Αρνητική ρύθμιση της μεταβίβασης του σήματος της αυξητικής ορμόνης σε παιδιά με ανεπάρκεια αύξησης

Abstract

Growth Hormone (GH) plays an important role in postnatal linear growth, skeletal development, protein, lipid and carbohydrate metabolism, bone turnover and immune function. Defects in the GH secretion and function in children can cause growth retardation. Several clinical entities of growth retardation have been described, including defects in pituitary GH secretion, spontaneous 24h GH secretion, GH receptor number or function, post-receptor signaling and IGF-I synthesis or function. In this study, one patient with Growth Hormone Transduction Defect (GHTD) was studied. GHTD is characterized by severe short stature with normal provoked and spontaneous GH secretion, low IGF-I concentrations, impaired phosphorylation of the transcriptional factor STAT3 and overexpression of the cyclin-dependent kinase inhibitor, p21. Furthermore, GHTD patients have significantly increased IGF-I concentrations after induction with hGH during the IGF-I generation test, and significant ‘catch-up’ growth after hGH therapy. No mutations were found in STAT3, GHR and GH1 gene in the GHTD patients. Primary fibroblast cultures were established from gingival biopsies obtained from the GHTD patient and one control. The GH signaling molecules and the negative regulators of GH were studied, as well as the role of protein CIS in the impaired GH signaling and the effect of CIS silencing on GH signaling. Furthermore, the possible crosstalk between the GH and EGF signaling cascades was examined, as well as its role in the restoration of the impaired GH signaling and the clinical response after therapy with exogenous hGH. The protein expression of the studied molecules was studied by Western Immunoblotting, their cellular localization by Immunofluoresence and the protein-protein interactions by Co-immunoprecipitation. The results of this study support the hypothesis that impaired GH signaling in GHTD children is mediated by the overexpression of ubiquitinated CIS, which causes rapid and excessive translocation of the GHR to the proteasomes for degradation. The results also showed that the restoration of physiological GH signaling after the silencing of CIS involves the restoration of the GHR to the plasma membrane for normal activation by GH, as well as the activation of the EGFR pathway. In addition, there is vigorous crosstalking between the GH and EGF signaling pathways during exogenous hGH treatment in the GHTD children, resulting in the accelerated growth seen in these children after hGH therapy.