Context: NF-kappaB is a family of transcription factors involved in cell proliferation, differentiation, and apoptosis.
Objective: We have recently demonstrated that NF-kappaB 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-kappaB pathway exhibit growth failure, which suggests a possible regulatory role for NF-kappaB in statural growth. We have previously reported a child with ectodermal dysplasia, immunodeficiency, and growth retardation, harboring a heterozygous mutation of IkappaBalpha, an essential component of the NF-kappaB pathway. Since he was found with low IGF-l and IGFBP-3, and elevated GH secretion, an IGF-l generation test was carried out: baseline IGF-l 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-l induced cell proliferation and NF-kappaB 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 IkappaBalpha mutation), GH and IGF-l elicited an attenuated stimulatory effect. In addition, GH stimulated STAT5 phosphorylation and IGF-l mRNA expression in controls ' and the father's fibroblasts, while IGF-l 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-l in the patient's fibroblasts.
Conclusion: Our findings suggest that this patient's IkappaBalpha mutation caused GH and IGF-l resistance which, in turn, contributed to his growth failure.