Journal article
Growth Hormone and Insulin-Like Growth Factor I Insensitivity of Fibroblasts Isolated from a Patient with an I kappa B alpha Mutation
The journal of clinical endocrinology and metabolism, v 95(3), pp 1220-1228
01 Mar 2010
PMID: 20080849
Featured in Collection : UN Sustainable Development Goals @ Drexel
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)
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Details
- Title
- Growth Hormone and Insulin-Like Growth Factor I Insensitivity of Fibroblasts Isolated from a Patient with an I kappa B alpha Mutation
- Creators
- Shufang Wu - St. Christopher's Hospital for ChildrenMarie J. Walenkamp - Leiden University Medical CenterArjan Lankester - Leiden University Medical CenterMartin Bidlingmaier - Ludwig-Maximilians-Universität MünchenJan M. Wit - Leiden University Medical CenterFrancesco De Luca - St. Christopher's Hospital for Children
- Publication Details
- The journal of clinical endocrinology and metabolism, v 95(3), pp 1220-1228
- Publisher
- Endocrine Soc
- Number of pages
- 9
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pediatrics; College of Medicine
- Web of Science ID
- WOS:000275197500029
- Scopus ID
- 2-s2.0-77749239998
- Other Identifier
- 991019169712304721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Endocrinology & Metabolism