Endocrinology, Vol 137, 4308-4315, Copyright © 1996 by Endocrine Society

ARTICLES

Recombinant human growth hormone (GH)-binding protein enhances the growth-promoting activity of human GH in the rat

RG Clark, DL Mortensen, LM Carlsson, SA Spencer, P McKay, M Mulkerrin, J Moore and BC Cunningham
Genentech, Inc., South San Francisco, California 94080-4990, USA. rossc@gene.com

To address the role of the GH-binding protein (GHBP) in GH physiology, two forms of recombinant human GHBP (rhGHBP) were given alone or in combination with rhGH to hypophysectomized rats or GH-deficient dwarf rats. Hypophysectomized rats were given daily sc injections of excipient, hGH, rhGHBP, or rhGH plus rhGHBP (produced in Escherichia coli) for 7 days. Injections of rhGH induced dose-related body weight gain and bone growth that were increased by the coadministration of rhGHBP with rhGH; rhGHBP alone had no effect. Serum insulin-like growth factor increased 24 h later when rhGH was given together with rhGHBP (P < 0.01), but not when rhGH was given alone. E. coli-derived rhGHBP also enhanced the bioactivity of coadministered rhGH in the GH-deficient dwarf rat. In contrast, the glycosylated rhGHBP, made in human A293 cells, inhibited the growth-promoting activity of coadministered rhGH. The opposite effects of these two forms of rhGHBP could be explained by clearance studies that showed radiolabeled rhGH bound to A293 cell- derived rhGHBP to be cleared more rapidly from the blood than free rhGH. Natural rabbit GHBP and E. coli-derived rhGHBP both prolonged the presence of rhGH in blood. It is proposed that by slowing the clearance of GH, GHBP increased the bioactivity of GH. In summary, codelivery of rhGHBP and rhGH caused a dose-dependent enhancement of the activity of rhGH in two rat models of GH deficiency. This suggests that endogenous circulating GHBP may increase the activity of blood-borne GH in a similar manner.

This article has been cited by other articles:

				R. A. Hill, D. J. Flint, and J. M. Pell Antibodies as molecular mimics of biomolecules: roles in understanding physiological functions and mechanisms Advan Physiol Educ, December 1, 2008; 32(4): 261 - 273. [Abstract] [Full Text] [PDF]

				A. Giustina, G. Mazziotti, and E. Canalis Growth Hormone, Insulin-Like Growth Factors, and the Skeleton Endocr. Rev., August 1, 2008; 29(5): 535 - 559. [Abstract] [Full Text] [PDF]

				J. Frystyk, C. M. Andreasen, and S. Fisker Determination of Free Growth Hormone J. Clin. Endocrinol. Metab., August 1, 2008; 93(8): 3008 - 3014. [Abstract] [Full Text] [PDF]

				X. Wang, K. He, M. Gerhart, J. Jiang, R. J. Paxton, R. K. Menon, R. A. Black, G. Baumann, and S. J. Frank Reduced Proteolysis of Rabbit Growth Hormone (GH) Receptor Substituted with Mouse GH Receptor Cleavage Site Mol. Endocrinol., October 1, 2003; 17(10): 1931 - 1943. [Abstract] [Full Text] [PDF]

				C V Clevenger and J B Kline Prolactin receptor signal transduction Lupus, October 1, 2001; 10(10): 706 - 718. [Abstract] [PDF]

				S. Fisker, K. Kristensen, A. M. Rosenfalck, S. B. Pedersen, L. Ebdrup, B. Richelsen, J. Hilsted, J. S. Christiansen, and J. O. L. Jørgensen Gene Expression of a Truncated and the Full-Length Growth Hormone (GH) Receptor in Subcutaneous Fat and Skeletal Muscle in GH-Deficient Adults: Impact of GH Treatment J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 792 - 796. [Abstract] [Full Text]

