Endocrinology, Vol 137, 2694-2702, Copyright © 1996 by Endocrine Society

ARTICLES

Insulin-like growth factor I and insulin down-regulate growth hormone (GH) receptors in rat osteoblasts: evidence for a peripheral feedback loop regulating GH action

K Leung, IA Rajkovic, E Peters, I Markus, JJ Van Wyk and KK Ho
Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales, Australia.

The anabolic actions of GH are mediated by the production of insulin- like growth factor I (IGF-I) from the liver and by local production of IGF-I in extrahepatic tissues. Insulin facilitates the hepatic production of IGF-I by up-regulating GH receptors (GHRs) in the liver and augmenting the IGF-I response to GH. Although GHRs have also been identified in extrahepatic tissues that produce IGF-I, the possibility that IGF-I and insulin might partake in GHR regulation, thereby modulating the effects of GH locally has not received detailed study. The aim of this study was to investigate whether IGF-I and insulin are involved in the local regulation of GHRs, using osteoblasts as a model of GH-responsive extrahepatic tissues. We have used UMR106.06, a well differentiated rat osteoblast-like cell line that expresses GHRs and exhibits a mitogenic response to GH. IGF-I and insulin (0-10 nM) increased cell number and reduced [125I]GH binding in a concentration- dependent manner, with ED50 values of 0.8 and 0.3 nM, respectively. Although IGF-I increased cell number maximally by 36.9 +/- 1.2% (mean +/- SE) above the control value and insulin by 104.8 +/- 5.7% (P < 0.001), they decreased GH binding to 47.0 +/- 9.3% (P < 0.01) and 29.8 +/- 8.7% of the control value (P < 0.001), respectively. Scatchard analysis revealed that the down-regulation of GH binding was attributed to reduced receptor numbers and not binding affinity. The effects of IGF-I and insulin at submaximal concentrations were additive, although the combined effects did not exceed the maximal effect of either growth factor alone. Addition of an anti-IGF-I receptor antibody (alpha IR3) reversed the inhibition of GH binding induced by IGF-I, but not that caused by insulin; similarly, an antiinsulin receptor antibody (29B4) attenuated the inhibitory effect of insulin only. Addition of alpha IR3 alone or an ant-IGF-I antibody (Sm1.2) decreased cell number and increased GH binding in a concentration-dependent mode. GH at 1.5 nM significant increased cell number by 19.3 +/- 2.4% above the control level (P < 0.01), an increase that was reversed by alpha IR3. GH increased GH binding by 32.4 +/- 7.2% (P < 0.05) in cells treated with alpha IR3 to remove the secondary effect of IGF-I. In summary, IGF-I and insulin acted via specific receptors to stimulate cell proliferation and down-regulate GHRs in osteoblasts. GH stimulated cell proliferation, an action mediated by local production of IGF-I, and GH enhanced its own binding. The collective data suggest the presence of a peripheral negative feedback loop that allows IGF-I to limit locally the response of extrahepatic tissues to circulating GH.

This article has been cited by other articles:

				L. Jette, R. Leger, K. Thibaudeau, C. Benquet, M. Robitaille, I. Pellerin, V. Paradis, P. van Wyk, K. Pham, and D. P. Bridon Human Growth Hormone-Releasing Factor (hGRF)1-29-Albumin Bioconjugates Activate the GRF Receptor on the Anterior Pituitary in Rats: Identification of CJC-1295 as a Long-Lasting GRF Analog Endocrinology, July 1, 2005; 146(7): 3052 - 3058. [Abstract] [Full Text] [PDF]

				T. J. Marcell Review Article: Sarcopenia: Causes, Consequences, and Preventions J. Gerontol. A Biol. Sci. Med. Sci., October 1, 2003; 58(10): M911 - 916. [Abstract] [Full Text] [PDF]

				T. K. Hansen, J. O. L. Jorgensen, and J. S. Christiansen Body Composition and Circulating Levels of Insulin, Insulin-Like Growth Factor-Binding Protein-1 and Growth Hormone (GH)-Binding Protein Affect the Pharmacokinetics of GH in Adults Independently of Age J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2185 - 2193. [Abstract] [Full Text] [PDF]

				T. J. Marcell, S. M. Harman, R. J. Urban, D. D. Metz, B. D. Rodgers, and M. R. Blackman Comparison of GH, IGF-I, and testosterone with mRNA of receptors and myostatin in skeletal muscle in older men Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1159 - E1164. [Abstract] [Full Text] [PDF]

				K.-C. Leung, N. Doyle, M. Ballesteros, M. J. Waters, and K. K. Y. Ho Insulin Regulation of Human Hepatic Growth Hormone Receptors: Divergent Effects on Biosynthesis and Surface Translocation J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4712 - 4720. [Abstract] [Full Text]

				M. Ballesteros, K.-C. Leung, R. J. M. Ross, T. P. Iismaa, and K. K. Y. Ho Distribution and Abundance of Messenger Ribonucleic Acid for Growth Hormone Receptor Isoforms in Human Tissues J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2865 - 2871. [Abstract] [Full Text]

				O. Kecha, F. Brilot, H. Martens, N. Franchimont, C. Renard, R. Greimers, M.-P. Defresne, R. Winkler, and V. Geenen Involvement of Insulin-Like Growth Factors in Early T Cell Development: A Study Using Fetal Thymic Organ Cultures Endocrinology, March 1, 2000; 141(3): 1209 - 1217. [Abstract] [Full Text] [PDF]

				D. Deplewski and R. L. Rosenfield Growth Hormone and Insulin-Like Growth Factors Have Different Effects on Sebaceous Cell Growth and Differentiation Endocrinology, September 1, 1999; 140(9): 4089 - 4094. [Abstract] [Full Text]

				C. Jux, K. Leiber, U. Hugel, W. Blum, C. Ohlsson, G. Klaus, and O. Mehls Dexamethasone Impairs Growth Hormone (GH)-Stimulated Growth by Suppression of Local Insulin-Like Growth Factor (IGF)-I Production and Expression of GH- and IGF-I-Receptor in Cultured Rat Chondrocytes Endocrinology, July 1, 1998; 139(7): 3296 - 3305. [Abstract] [Full Text] [PDF]

				C. Ohlsson, B.-A. Bengtsson, O. G. P. Isaksson, T. T. Andreassen, and M. C. Slootweg Growth Hormone and Bone Endocr. Rev., February 1, 1998; 19(1): 55 - 79. [Abstract] [Full Text]

				K.-C. Leung and K. K. Y. Ho Stimulation of Mitochondrial Fatty Acid Oxidation by Growth Hormone in Human Fibroblasts J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 4208 - 4213. [Abstract] [Full Text] [PDF]

				K.-C. Leung, M. J. Waters, I. Markus, W. R. Baumbach, and K. K. Y. Ho Insulin and insulin-like growth factor-I acutely inhibit surface translocation of growth hormone receptors in osteoblasts: A novel mechanism of growth hormone receptor regulation PNAS, October 14, 1997; 94(21): 11381 - 11386. [Abstract] [Full Text] [PDF]