Growth hormone signaling in fibroblasts from newborn boys and prepubertal boys

• In this revised manuscript, we show that GH-sensitivity is attenuated in newborn versus prepubertal boys using the skin fibroblast cell in vitro model in boys.
• This is the first molecular approach that would explain why infants grow so quickly following birth, at a time when serum GH levels are very high, but serum IGF-I levels are relatively low, an unusual situation that is not observed at any other time during postnatal life.
• The attenuation on GH signaling observed in fibroblasts of newborns appears to be related to a reduction in GHR content and a lack of JAK2/STAT5 phosphorylation in response to rhGH stimulation.

Background/aimResponsiveness to GH in target cells is mediated by its receptor, which activates the Janus kinase-2 (JAK2) and STAT5 (signal transducers and activators of transcription 5) leading to the expression of IGF-1 and IGFALS. The aim of this study was to compare the GH signaling pathway in newborns and prepubertal boys.Subjects and methodsWe determined the GHR protein content and the effect of stimulation with recombinant human GH (rhGH; 200 ng/mL) on JAK2 and STAT5 phosphorylation in skin fibroblast cultures obtained from newborns and prepubertal boys. The transcript levels of IGFALS and IGF-I, were also studied and compared after 16 h or 24 h of stimulation with GH in both study groups.ResultsNewborn infants showed less GHR protein than the prepubertal boys. After rhGH stimulation, JAK2 and STAT5 phosphorylation was absent in skin fibroblasts from newborns, but was clearly detectable in prepubertal boys. After 16 h of treatment with rhGH, IGFALS and IGF-I transcript levels increased in the prepubertal boys when compared to baseline. In newborns, however, we did not observe a response after 16 and 24 h of rhGH stimulation.ConclusionThe significant attenuation of the GH signaling pathway observed in fibroblasts from newborn boys appears to be related to a reduction in GHR content and lack of phosphorylation of JAK2 and STAT5 in response to rhGH. This might impair STAT5 dimer formation, leading to a reduction in the transcript levels of IGFALS and IGF-I during the newborn period.