Endocrine Abstracts (2005) 9 P85

Tissue specific regulation of IGF-1 expression by GH

BW Ogunkolade1, S Khalaf1, PA Kelly1, SA Bustin2, P Kelly3, N Binart3, JJ Kopchick4 & PJ Jenkins1


1Division of Endocrinology, William Harvey Research Institute, St. Bartholomew's Hospital, London, UK; 2Academic Department of Surgery, The Royal London Hospital, London, UK; 3Unite 584, Faculte de Medecine Necker-Enfants Malades, Paris, France; 4Biotechnology Institute and Department of Biomedical Sciences, Ohio University, Athens, Ohio, USA.


Introduction:

Hepatic IGF-I is generally believed to be regulated by pituitary-derived GH. However recent studies have emphasized the importance of paracrine/autocrine IGF-I in normal growth and development, as well as some malignancies. However, it remains unclear how locally produced IGF-I is regulated. The aim of this project was to investigate IGF-I expression in different tissues from the growth hormone receptor knock-out (GHR-KO) mouse.

Methods:

Total RNA were extracted from frozen tissue samples (liver, colon, breast, muscle, heart and small bowel) obtained from nine GHR-KO and eight wild type (Wt) mice. Gene-specific primers and probes to IGF-I, IGFIR, GH, GHR and IGFBP3 were designed. mRNA expression levels to these genes were quantified by real-time RT-PCR. Immunohistochemistry was performed on tissue slides using standard protocol.

Results:

IGF-I mRNA expression was significantly higher in the liver and breast of the Wt (median copy number per microgram total RNA of 2.32E+07 and 6.91E+06 respectively) compared to GHR-KO (respectively 4.54E+06 and 1.71E+06 copy number per microgram total RNA; p<0.002). There was no difference in IGF-I mRNA levels in the colon, heart, muscle and small bowel. IHC confirmed these results at a protein level. Liver samples from GHR-KO mice had significantly higher levels of IGF-IR mRNA than livers from the Wt mice (median copy number per microgram total RNA of 2.23E+05 and 4.18E+04 respectively, p<0.05). There was no difference in IGF-IR mRNA expression between GHR-KO and Wt mice in other tissues studied. GHR mRNA level was observed in the GHR-KO mice compared to the Wt in all tissues.

Conclusions:

The reduction in hepatic and breast IGF-I mRNA expression in the GHR-KO mice suggests that the regulation is predominantly dependent on the GH/GHR axis with some GH/GHR independent basal IGF-I expression. This GH/GHR independent axis appears to be regulating IGF-I expression in the colon and other tissues.

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