Growth inhibition in giant growth hormone transgenic mice by overexpression of insulin-like growth factor-binding protein-2

To clarify the role of insulin-like growth factor (IGF)-binding protein-2 ( IGFBP-2) in postnatal growth regulation, we crossed hemizygous CMV-IGFBP-2 transgenic mice with hemizygous PEPCK-bGH transgenic mice, which are charac terized by serum GH levels in the range of 2 mug/ml. Four genetic groups we re obtained: animals carrying both transgenes (GB), the GH (G) or the IGFBP -2 transgene (B), and nontransgenic controls (C). Male offspring were analy zed for serum levels of IGF-I, for serum and tissue levels of IGFBP-2, and for body and organ growth. Serum IGF-I levels were 2- to 3-fold increased ( P < 0.001) in the GH-overexpressing groups, with no difference between G an d GB mice. Serum IGFBP-2 levels were 4- to 9-fold (P < 0.001) increased bot h in B and GB vs. C and G mice. Western immunoblot analysis did not reveal differences in tissue IGFBP-2 levels between B and GB mice. IGFBP-2 levels were highest in pancreas, followed by skeletal muscle, heart, kidney, brain , skin, and spleen. No elevation of IGFBP-2 was found in the liver. Body we ight gain of G and GB mice was significantly increased vs. C and B mice, re sulting in almost 2-fold increased body weights at the age of 15 weeks. How ever, there was a significant reduction in body weight of GB vs. G mice (17 %; P < 0.001) and of B vs. C mice (13%; P < 0.05). This was primarily cause d by a marked reduction of carcass weight (GB us. G, 27%; B us. C, 21%; P < 0.001). Measurements of nose-rump-length, organ (brain, heart, spleen, liv er, pancreas, kidney), and tissue weights (skin, carcass, abdominal fat) in 5- and 15-week-old mice revealed several indications that the growth-inhib iting effect of IGFBP-2 overexpression was more marked in high-GH/IGF-I mic e: 1) At 5 weeks of age, GB mice displayed a significant reduction of all g rowth parameters except for the weight of abdominal fat, when compared with G mice, whereas only brain weight was significantly reduced in B vs. C mic e. 2) In 15-week-old animals, a significant reduction in all growth paramet ers, except for spleen and abdominal fat weights, was seen in GB us. G mice , whereas only nose-rump-length and the weights of carcass and brain were s ignificantly reduced in B vs. C mice. Our study demonstrates, for the first time, the potential of IGFBP-2 to inhibit GH-stimulated growth in giant tr ansgenic mice, providing further evidence for an inhibitory effect of this IGFBP in vivo.