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Growth hormone/JAK-STAT axis signal-transduction defect. A novel treatable cause of growth failure

Andrea P Rojas-Gil1, Panos G Ziros, Leonor Diaz

  • 1Division of Pediatric Endocrinology, Department of Pediatrics, University of Patras School of Medicine, Greece.

The FEBS Journal
|August 4, 2006
PubMed

Insights

Idiopathic short stature in children may stem from impaired growth hormone signaling. High doses of human growth hormone effectively treated this condition by restoring signal transducer and activator of transcription-3 (STAT3) activation.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Idiopathic short stature (ISS) is a complex condition.
  • Growth hormone (GH) resistance can contribute to growth delay.
  • The role of STAT3 signaling in GH response is not fully understood.

Purpose of the Study:

  • To investigate the role of signal transducer and activator of transcription-3 (STAT3) in idiopathic short stature.
  • To explore the effect of human growth hormone (hGH) on STAT3 activation in patients with ISS.
  • To identify potential therapeutic strategies for ISS.

Main Methods:

  • Primary fibroblast cultures from four ISS patients were analyzed.
  • Western blotting was used to assess protein levels and STAT3 activation.
  • Cell cycle analysis was performed.
  • In vitro and in vivo responses to human growth hormone were evaluated.

Main Results:

  • Fibroblasts from ISS patients showed reduced STAT3 activation and cell-cycle arrest.
  • Elevated p21(WAF/CIPI) and reduced cyclin levels were observed in ISS patients.
  • High-dose hGH treatment restored STAT3 activation and normalized p21(WAF/CIPI) levels in vitro.
  • Exogenous hGH significantly increased growth velocity in treated children.

Conclusions:

  • ISS may be linked to a functional defect in the GH signaling pathway involving STAT3.
  • High-dose hGH therapy can overcome this signaling aberration and improve growth.
  • This study provides a novel therapeutic insight for specific cases of idiopathic short stature.

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