice.

    Article Snippet: We cultured MC3T3-E1 (Subclone 4, CRL-2593, ATCC) osteoblasts for 21 days in osteoblast differentiation medium of similar composition containing 10 mmol/L bGP and 0/25/50 ng/mL of mouse recombinant FGF23 (R&D Systems).

    Techniques: Electron Microscopy, Fluorescence, Microscopy, Imaging, Staining, Modification

    Figure 6. Osteocyte-specific deletion of Fgf23 restores osteoblast differentiation but does not restore impaired mineralization in Dmp1KO primary osteoblast cultures. Bone marrow stromal cells were isolated from 12-week-old WT (n ≥ 3), Fgf23Dmp1-cKO (n ≥ 3), Dmp1KO (n ≥ 3), and Dmp1KO Fgf23Dmp1-cKO (n ≥ 4) mice, then cultured for 14 (D14) and 21 (D21) days in osteoblast differentiation medium containing 3, 7, or 10 mM of beta-glycerophosphate (bGP). Levels of (A) total DMP1 (cDMP1) and (B) total FGF23 (cFGF23) in conditioned media collected at D21. (C and D) Alkaline phosphatase (ALP) staining and quantification and (E and F) alizarin red S (ARS) staining and quantification. Values are expressed as mean ± SEM; P < 0.05 vs. bGP treatment–matched

    Journal: JCI insight

    Article Title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

    doi: 10.1172/jci.insight.156850

    Figure Lengend Snippet: Figure 6. Osteocyte-specific deletion of Fgf23 restores osteoblast differentiation but does not restore impaired mineralization in Dmp1KO primary osteoblast cultures. Bone marrow stromal cells were isolated from 12-week-old WT (n ≥ 3), Fgf23Dmp1-cKO (n ≥ 3), Dmp1KO (n ≥ 3), and Dmp1KO Fgf23Dmp1-cKO (n ≥ 4) mice, then cultured for 14 (D14) and 21 (D21) days in osteoblast differentiation medium containing 3, 7, or 10 mM of beta-glycerophosphate (bGP). Levels of (A) total DMP1 (cDMP1) and (B) total FGF23 (cFGF23) in conditioned media collected at D21. (C and D) Alkaline phosphatase (ALP) staining and quantification and (E and F) alizarin red S (ARS) staining and quantification. Values are expressed as mean ± SEM; P < 0.05 vs. bGP treatment–matched

    Article Snippet: We cultured MC3T3-E1 (Subclone 4, CRL-2593, ATCC) osteoblasts for 21 days in osteoblast differentiation medium of similar composition containing 10 mmol/L bGP and 0/25/50 ng/mL of mouse recombinant FGF23 (R&D Systems).

    Techniques: Isolation, Cell Culture, Staining

    Figure 7. Canonical pathways altered in Dmp1KO osteoblasts are differentially regulated by FGF23 and by DMP1. Bulk RNA-sequencing analysis was performed on bone marrow stromal cells isolated from 12-week-old WT (n = 3), Fgf23Dmp1-cKO (n = 3), Dmp1KO (n = 3), and Dmp1KO Fgf23Dmp1-cKO (n = 3) mice and cultured for 21 days in osteoblast differentiation medium containing 10 mM of beta-glycerophosphate. (A) Venn diagram identifies genes showing altered expression in Dmp1KO but not in Dmp1KO Fgf23cKO osteoblasts (tan area). Heatmaps represent the expression of (B) Fgf23 and (C) genes identified in A and used in Ingenuity Pathway Analysis (IPA; QIAGEN) to define the most represented canonical pathways regulated by FGF23. (D) Venn diagram identifies genes showing altered expression in Dmp1KO and in Dmp1KO Fgf23cKO osteoblasts (burgundy area). Heatmaps represent the expression of (E) Dmp1 and (F) genes identified in D and used in IPA to define the most represented canonical pathways regulated by DMP1. Statistical tests were unpaired t test and corrected by the false discovery rate (P < 0.1).

    Journal: JCI insight

    Article Title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

    doi: 10.1172/jci.insight.156850

    Figure Lengend Snippet: Figure 7. Canonical pathways altered in Dmp1KO osteoblasts are differentially regulated by FGF23 and by DMP1. Bulk RNA-sequencing analysis was performed on bone marrow stromal cells isolated from 12-week-old WT (n = 3), Fgf23Dmp1-cKO (n = 3), Dmp1KO (n = 3), and Dmp1KO Fgf23Dmp1-cKO (n = 3) mice and cultured for 21 days in osteoblast differentiation medium containing 10 mM of beta-glycerophosphate. (A) Venn diagram identifies genes showing altered expression in Dmp1KO but not in Dmp1KO Fgf23cKO osteoblasts (tan area). Heatmaps represent the expression of (B) Fgf23 and (C) genes identified in A and used in Ingenuity Pathway Analysis (IPA; QIAGEN) to define the most represented canonical pathways regulated by FGF23. (D) Venn diagram identifies genes showing altered expression in Dmp1KO and in Dmp1KO Fgf23cKO osteoblasts (burgundy area). Heatmaps represent the expression of (E) Dmp1 and (F) genes identified in D and used in IPA to define the most represented canonical pathways regulated by DMP1. Statistical tests were unpaired t test and corrected by the false discovery rate (P < 0.1).

