The effect of GH treatment on serum FGF23 and Klotho in GH-deficient children

Efthymiadou, Alexandra; Kritikou, Dimitra; Mantagos, Stefanos; Chrysis, Dionisios

doi:10.1530/eje-15-1018

Cited by 12 publications

(16 citation statements)

References 31 publications

(40 reference statements)

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“…In agreement with other studies, our study showed that cFGF23 increases after GH therapy [ 25 , 40 ]. However, previous studies also reported an increase in serum phosphate concentrations, which was not observed in the present study.…”

Section: Discussionsupporting

confidence: 93%

“…These results are in line with previous studies showing that GH therapy increases α-Klotho concentrations in GH deficient, paediatric and adult patients [ 24 , 25 ]. Although the increment of α-Klotho concentrations was more prominent in the small study group of Locher et al.…”

Section: Discussionsupporting

confidence: 93%

“…Recent data showed a complex relationship between growth hormone (GH) and α-Klotho concentrations [ 23 ]. Whether IGF-1 or GH directly affects α-Klotho concentrations is still unknown, although small pilot studies showed that GH replacement therapy in both children and adults with GH deficiency increased α-Klotho concentrations [ 24 , 25 ]. However, the effect of administration of exogenous GH on the α-Klotho concentration in subjects with CKD and healthy controls is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Influence of exogenous growth hormone administration on circulating concentrations of α-klotho in healthy and chronic kidney disease subjects: a prospective, single-center open case-control pilot study

Adema

Zuijdewijn

Hoenderop³

et al. 2018

BMC Nephrol

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BackgroundThe CKD-associated decline in soluble α-Klotho (α-Klotho) levels is considered detrimental. Some studies suggest a direct induction of α-Klotho concentrations by growth hormone (GH). In the present study, the effect of exogenous GH administration on α-Klotho concentrations in a clinical cohort with mild chronic kidney disease (CKD) and healthy subjects was studied.MethodsA prospective, single-center open case-control pilot study was performed involving 8 patients with mild CKD and 8 healthy controls matched for age and sex. All participants received subcutaneous GH injections (Genotropin®, 20 mcg/kg/day) for 7 consecutive days. α-Klotho concentrations were measured at baseline, after 7 days of therapy and 1 week after the intervention was stopped.Resultsα-Klotho concentrations were not different between CKD-patients and healthy controls at baseline (554 (388–659) vs. 547 (421–711) pg/mL, P = 0.38). Overall, GH therapy increased α-Klotho concentrations from 554 (405–659) to 645 (516–754) pg/mL, P < 0.05). This was accompanied by an increase of IGF-1 concentrations from 26.8 ± 5.0 nmol/L to 61.7 ± 17.7 nmol/L (P < 0.05). GH therapy induced a trend toward increased α-Klotho concentrations both in the CKD group (554 (388–659) to 591 (358–742) pg/mL (P = 0.19)) and the healthy controls (547 (421–711) pg/mL to 654 (538–754) pg/mL (P = 0.13)). The change in α-Klotho concentration was not different for both groups (P for interaction = 0.71). α-Klotho concentrations returned to baseline levels within one week after the treatment (P < 0.05).ConclusionsGH therapy increases α-Klotho concentrations in subjects with normal renal function or stage 3 CKD. A larger follow-up study is needed to determine whether the effect size is different between both groups or in patients with more severe CKD.Trial registrationThis trial is registered in EudraCT (2013–003354-24).Electronic supplementary materialThe online version of this article (10.1186/s12882-018-1114-z) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Influence of exogenous growth hormone administration on circulating concentrations of α-klotho in healthy and chronic kidney disease subjects: a prospective, single-center open case-control pilot study

Adema

Zuijdewijn

Hoenderop³

et al. 2018

BMC Nephrol

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“…PD0325901 administration blocked this pathway completely, and it is of note that addition of GH treatment did not reverse this effect or the elevation of FGF23 serum levels. In agreement with these results, former studies have found a positive correlation between GH and FGF23 levels (32,33), probably mediated by the signal transducer and activator of transcription pathway. However, MAPK i treatment reduced, although did not normalize, circulating FGF23 concentrations even in the Hyp-MAPK i -GH group.…”

Section: Discussionsupporting

confidence: 88%

MAPK inhibition and growth hormone: a promising therapy in XLH

et al. 2019

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X‐linked hypophosphatemia (XLH) leads to growth retardation and bone deformities, which are not fully avoided by conventional treatment with phosphate and vitamin D analogs. Pediatric patients have been treated with growth hormone (GH), and recent findings suggest that blocking fibroblast growth factor 23 actions may be the most effective therapy, but its effects on growth are not known. We here report the effect of MAPK inhibition alone or associated with GH on growth and growth plate and bone structure of young Hyp (the XLH animal model) mice. Untreated Hyp mice were severely growth retarded and had marked alterations in both growth plate structure and dynamics as well as defective bone mineralization. GH accelerated growth and improved mineralization and the cortical bone, but it failed in normalizing growth plate and trabecular bone structures. MAPK inhibition improved growth and rickets and, notably, almost normalized the growth plate organization. The administration of a MAPK pathway inhibitor plus GH was the most beneficial treatment because of the positive synergistic effect on growth plate and bone structures. Thus, the growth‐promoting effect of GH is likely linked to increased risk of bone deformities, whereas the association of GH and MAPK inhibition emerges as a promising new therapy for children with XLH.—Fuente, R., Gil‐Peña, H., Claramunt‐Taberner, D., Hernández‐Frías, O., Fernández‐Iglesias, Á., Alonso‐Durán, L., Rodríguez‐Rubio, E., Hermida‐Prado, F., Anes‐González, G., Rubio‐Aliaga, I., Wagner, C, Santos, F. MAPK inhibition and growth hormone: a promising therapy in XLH. FASEB J. 33,8349–8362 (2019). http://www.fasebj.org

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“…Bone growth requires a positive phosphate balance, and IGF1 indeed elevates serum phosphate concentration by stimulating renal phosphate reabsorption and calcitriol formation (44), which are effects expected to enhance FGF23 production. In line with this, a positive association of IGF1 with FGF23 was observed (45), and an elevation of FGF23 was found in patients with acromegaly (46) and in GH-deficient children treated with recombinant GH (47,48). Therefore, IGF1 may have opposing effects on FGF23: A direct FGF23-lowering effect was demonstrated in our study, limiting the indirect FGF23-stimulating actions of IGF1, which may otherwise counteract its phosphate-retaining effect.…”

Section: Discussionsupporting

confidence: 85%

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

Bär

Feger

Fajol

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

103

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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.

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The effect of GH treatment on serum FGF23 and Klotho in GH-deficient children

Cited by 12 publications

References 31 publications

Influence of exogenous growth hormone administration on circulating concentrations of α-klotho in healthy and chronic kidney disease subjects: a prospective, single-center open case-control pilot study

Influence of exogenous growth hormone administration on circulating concentrations of α-klotho in healthy and chronic kidney disease subjects: a prospective, single-center open case-control pilot study

MAPK inhibition and growth hormone: a promising therapy in XLH

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

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