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Overexpression of Gly⁵⁶/Gly⁸⁰/Gly⁸¹-Mutant Insulin-Like Growth Factor-Binding Protein-3 in Transgenic Mice

Departments of Physiology (J.V.S., Y.G., S.M., A.L., L.J.M.) and Internal Medicine (L.J.M.), University of Manitoba, Winnipeg, Canada R3E 0W3; Center of Reproductive Medicine, Shenzhen Hospital of Peking University (Y.G.), Shenzhen 518036, Peoples Republic of China; and Division of Endocrinology, Department of Pediatrics, Mattel Children’s Hospital, University of California (P.C.), Los Angeles, California 90095-1752

Address all correspondence and requests for reprints to: Dr. L. J. Murphy, Department of Physiology, University of Manitoba, Winnipeg, Canada R3E 0W3. E-mail: ljmurph{at}cc.umanitoba.ca.

IGF-independent effects of IGF-binding protein-3 (IGFBP-3) have been demonstrated in vitro; however, the physiological significance of these effects in vivo is unclear. We generated two transgenic (Tg) mouse strains that overexpress a human Gly⁵⁶/Gly⁸⁰/Gly⁸¹-mutant IGFBP-3 cDNA. This mutant has a markedly reduced affinity for the IGFs, but retains the IGF-independent effects. Serum levels of mutant IGFBP-3 were 156 ± 12 and 400 ± 24 ng/ml in hemizygous mice of strains 5005 and 5012, respectively. When Tg and wild-type mice were compared, there was no reduction in birth weight, litter size, or postnatal growth. Despite differences in transgene expression in various tissues, relative organ weight was similar in Tg and wild-type mice, with exception of brain, where a modest reduction in brain weight was observed in the high-expressing 5012 lineage. There was also a significant reduction in proliferating cell nuclear antigen-staining cells observed in the periventricular region of the developing brain in embryonic d 18 Tg embryos. In the higher expressing 5012 Tg strain, IGF-I and murine IGFBP-3 levels, marker of GH action were increased. Furthermore, there was a positive correlation between mutant IGFBP-3 levels and IGF-I levels and between mutant IGFBP-3 levels and murine IGFBP-3 (P = 0.002 and P < 0.001, respectively). These data indicate that overexpression of mutant IGFBP-3 is not associated with growth retardation. The higher levels of IGF-I and murine IGFBP-3 in the 5012 Tg strain suggest that the growth inhibitory effect of mutant IGFBP-3 may be compensated for by other mechanisms.

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