    Article Snippet: We cultured MC3T3-E1 (Subclone 4, CRL-2593, ATCC) osteoblasts for 21 days in osteoblast differentiation medium of similar composition containing 10 mmol/L bGP and 0/25/50 ng/mL of mouse recombinant FGF23 (R&D Systems).

    Techniques: RNA Sequencing, Isolation, Cell Culture, Expressing

    Figure 9. FGF23 targets osteoprogenitors via FGFR/ERK/PI3K signaling. Single-cell RNA-sequencing analysis was performed on bone marrow stromal cells isolated from 12-week-old WT (n = 3), Fgf23Dmp1-cKO (n = 3), Dmp1KO (n = 3), and Dmp1KO Fgf23Dmp1-cKO (n = 3) mice and cultured for 21 days in osteoblast differentiation medium containing 10 mM of beta-glycerophosphate. (A) Venn diagram identifies genes showing altered expression in Dmp1KO but not in Dmp1KO Fgf23cKO osteoblasts (colored area) in each cluster of differentiation. (B) Heatmaps represent the expression of genes identified in A in the osteo- progenitor cluster (green dot) and used in Ingenuity Pathway Analysis (IPA) to define the most represented canonical pathways regulated by FGF23. (C–J) Violin plots representing the expression of most regulated target genes in Dmp1KO and corrected in Dmp1KO Fgf23cKO osteoprogenitors. (K) IPA gene network analysis showing most connected gene targets in the osteoprogenitor cluster and identifying FGF receptor 1 (FGFR1), ERK1/2, and PI3K/AKT as common regulators of these targets. Statistical tests were Mann-Whitney’s U test and corrected by the false discovery rate (P < 0.1).

    Journal: JCI insight

    Article Title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

    doi: 10.1172/jci.insight.156850

    Figure Lengend Snippet: Figure 9. FGF23 targets osteoprogenitors via FGFR/ERK/PI3K signaling. Single-cell RNA-sequencing analysis was performed on bone marrow stromal cells isolated from 12-week-old WT (n = 3), Fgf23Dmp1-cKO (n = 3), Dmp1KO (n = 3), and Dmp1KO Fgf23Dmp1-cKO (n = 3) mice and cultured for 21 days in osteoblast differentiation medium containing 10 mM of beta-glycerophosphate. (A) Venn diagram identifies genes showing altered expression in Dmp1KO but not in Dmp1KO Fgf23cKO osteoblasts (colored area) in each cluster of differentiation. (B) Heatmaps represent the expression of genes identified in A in the osteo- progenitor cluster (green dot) and used in Ingenuity Pathway Analysis (IPA) to define the most represented canonical pathways regulated by FGF23. (C–J) Violin plots representing the expression of most regulated target genes in Dmp1KO and corrected in Dmp1KO Fgf23cKO osteoprogenitors. (K) IPA gene network analysis showing most connected gene targets in the osteoprogenitor cluster and identifying FGF receptor 1 (FGFR1), ERK1/2, and PI3K/AKT as common regulators of these targets. Statistical tests were Mann-Whitney’s U test and corrected by the false discovery rate (P < 0.1).

    Article Snippet: We cultured MC3T3-E1 (Subclone 4, CRL-2593, ATCC) osteoblasts for 21 days in osteoblast differentiation medium of similar composition containing 10 mmol/L bGP and 0/25/50 ng/mL of mouse recombinant FGF23 (R&D Systems).

