title: Skin fibroblasts of children with idiopathic short stature show an increased mitogenic response to IGF-I and secrete more IGFBP-3.
abstract: OBJECTIVE
  To study differences in cellular parameters of GH and IGF-I responsiveness in skin fibroblasts of 14 children with idiopathic short stature (ISS) treated with recombinant human GH and 13 children with normal height. Secondly, to investigate whether these cellular parameters can predict the growth response to GH treatment in children with ISS.
  
  
  METHODS
  The mitogenic responsiveness to GH and IGF-I was investigated by 3H-Thymidine incorporation. Insulin-like growth factor binding protein-3 (IGFBP-3) levels in the media were measured by radioimmunoassay (RIA).
  
  
  RESULTS
  No significant mitogenic responses were observed to various doses of GH (1000, 5000 or 50.000 ng/ml) in children with ISS or controls. ISS fibroblasts showed an increased mitogenic response to IGF-I (10 ng/ml) compared to controls (mean +/- SD 5.9 +/- 2.4- vs. 4.2 +/- 1.5-fold stimulation, P < 0.05), and GH enhanced this effect in both groups. IGFBP-3 secretion was increased in ISS fibroblasts when compared to controls under all conditions examined (basal, 200 and 5000 ng/ml GH, 10 ng/ml IGF-I for 24 and 48 h). High IGFBP-3 levels were related to low mitogenic responses to IGF-I or to GH + IGF-I in children with ISS (r = -0.7, P < 0.05), but not in controls. Within the ISS group, an enhanced mitogenic response to IGF-I in vitro was related to more extreme short stature before GH treatment (r = -0.70, P < 0.05) and to a relatively impaired response to high dose GH treatment in vivo (r = -0.52, P < 0.05).
  
  
  CONCLUSIONS
  The demonstration of high IGFBP-3 levels and enhanced mitogenic response to IGF-I shows that ISS fibroblasts have different cellular characteristics compared to controls of normal height. It is hypothesized that in ISS an alteration of the signal transduction pathway between the GH receptor and IGFBP-3 synthesis results in a local imbalance with high IGFBP-3 levels and lower IGF-I availability for the IGF-I receptor. This may be reflected by an increased IGF-I responsiveness in vitro which is associated with an impaired capacity to grow in vivo.
authors.affiliation: Department of Pediatrics, Leiden University Medical Center J6-204, PO Box 9600, 2300 RC Leiden, the Netherlands. clauskamp@wanadoo.nl
authors.forename: Gerdine A
authors.initials: GA
authors.lastname: Kamp
authors.forename: D M
authors.initials: DM
authors.lastname: Ouwens
authors.forename: C M
authors.initials: CM
authors.lastname: Hoogerbrugge
authors.forename: A H
authors.initials: AH
authors.lastname: Zwinderman
authors.forename: J A
authors.initials: JA
authors.lastname: Maassen
authors.forename: J M
authors.initials: JM
authors.lastname: Wit
mesh_terms: D000293:Adolescent; D018929:Cell Culture Techniques; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006130:Growth Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019382:Human Growth Hormone / Q000627:therapeutic use; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008938:Mitosis / Q000187:drug effects; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I