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J Bone Miner Res. 2019 May 17. doi: 10.1002/jbmr.3761. [Epub ahead of print]

Glucocorticoids Decrease Longitudinal Bone Growth in Paediatric Kidney Transplant Recipients by Stimulating the FGF23/FGFR3 Signalling Pathway.

Author information

1
Division of Nephrology, Hospital Luis Calvo Mackenna, Santiago, Chile.
2
Division of Nephrology, Clínica Alemana de Santiago, Santiago, Chile.
3
Division of Nephrology, Department of Medicine, Hospital Clínico Universidad de Chile, Santiago, Chile.
4
Centro de Investigación Clínica Avanzada, Hospital Clínico Universidad de Chile, Santiago, Chile.
5
Clinica Las Condes, Santiago, Chile.
6
Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
7
Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile.
8
Millennium Institute on Immunology and Immunotherapy (MIII), Santiago, Chile.
9
Department of Anatomic Pathology, Hospital Clínico Universidad de Chile, Santiago, Chile.
10
Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andrés Bello, Santiago, Chile.
11
FONDAP Center for Genome Regulation, Universidad Andres Bello, Santiago, Chile.
12
Division of Nephrology, Hospital de Niños Roberto del Río, Santiago, Chile.
13
Pediatric Nephrology Unit, Hospital Doctor Exequiel González Cortés, Santiago, Chile.
14
Pediatric Endocrinology Unit, Pontificia Universidad Católica de Chile, Santiago, Chile.
15
Institute of Maternal and Child Research, Universidad de Chile, Santiago, Chile.

Abstract

Renal transplantation (RTx) is an effective therapy to improve clinical outcomes in paediatric patients with terminal chronic kidney disease. However, chronic immunosuppression with glucocorticoids (GC) reduces bone growth and mineral density. The mechanisms causing GC-induced growth impairment have not been fully clarified. Fibroblast growth factor 23 (FGF23) is a peptide hormone that regulates phosphate homeostasis and bone growth. In pathological conditions, FGF23 excess or abnormal FGF receptors (FGFR) activity leads to bone growth impairment. Experimental data indicates that FGF23 expression is induced by chronic GC exposure. Therefore, we hypothesize that GC impairs bone growth by increasing FGF23 expression, which has direct effects on bone growth plate. In a post-hoc analysis of a multicentric randomized clinical trial of prepubertal RTx children treated with early GC withdrawal or chronic GC treatment, we observed that GC withdrawal was associated with improvement in longitudinal growth and bone mineral density, and lower plasma FGF23 levels as compared to chronic GC group. In prepubertal rats, GC-induced bone growth retardation correlated with increased plasma FGF23 and bone FGF23 expression. Additionally, GC treatment decreased FGFR1 expression while increased FGFR3 expression in mouse tibiae explants. Blockage of FGF23 receptors using a pan-FGFR antagonist (PD173074), C-terminal FGF23 (FGF23180-205 ) which blocks the binding of FGF23 with FGFR-Klotho complex or a specific FGFR3 antagonist (P3), prevented GC-induced growth impairment in vitro. Finally, local administration of PD173074 into tibiae growth plate of GC-treated rats ameliorated cartilage growth impairment. These results show that GC treatment partially reduces longitudinal bone growth via upregulation of FGF23 and FGFR3 expression, thus suggesting that the FGF23/Klotho/FGFR3 axis at the growth plate could be a potential therapeutic target for the management of GC-induced growth impairment in children. This article is protected by copyright. All rights reserved.

KEYWORDS:

CLINICAL TRIALS; CORTICOSTEROIDS; PRECLINICAL STUDIES; PTH/VIT D/FGF23

PMID:
31099911
DOI:
10.1002/jbmr.3761

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