Background: Infants born small for gestational age (SGA) usually show catch up growth within the first few years of life. However in the UK ~1500 SGA children each year remain small, with no clear endocrine cause with rare genetic syndromes accounting for only a minority of cases. In order to define growth factor activation in these children we have initiated an assessment of cell growth and signalling in response to GH and IGF1 in fibroblast cell lines.
Methods: Skin biopsies were obtained with local ethics approval from healthy children (n=4) and SGA children without post-natal catch up growth (n=4). Fibroblasts were isolated and cell growth measured by cell counting and BrdU incorporation, and apoptosis by TUNEL staining. Growth factor signalling was assessed by western blotting for both total and phospho isoforms of MAPK, Akt and Stat5b.
Results: Under basal and GH stimulated conditions proliferation in SGA cells is comparable to controls, whereas response to IGF1 is significantly reduced. However when treated with a combination of GH and IGF1 SGA cells grew at a similar rate to controls, with cell proliferation much greater than with GH alone. Apoptosis was also increased in SGA cells compared to controls. Stat5b, Akt and MAPK were present at similar levels in SGA and control cells. Stat5b activation by GH was decreased in SGA cells compared to controls while activation of MAPK was similar. A different pattern of IGF1 induced Akt activation was found with Akt 2 activation occurring in SGA but not control cells.
Conclusion: Decreased IGF1 stimulated cell growth, increased rates of apoptosis and altered GH and IGF1 signalling are associated with a non catch up SGA phenotype. The combination of GH and IGF1 rescues poor cellular growth, which may suggest a role for such combination treatment in vivo in these patients.