Endocrinology, Vol 137, 447-454, Copyright © 1996 by Endocrine Society

ARTICLES

The human growth hormone (hGH) antagonist G120RhGH does not antagonize GH in the rat, but has paradoxical agonist activity, probably via the prolactin receptor

A Mode, P Tollet, T Wells, DF Carmignac, RG Clark, WY Chen, JJ Kopchick and IC Robinson
Karolinska Institute, Department of Medical Nutrition, Huddinge University Hospital, NOVUM, Sweden.

Human GH (hGH) acts by dimerizing two hGH receptors that bind to different sites in hGH. G120RhGH, an analog mutated in the second binding site to prevent receptor dimerization, acts as an antagonist in vitro. We have now tested the activity of this analog in vivo in rats with low or absent endogenous GH secretion. Surprisingly, treatment with G120RhGH failed to antagonize the effects of infusions or injections of hGH in hypophysectomized (Hx) rats and had little effect on hepatic GH-sensitive CYP2C transcripts in GH-deficient dwarf (dw) rats. Paradoxically, G120RhGH stimulated skeletal growth when infused into Hx rats; a pulsatile iv infusion was more effective than a continuous pattern. Coinfusion of G120RhGH with hGH produced an additive effect on growth. In addition, continuous, but not pulsatile, G120RhGH infusion elevated hepatic 2C12 messenger RNA (mRNA) expression and reduced 2C11 mRNA expression in Hx rats. The direct effects of G120RhGH on hepatic CYP2C transcripts were confirmed in cultured hepatocytes in vitro, which also revealed a significant action of PRL in elevating 2C12 mRNA expression. Binding studies revealed that G120RhGH bound preferentially to hepatic PRL receptors, as [125I]G120hGH was completely displaced by ovine PRL but was unaffected by bGH, a specific GH receptor ligand. The weak growth-promoting effects of G120RhGH were similar to those induced by recombinant hPRL in Hx rats. Our results show that G120RhGH is a poor in vivo GH antagonist in the rat, but shows a paradoxical agonist effect, probably mediated by PRL receptors in this species.

This article has been cited by other articles:

				V. Goffin, S. Bernichtein, P. Touraine, and P. A. Kelly Development and Potential Clinical Uses of Human Prolactin Receptor Antagonists Endocr. Rev., May 1, 2005; 26(3): 400 - 422. [Abstract] [Full Text] [PDF]

				S. Bernichtein, C. Kayser, K. Dillner, S. Moulin, J. J. Kopchick, J. A. Martial, G. Norstedt, O. Isaksson, P. A. Kelly, and V. Goffin Development of Pure Prolactin Receptor Antagonists J. Biol. Chem., September 19, 2003; 278(38): 35988 - 35999. [Abstract] [Full Text] [PDF]

				D. Landau, E. Israel, I. Rivkis, L. Kachko, B. F. Schrijvers, A. Flyvbjerg, M. Phillip, and Y. Segev The effect of growth hormone on the development of diabetic kidney disease in rats Nephrol. Dial. Transplant., April 1, 2003; 18(4): 694 - 702. [Abstract] [Full Text] [PDF]

				J. J. Kopchick, C. Parkinson, E. C. Stevens, and P. J. Trainer Growth Hormone Receptor Antagonists: Discovery, Development, and Use in Patients with Acromegaly Endocr. Rev., October 1, 2002; 23(5): 623 - 646. [Abstract] [Full Text] [PDF]

				S. Jeay, G. E. Sonenshein, M.-C. Postel-Vinay, and E. Baixeras Growth Hormone Prevents Apoptosis through Activation of Nuclear Factor-{kappa}B in Interleukin-3-Dependent Ba/F3 Cell Line Mol. Endocrinol., May 1, 2000; 14(5): 650 - 661. [Abstract] [Full Text]

				E Juarez-Aguilar, F Castro-Munozledo, N. Guerra-Rodriguez, D Resendez-Perez, H. Martinez-Rodriguez, H. Barrera-Saldana, and W Kuri-Harcuch Functional domains of human growth hormone necessary for the adipogenic activity of hGH/hPL chimeric molecules J. Cell Sci., January 9, 1999; 112(18): 3127 - 3135. [Abstract] [PDF]

				Y. Wei, J. Li, W. Y. Chen, and T. E. Wagner Human Growth Hormone Antagonist (G120R) Delivered by a Murine Yolk Sac Cell-Derived Mini-Organ Decreases the Growth Rate of Mice Stem Cells, September 1, 1997; 15(5): 364 - 367. [Abstract] [Full Text]

				R. Clark The Somatogenic Hormones and Insulin-Like Growth Factor-1: Stimulators of Lymphopoiesis and Immune Function Endocr. Rev., April 1, 1997; 18(2): 157 - 179. [Abstract] [Full Text]

				C. A. Gebert, S.-H. Park, and D. J. Waxman Regulation of Signal Transducer and Activator of Transcription (STAT) 5b Activation by the Temporal Pattern of Growth Hormone Stimulation Mol. Endocrinol., April 1, 1997; 11(4): 400 - 414. [Abstract] [Full Text]

				V. Goffin, S. Kinet, F. Ferrag, N. Binart, J. A. Martial, and P. A. Kelly Antagonistic Properties of Human Prolactin Analogs That Show Paradoxical Agonistic Activity in the Nb2 Bioassay J. Biol. Chem., July 12, 1996; 271(28): 16573 - 16579. [Abstract] [Full Text] [PDF]