Background: Fibroblast growth factor 21 (FGF21) is a key metabolic regulator in the adaptation to fasting. In food-restricted mice, inhibition of skeletal growth appears to be mediated by the antagonistic effect of FGF21 on GH action in the liver and in the growth plate (Kubicky et al. 2012, Yu et al. 2012). The role of FGF21 in growth regulation in humans is currently unknown.
Objective and hypothesis: To provide mechanistic insights into the reduced caloric intake associated with GH insensitivity and growth failure we hypothesized that FGF21 inhibits GH action in human chondrocytes by blocking post-receptor GH signaling.
Methods: We established chondrocyte primary cultures from costal cartilage of pediatric patients undergoing reconstructive surgery. We first assessed the integrity of the GH-receptor and IGF1 receptor signaling by western blotting, and expression of the FGF21 receptor complex by RT-PCR. Next we tested the effect of recombinant FGF21 on basal and GH-induced suppressor of cytokine signaling 2 (SOCS2) expression, basal and GH-induced IGF1 expression by qPCR, and basal and GH/IGF1-induced cell proliferation by Methylene Blue assay.
Results: Human chondrocyte cultures expressed GH-receptor and responded to recombinant to GH and IGF1 through phosphorylation of ERK1/2, AKT and STAT5, and expressed the complex FGFR1c/βKLOTHO, the preferred FGF21 receptor. FGF21 significantly up-regulated basal and GH-induced SOCS2 expression. FGF21 also inhibited GH-induced IGF1 expression and cell proliferation, but did not affect IGF1-induced cell proliferation.
Conclusion: FGF21 blocks GH action in human chondrocytes by inhibiting post-receptor signaling involving induction of SOCS2 and inhibition of IGF1 expression. These data provide a new mechanistic insight into GH resistance secondary to reduced caloric intake.
13 Nov 2013
British Society for Paediatric Endocrinology and Diabetes