ESPEYB17 5. Bone, Growth Plate and Mineral Metabolism Translational Highlights (3 abstracts)
5.8. Glucocorticoids decrease longitudinal bone growth in pediatric kidney transplant recipients by stimulating the FGF23/FGFR3 signaling pathway
Delucchi Á , Toro L , Alzamora R , Barrientos V , González M , Andaur R , León P , Villanueva F , Galindo M , Las Heras F , Montecino M , Moena D , Lazcano A , Pinto V , Salas P , Reyes ML , Mericq V & Michea L
Division of Nephrology, Department of Medicine, Hospital Clínico Universidad de Chile, Santiago, Chile
To read the full abstract: J Bone Miner Res. 2019;34(10):1851–1861.
In brief: In a pediatric kidney transplant cohort, glucocorticoid treatment was independently associated with FGF23 levels. Using in vivo and in vitro rat model systems, blocking of Fgfr signalling rescued glucocorticoid-induced skeletal manifestations.
Commentary: The deleterious effects of chronic glucocorticoid (GC) treatment on the growing skeleton represent a major cause of short stature and secondary osteoporosis in children. Based on associations between GC intake and FGF23 levels in renal transplant patients, Delucchi et al. investigated a potential role of FGF23 in the pathogenesis of GC-induced skeletal symptoms. In a translational approach, the authors identified associations between GC-exposure, skeletal manifestations and FGF23 levels in a pediatric kidney transplant cohort. As expected, early GC-withdrawal was associated with improved height-z scores and BMD in renal transplant patients. Further, FGF23 levels positively correlated with GC-dosage independently of renal function, PTH and calcitriol levels. In a subsequent step, consistent with their hypothesis, they found a stimulating effect of GCs on skeletal FGF23 expression. Blocking of FGFR3, the major receptor for FGF23 action, rescued the phenotype including normalization of linear growth and histologic growth plate phenotype. In addition, local administration of a FGFR antagonist (PD173074) completely ameliorated the growth inhibiting effect of GCs in growing rats.
With the combination of clinical and animal data, these authors approached the immanent clinical challenge of GC-induced bone disease. The identification of FGF23 as a potential player in the deleterious effects of GC on the skeleton opens the perspective of pharmacologic interventions, including FGFR3 inhibition or FGF23-blocking antibodies, as modulators of the described mechanisms. Although the precise regulation of GC-induced FGF23 expression remains unclear, the work of Delucchi et al. raise a new alternative in the development of treatments to improve skeletal health in patients with chronic GC-treatment.
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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