				Y. Zhang, J. Jiang, R. A. Black, G. Baumann, and S. J. Frank Tumor Necrosis Factor-{{alpha}} Converting Enzyme (TACE) Is a Growth Hormone Binding Protein (GHBP) Sheddase: The Metalloprotease TACE/ADAM-17 Is Critical for (PMA-Induced) GH Receptor Proteolysis and GHBP Generation Endocrinology, December 1, 2000; 141(12): 4342 - 4348. [Abstract] [Full Text] [PDF]

				Y. Hashimoto, T. Kamioka, M. Hosaka, K. Mabuchi, A. Mizuchi, Y. Shimazaki, M. Tsunoo, and T. Tanaka Exogenous 20K Growth Hormone (GH) Suppresses Endogenous 22K GH Secretion in Normal Men J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 601 - 606. [Abstract] [Full Text]

				L. Rui, S. F. Archer, L. S. Argetsinger, and C. Carter-Su Platelet-derived Growth Factor and Lysophosphatidic Acid Inhibit Growth Hormone Binding and Signaling via a Protein Kinase C-dependent Pathway J. Biol. Chem., January 28, 2000; 275(4): 2885 - 2892. [Abstract] [Full Text] [PDF]

				J. D. Wallace, R. C. Cuneo, R. Baxter, H. Orskov, N. Keay, C. Pentecost, R. Dall, T. Rosen, J. O. Jorgensen, A. Cittadini, et al. Responses of the Growth Hormone (GH) and Insulin-Like Growth Factor Axis to Exercise, GH Administration, and GH Withdrawal in Trained Adult Males: A Potential Test for GH Abuse in Sport J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3591 - 3601. [Abstract] [Full Text] [PDF]

				Y.-N. Sun, H. J. Lee, R. R. Almon, and W. J. Jusko A Pharmacokinetic/Pharmacodynamic Model for Recombinant Human Growth Hormone Effects on Induction of Insulin-Like Growth Factor I in Monkeys J. Pharmacol. Exp. Ther., June 1, 1999; 289(3): 1523 - 1532. [Abstract] [Full Text]

				A. Edens and F. Talamantes Alternative Processing of Growth Hormone Receptor Transcripts Endocr. Rev., October 1, 1998; 19(5): 559 - 582. [Abstract] [Full Text]

				G. P. Frick, L.-R. Tai, W. R. Baumbach, and H. M. Goodman Tissue Distribution, Turnover, and Glycosylation of the Long and Short Growth Hormone Receptor Isoforms in Rat Tissues Endocrinology, June 1, 1998; 139(6): 2824 - 2830. [Abstract] [Full Text] [PDF]

				J. Alele, J. Jiang, J. F. Goldsmith, X. Yang, H. G. Maheshwari, R. A. Black, G. Baumann, and S. J. Frank Blockade of Growth Hormone Receptor Shedding by a Metalloprotease Inhibitor Endocrinology, April 1, 1998; 139(4): 1927 - 1935. [Abstract] [Full Text] [PDF]

				M. Tzanela, C. Wagner, and G. Shaffer Tannenbaum Recombinant Human Growth Hormone-Binding Protein Fails to Enhance the in Vivo Bioactivity of Human Growth Hormone in Normal Rats Endocrinology, December 1, 1997; 138(12): 5316 - 5324. [Abstract] [Full Text] [PDF]

				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]

				J. B. Kline and C. V. Clevenger Identification and Characterization of the Prolactin-binding Protein in Human Serum and Milk J. Biol. Chem., June 29, 2001; 276(27): 24760 - 24766. [Abstract] [Full Text] [PDF]

				Y. Zhang, R. Guan, J. Jiang, J. J. Kopchick, R. A. Black, G. Baumann, and S. J. Frank Growth Hormone (GH)-induced Dimerization Inhibits Phorbol Ester-stimulated GH Receptor Proteolysis J. Biol. Chem., June 29, 2001; 276(27): 24565 - 24573. [Abstract] [Full Text] [PDF]