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P Molnar and L J Murphy


Previous studies have established that the IGFs are involved in oestrogen-induced uterine proliferation. IGF-binding proteins (IGFBPs) are present in most biological fluids and tissues and may modulate the actions of the IGFs. We examined uterine, hepatic and renal expression of the IGFBPs throughout the oestrous cycle and investigated the effects of oestradiol (OE2) on IGFBP expression in ovariectomized (ovx) rats. Uterine expression of IGFBPs-1 and -3 showed a definite variation throughout the oestrous cycle with highest levels during dioestrus. In the liver and kidney the changes in IGFBP-1 and IGFBP-3 mRNA abundance were the opposite of those observed in the uterus, with the highest levels observed during oestrus. Administration of OE2 to ovx rats decreased uterine IGFBP-3 mRNA and increased IGFBP-4 mRNA levels. In these rats there were no consistent changes in renal IGFBP-1 or IGFBP-3 mRNAs; however, a significant increase in IGFBP-4 mRNA was observed in this tissue, as in the uterus. In the liver an increase in IGFBP-1 mRNA and a decrease in IGFBP-3 mRNA levels were observed in rats treated with OE2. Despite changes in uterine, hepatic and renal IGFBP mRNA levels, no significant variation was seen in serum IGFBPs as determined by ligand blotting of sera. These data demonstrate that there is a cyclical variation in the expression of the IGFBPs in the uterus, kidney and liver, and that OE2 is able to modulate differentially IGFBP expression in these tissues.

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L J Murphy, P Molnar, X Lu, and H Huang


Transgenic mice which expressed human IGF-binding protein-3 (hIGFBP-3) were generated by pronuclear injection of an hIGFBP-3 cDNA driven by the mouse metallothionein 1 promoter. Two of the seven founder mice had measurable levels of hIGFBP-3 in the circulation. The serum levels of hIGFBP-3 increased as the mice were bred to homozygosity and were further induced by supplementing the drinking water with 25 mm ZnCl2. While the birth weight, litter size and body weight of transgenic mice were not significantly different from non-transgenic litter mates or wild-type mice derived from the same genetic background, the transgenic mice demonstrated selective organomegaly. The spleen, liver and heart of mice derived from both founders were significantly heavier compared with organs from non-transgenic mice (P<0·05, P<0·005 and P<0·01 respectively). The weights of the brain and kidney were similar in transgenic and non-transgenic mice. Expression of the transgene was detected in the kidney, small intestine and colon by Northern blot analysis.

Western ligand blotting of serum from transgenic mice did not demonstrate any change in the abundance of the IGFBPs detected by this method. When serum from transgenic mice was incubated with 125I-labeled IGF-I and analyzed by Sephacryl S-200 chromatography under neutral conditions a significantly (P<0·05) increased amount of the radioactivity was found in the 140 kDa ternary complex compared with serum from wild-type mice. Immunoreactive hIGFBP-3 was detected in the 140 kDa ternary complex but the majority of immunoreactive hIGFBP-3 present in transgenic mouse serum eluted in later fractions indicating that it was not associated with the acid-labile subunit. These data demonstrate that modest constitutive expression of hIGFBP-3 has a selective effect on organ growth and development. The establishment of these IGFBP-3 transgenic mouse strains may provide useful models to investigate further the physiological role of IGFBP-3.