Growth Hormone and Insulin-Like Growth Factor I Insensitivity of Fibroblasts Isolated from a Patient with an I kappa B alpha Mutation

Abstract

Context: NF-kappa B is a family of transcription factors involved in cell proliferation, differentiation, and apoptosis. Objective: We have recently demonstrated that NF-kappa B is expressed in the growth plate and it mediates the growth-promoting effects of IGF-I on chondrogenesis and longitudinal bone growth. Humans with defects of the NF-kappa B pathway exhibit growth failure, which suggests a possible regulatory role for NF-kappa B in statural growth. We have previously reported a child with ectodermal dysplasia, immunodeficiency, and growth retardation, harboring a heterozygous mutation of I kappa B alpha, an essential component of the NF-kappa B pathway. Since he was found with low IGF-I and IGFBP-3, and elevated GH secretion, an IGF-I generation test was carried out: baseline IGF-I was low and only responded to a high dose of GH. Thus, the diagnosis of GH resistance was made. Results: To assess the underlying mechanisms of his GH resistance, we cultured the patient's skin fibroblasts with GH and/or IGF-I. While both GH and IGF-I induced cell proliferation and NF-kappa B activity in controls' fibroblasts, they had no effect on the patient's fibroblasts. In the fibroblasts of the patient's father (who displays mosaicism for the I kappa B alpha mutation), GH and IGF-I elicited an attenuated stimulatory effect. In addition, GH stimulated STAT5 phosphorylation and IGF-I mRNA expression in controls' and the father's fibroblasts, while IGF-I induced PI3K activity and mRNA and protein expression of TDAG51, a target gene for IGF-I. In contrast, none of these effects was elicited by GH or IGF-I in the patient's fibroblasts. Conclusion: Our findings suggest that this patient's I kappa B alpha mutation caused GH and IGF-I resistance which, in turn, contributed to his growth failure. (J Clin Endocrinol Metab 95: 1220-1228, 2010)Transplantation and immunomodulatio