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Human Insulin-Like Growth Factor (IGF) Binding Protein-1 Inhibits IGF-I-Stimulated Body Growth but Stimulates Growth of the Kidney in Snell Dwarf Mice

Department of Pediatric Endocrinology (S.C.v.B.-O., J.G.K., M.G.G., C.M.H., R.J.B., J.A.K.), University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands; and Laboratory of Pediatrics (M.v.K., D.J.L.-K., S.L.S.D., J.W.N.), Subdivision of Molecular Endocrinology, Erasmus University, 3015 GD Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: S. C. van Buul-Offers, University Medical Center Utrecht, Wilhelmina Children’s Hospital, Department of Pediatric Endocrinology, Room KC3.063.0, P.O. Box 85090, 3508 AB Utrecht, The Netherlands. E-mail: s.vanbuul{at}wkz.azu.nl

The actions of insulin-like growth factor-I (IGF-I) are modulated by IGF binding proteins (IGFBPs). The effects of IGFBP-1 in vivo are insufficiently known, with respect to inhibitory or stimulatory actions on IGF-induced growth of specific organs. Therefore, we studied the effects of IGFBP-1 on IGF-I-induced somatic and organ growth in pituitary-deficient Snell dwarf mice. Human GH, IGF-I, IGFBP-1, and a preequilibrated combination of equimolar amounts of IGF-I and IGFBP-1 were administered sc during 4 weeks.

Treatment with IGF-I alone induced a significant increase in body length (108% of control) and weight (112%) as well as an increase in weight of the submandibular salivary glands (135%), kidneys (124%), femoral muscles (111%), testes (129%), and spleen (126%) compared with saline-treated controls. IGFBP-1 alone induced a significant increase in weight of the kidneys (152% of control). Coadministration of IGF-I with IGFBP-1 neutralized the stimulating effects of IGF-I on body length and weight as well as on the femoral muscles and testes. In contrast, the weights of the submandibular salivary glands (143%) were not significantly different from those of IGF-I-treated animals, whereas the weights of the kidneys (171%) and spleen (156%) were significantly increased compared with IGF-I-treated mice. The effect of IGFBP-1 plus IGF-I on kidney weight was not significantly greater than the effect of IGFBP-1 alone.

Western ligand blotting showed induction of the IGFBP-3 doublet as well as IGFBPs with molecular masses of 24 kDa, most probably IGFBP-4, by human GH, IGF-I alone, and IGF-I in combination with IGFBP-1.

Our data show that coadministration of IGFBP-1 inhibits IGF-I-induced body growth of GH-deficient mice but significantly stimulates the growth promoting effects of IGF-I on the kidneys and the spleen. These data warrant further investigation because differences in concentrations of IGFBP-1 occurring in vivo may influence IGF-I-induced anabolic processes.

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