    Techniques: RNA Sequencing, Isolation, Cell Culture, Expressing

    Figure 10. FGF23 directly inhibits osteoblast differentiation. (A–C) mRNA expression of markers of osteoblast differentiation in MC3T3-E1 osteoblasts cultured for 21 days and treated with recombinant FGF23 (0, 25, and 50 ng/mL) for the last 6 and 48 hours of culture (n ≥ 4). Levels of (D) total DMP1 (cDMP1) and (E) total FGF23 (cFGF23) measured by ELISA in conditioned culture media from bone marrow stromal cells (BMSCs) isolated from 12-week-old WT (n ≥ 4), Fgf23Dmp1-cKO (n ≥ 5), Dmp1KO (n ≥ 5), and Dmp1KO Fgf23Dmp1-cKO (n ≥ 5) mice, then cocultured for 21 days with BMSCs iso- lated from the same group (isogenic), or immor- talized BMSCs displaying genetic overexpression of Fgf23 (Fgf23TG) or Dmp1 (Dmp1TG). (F and G) Alkaline phosphatase (ALP) staining and quanti- fication and (H and I) alizarin red S (ARS) staining and quantification. Values are expressed as mean ± SEM; P < 0.05 vs. (A–C) time point–matched

    Journal: JCI insight

    Article Title: FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice.

    doi: 10.1172/jci.insight.156850

    Figure Lengend Snippet: Figure 10. FGF23 directly inhibits osteoblast differentiation. (A–C) mRNA expression of markers of osteoblast differentiation in MC3T3-E1 osteoblasts cultured for 21 days and treated with recombinant FGF23 (0, 25, and 50 ng/mL) for the last 6 and 48 hours of culture (n ≥ 4). Levels of (D) total DMP1 (cDMP1) and (E) total FGF23 (cFGF23) measured by ELISA in conditioned culture media from bone marrow stromal cells (BMSCs) isolated from 12-week-old WT (n ≥ 4), Fgf23Dmp1-cKO (n ≥ 5), Dmp1KO (n ≥ 5), and Dmp1KO Fgf23Dmp1-cKO (n ≥ 5) mice, then cocultured for 21 days with BMSCs iso- lated from the same group (isogenic), or immor- talized BMSCs displaying genetic overexpression of Fgf23 (Fgf23TG) or Dmp1 (Dmp1TG). (F and G) Alkaline phosphatase (ALP) staining and quanti- fication and (H and I) alizarin red S (ARS) staining and quantification. Values are expressed as mean ± SEM; P < 0.05 vs. (A–C) time point–matched

    Article Snippet: We cultured MC3T3-E1 (Subclone 4, CRL-2593, ATCC) osteoblasts for 21 days in osteoblast differentiation medium of similar composition containing 10 mmol/L bGP and 0/25/50 ng/mL of mouse recombinant FGF23 (R&D Systems).

    Techniques: Expressing, Cell Culture, Recombinant, Enzyme-linked Immunosorbent Assay, Isolation, Over Expression, Staining

    Figure 10. Transcriptional implications of treatments at Cyp27b1. ChIP-Seq analysis near Cyp27b1 for (A) BRD4, (B) RNA polymerase II, and (C) H3K36me3 from WT mice injected with 230 mg/kg bw PTH (30 min, PTH30), 30 mg/kg bw YKL-05 to 099 (1 h), 40 mg/kg bw SK-124 (1 h), 10 mg/kg bw 1,25(OH)2D3 (1 h), or 50 mg/kg bw FGF23 (1 h). Additional details as for Figure 2. Genomic region displayed is chr10: 126,469,260 to 126,490,800. bw, body weight; ChIP- Seq, chromatin immunoprecipitation; FGF23, fibroblast growth factor 23; 1,25(OH)2D3, 1,25-dihydroxyvitamin D3; PTH, parathyroid hormone.

    Journal: The Journal of biological chemistry

    Article Title: Rapid genomic changes by mineralotropic hormones and kinase SIK inhibition drive coordinated renal Cyp27b1 and Cyp24a1 expression via CREB modules.

    doi: 10.1016/j.jbc.2022.102559

    Figure Lengend Snippet: Figure 10. Transcriptional implications of treatments at Cyp27b1. ChIP-Seq analysis near Cyp27b1 for (A) BRD4, (B) RNA polymerase II, and (C) H3K36me3 from WT mice injected with 230 mg/kg bw PTH (30 min, PTH30), 30 mg/kg bw YKL-05 to 099 (1 h), 40 mg/kg bw SK-124 (1 h), 10 mg/kg bw 1,25(OH)2D3 (1 h), or 50 mg/kg bw FGF23 (1 h). Additional details as for Figure 2. Genomic region displayed is chr10: 126,469,260 to 126,490,800. bw, body weight; ChIP- Seq, chromatin immunoprecipitation; FGF23, fibroblast growth factor 23; 1,25(OH)2D3, 1,25-dihydroxyvitamin D3; PTH, parathyroid hormone.

    Article Snippet: The following reagents were used for in vivo injections: 1α,25(OH)2D3 was obtained from SAFC Global, PTH (1–84 human) was obtained from Bachem (H-1370.0100), mouse FGF23 from R&D Systems (2629-FG-025), YKL-05-099 (27), and SK-124 (26).

    Techniques: ChIP-sequencing, Injection, Chromatin Immunoprecipitation