Background: Both undernutrition and chronic inflammation impair linear growth through resistance to GH. Fibroblast growth factor 21 (FGF21) is known as an important regulator of the metabolic adaptation to fasting. Elevated expression of FGF21, secondary to prolonged undernutrition has been identified to develop GH resistance and subsequent attenuation of skeletal growth and growth plate chondrogenesis in both mice and human. However, the mechanism of FGF21s actions remains largely unknown. Molecular understanding of this process may open avenues for novel therapeutic intervention to enhance linear growth of children with secondary GH resistance.
Objective and hypotheses: We envisage that elevated FGF21 exposure has a key role in GH resistance by direct action on human chondrocytes. The objective of this study is to unravel the mechanistic interplay of FGF21 in GH-receptor (GHR) signalling.
Method: Hek-293 stable lines were generated with human/mouse GHR over-expression. Time course evaluation with cycloheximide, without/with; GH and recombinant FGF21 treatment for 1 8 h revealed GHR half-life. Hek-293 human/mouse GHR cells were treated without/with; recombinant FGF21 and GH for 0, 10 or 30 minutes and assessed for signal transducer and activator of transcription 5 (STAT5) and phosphorylated-STAT5 expression.
Results: Validation of stable lines confirmed the expression of FGF21 receptor complex; FGFR1 iiiC/β-Klotho and the molecular integrity of GHR signalling. We identified two interrelated mechanisms for GH resistance after exposure to FGF21. i) FGF21 significantly reduced GHR half-life overtime. ii) GH induced the activation STAT5 phosphorylation and downstream signalling which was inhibited by FGF21 exposure. Future work will determine the role of FGF21 in GH resistance under chondrogenic differentiation.
Conclusion: Chronic FGF21 exposure increases GHR turnover and inhibits early upstream in GHR signalling, implicating a fundamental role for FGF21 in GH resistance secondary to chronic childhood conditions.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology