Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

The Dual Effector Theory

Claes Ohlsson, Anders Lindahl, Jörgen Isgaard, Anders Nilsson, Olle G. P. Isaksson

10.1002/cphy.cp070516

Source: Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth

Originally published: 1999

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Studies Investigating the Validity of the Dual Effector Theory
1.1 Differences Between Growth Hormone and Insulin‐like Growth Factor I Actions In Vivo in Animals
1.2 Differences in Effects of Growth Hormone and Insulin‐like Growth Factor I In Vivo in Humans
1.3 Localization of Growth Hormone Receptors: Indirect Evidence for a Local Effect of Growth Hormone
1.4 Local Action of Growth Hormone on Tissues
1.5 Effects of Growth Hormone and Insulin‐like Growth Factor I on Cells of Different Maturation
1.6 Evidence In Vivo for a Stimulatory Effect of Growth Hormone, but not of Insulin‐like Growth Factor I, on Progenitor Cells in the Growth Plate
2 Conclusion and Discussion
3 Modified Dual Effector Theory of Growth Hormone and Insulin‐Like Growth Factor I Action in the Growth Plate
Figure 1. Figure 1.

Effects of local administration of growth hormone (GH) on longitudinal bone growth. In hypophysectomized male rats, GH was injected into the proximal growth plate of the right tibia. The contralateral leg received the same volume of saline. The two bars to the right represent rats that received saline in both the left and the right proximal growth plates of the tibia. Longitudinal bone growth was measured by the tetracycline method.

From Isaksson et al. 54 with permission
Figure 2. Figure 2.

The dual effector theory as originally proposed by Green et al. in 1985 42.

From Green 42 with permission
Figure 3. Figure 3.

Hypothetical model for the stimulatory effect of growth hormone (GH) on longitudinal bone growth based on the original dual effector theory introduced by Green et al. 42. IGF‐I, insulin‐like growth factor I.

From Isaksson et al. 55 with permission
Figure 4. Figure 4.

Effects of local administration of growth hormone (GH) on insulin‐like growth factor I (IGF‐I)‐immunoreactive cells in the tibial epiphyseal growth plate of hypophysectomized rats. The GH was injected daily for 5 days through a cannula implanted in the epiphysis of the right tibia. The left leg was injected with the same volume of saline. Rats were killed 18 h after the last injection. Sagittal sections of the epiphyseal growth plate of the proximal tibia were prepared and analyzed immunohistochemically for IGF‐I. A: Right leg treated with GH. B: Saline‐treated left leg. Note the difference in growth plate width and immunofluorescence of chondrocytes between the two photographs. Scale bar is 100 μm. Vertical arrow indicates width of the epiphyseal growth plate.

From Nilsson et al. 99 with permission
Figure 5. Figure 5.

Effects of growth hormone (GH) and insulin‐like growth factor I (IGF‐I) on the percentage of label‐retaining cells compared to control in the germinal layer of the epiphyseal growth plate of hypophysectomized rats prelabeled with [3H]thymidine for 14 days, followed by a 14‐day washout period. In the germinal cell layer, GH increased the number of labeled cells compared to that in the control leg, whereas IGF‐I showed no stimulatory effect.

From Ohlsson et al. 113 with permission
Figure 6. Figure 6.

Proposed mechanisms of action for growth hormone (GH) and insulin‐like growth factor I (IGF‐I) in stimulating growth of peripheral tissues and liver.
Figure 7. Figure 7.

A modified dual effector theory proposed by the authors for the mechanisms of action for growth hormone (GH) and insulin‐like growth factor I (IGF‐I) in stimulating longitudinal bone growth. Compare with the theory proposed earlier by the authors, which is shown in Figure 3.


Figure 1.

Effects of local administration of growth hormone (GH) on longitudinal bone growth. In hypophysectomized male rats, GH was injected into the proximal growth plate of the right tibia. The contralateral leg received the same volume of saline. The two bars to the right represent rats that received saline in both the left and the right proximal growth plates of the tibia. Longitudinal bone growth was measured by the tetracycline method.

From Isaksson et al. 54 with permission


Figure 2.

The dual effector theory as originally proposed by Green et al. in 1985 42.

From Green 42 with permission


Figure 3.

Hypothetical model for the stimulatory effect of growth hormone (GH) on longitudinal bone growth based on the original dual effector theory introduced by Green et al. 42. IGF‐I, insulin‐like growth factor I.

From Isaksson et al. 55 with permission


Figure 4.

Effects of local administration of growth hormone (GH) on insulin‐like growth factor I (IGF‐I)‐immunoreactive cells in the tibial epiphyseal growth plate of hypophysectomized rats. The GH was injected daily for 5 days through a cannula implanted in the epiphysis of the right tibia. The left leg was injected with the same volume of saline. Rats were killed 18 h after the last injection. Sagittal sections of the epiphyseal growth plate of the proximal tibia were prepared and analyzed immunohistochemically for IGF‐I. A: Right leg treated with GH. B: Saline‐treated left leg. Note the difference in growth plate width and immunofluorescence of chondrocytes between the two photographs. Scale bar is 100 μm. Vertical arrow indicates width of the epiphyseal growth plate.

From Nilsson et al. 99 with permission


Figure 5.

Effects of growth hormone (GH) and insulin‐like growth factor I (IGF‐I) on the percentage of label‐retaining cells compared to control in the germinal layer of the epiphyseal growth plate of hypophysectomized rats prelabeled with [3H]thymidine for 14 days, followed by a 14‐day washout period. In the germinal cell layer, GH increased the number of labeled cells compared to that in the control leg, whereas IGF‐I showed no stimulatory effect.

From Ohlsson et al. 113 with permission


Figure 6.

Proposed mechanisms of action for growth hormone (GH) and insulin‐like growth factor I (IGF‐I) in stimulating growth of peripheral tissues and liver.



Figure 7.

A modified dual effector theory proposed by the authors for the mechanisms of action for growth hormone (GH) and insulin‐like growth factor I (IGF‐I) in stimulating longitudinal bone growth. Compare with the theory proposed earlier by the authors, which is shown in Figure 3.

References
 1. Amselem, S., P. Duquesnoy, O. Attree, G. Novelli, S. Bousnina, M. C. Postel‐Vinay, and M. Goossens. Laron dwarfism and mutations of the growth hormone‐receptor gene. N. Engl. J. Med. 321: 989–995, 1989.
 2. Amselem, S., M. L. Sobrier, P. Duquesnoy, R. Rappaport, M. C. Postel‐Vinay, M. Gourmelen, B. Dallapiccola, and M. Goossens. Recurrent nonsense mutations in the growth hormone receptor from patients with Laron dwarfism. J. Clin. Invest. 87: 1098–1102, 1991.
 3. Andersson, L., H. Billig, L. Fryklund, H. A. Hansson, O. Isaksson, J. Isgaard, A. Nilsson, B. Rozell, A. Skottner, and S. Stemme. Localization of IGF‐I in adult rats. Immunohisto‐chemical studies. Acta Physiol. Scand. 126: 311–312, 1986.
 4. Andreassen, T. T., P. H. Jorgensen, A. Flyvbjerg, H. Orskov, and H. Oxlund. Growth hormone stimulates bone formation and strength of cortical bone in aged rats. J. Bone Miner. Res. 10: 1057–1067, 1995.
 5. Backeljauw, P., and L. Underwood. Prolonged treatment with recombinant insulin‐like growth factor‐I in children with growth hormone insensitivity syndrome–a clinical research center study. GHIS Collaborative Group. J. Clin. Endocrinol. Metab. 81: 3312–3317, 1996.
 6. Bagi, C. M., R. Brommage, L. Deleon, S. Adams, D. Rosen, and A. Sommer. Benefit of systemically administered rhIGF‐I. and rhIGF‐I/IGFBP‐3 on cancellous bone in ovariectomized rats. J. Bone Miner. Res. 9: 1301–1312, 1994.
 7. Baker, J., J. P. Liu, E. J. Robertson, and A. Efstratiadis. Role of insulin‐like growth factors in embryonic and postnatal growth. Cell 75: 73–82, 1993.
 8. Barnard, R., K. M. Haynes, G. A. Werther, and M. J. Waters. The ontogeny of growth hormone receptors in the rabbit tibia. Endocrinology 122: 2562–2569, 1988.
 9. Barnard, R., K. W. Ng, T. J. Martin, and M. J. Waters. Growth hormone (GH) receptors in clonal osteoblast‐like cells mediate a mitogenic response to GH. Endocrinology 128: 1459–1464, 1991.
 10. Behringer, R. R., T. M. Lewin, C. J. Quaife, R. D. Palmiter, R. L. Brinster, and A. J. D'Ercole. Expression of insulin‐like growth factor I stimulates normal somatic growth in growth hormone‐deficient transgenic mice. Endocrinology 127: 1033–1040, 1990.
 11. Behringer, R. R., L. S. Mathews, R. D. Palmiter, and R. L. Brinster. Dwarf mice produced by genetic ablation of growth hormone‐expressing cells. Genes Dev. 2: 453–461, 1988.
 12. Bentham, J., C. Ohlsson, A. Lindahl, O. Isaksson, and A. Nilsson. A double‐staining technique for detection of growth hormone and insulin‐like growth factor‐I binding to rat tibial epiphyseal chondrocytes. J. Endocrinol. 137: 361–367, 1993.
 13. Berg, M. A., J. Argente, S. Chernausek, R. Gracia, J. Guevara‐Aguirre, M. Hopp, L. Perez‐Jurado, A. Rosenbloom, S. P. Toledo, and U. Francke. Diverse growth hormone receptor gene mutations in Laron syndrome. Am. J. Hum. Genet. 52: 998–1005, 1993.
 14. Berg, M. A., J. Guevara‐Aguirre, A. L. Rosenbloom, R. G. Rosenfeld, and U. Francke. Mutation creating a new splice site in the growth hormone receptor genes of 37 Ecuadorean patients with Laron syndrome. Hum. Mutat. 1: 24–32, 1992.
 15. Blazar, B. R., C. A. Brennan, H. E. Broxmeyer, L. D. Shultz, and D. A. Vallera. Transgenic mice expressing either bovine growth hormone (bGH) or human GH releasing hormone (hGRH) have increased splenic progenitor cell colony formation and DNA synthesis in vitro and in vivo. Exp. Hematol. 23: 1397–1406, 1995.
 16. Brixen, K., M. Kassem, H. Nielsen, A. Loft, A. Flyvbjerg, and L. Mosekilde. Short‐term treatment with growth hormone stimulates osteoblastic and osteoclastic activity in osteopenic postmenopausal women: a dose response study. J. Bone Miner. Res. 10: 1865–1874, 1995.
 17. Brixen, K., H. K. Nielsen, L. Mosekilde, and A. Flyvbjerg. A short course of recombinant human growth hormone treatment stimulates osteoblasts and activates bone remodeling in normal human volunteers. J. Bone Miner. Res. 5: 609–618, 1990.
 18. Carlsson, B., S. Eden, A. Nilsson, C. Ohlsson, J. Tornell, K. Vikman, and O. G. Isaksson. Expression and physiological significance of growth hormone receptors and growth hormone binding proteins in rat and man. Acta Paediatr. Scand. Suppl. 379: 70–76, 1991.
 19. Cheek, D., and D. Hill. Effect of growth hormone on cell and somatic growth. In: Handbook of Physiology. Endocrinology, edited by E. Knobil and W. H. Sawyer. Washington, DC: Am. Physiol. Soc., 1974 sect. 7, vol. IV, p. 159–185.
 20. Clark, R., L. Carlsson, D. Mortensen, and M. Cronin. Additive effects on body growth of insulin‐like growth factor‐1 and growth hormone in hypophysectomized rats. Endocrinol. Metab. 1: 49–54, 1994.
 21. Clark, R., D. Mortensen, and L. Carlsson. Insulin‐like growth factor‐1 and growth hormone (GH) have distinct and overlapping effects in GH‐deficient rats. Endocrine 3: 297–304, 1995.
 22. D'Ercole, A. J., A. D. Stiles, and L. E. Underwood. Tissue concentrations of somatomedin C: further evidence for multiple sites of synthesis and paracrine or autocrine mechanisms of action. Proc. Natl. Acad. Sci. USA 81: 935–939, 1984.
 23. Daughaday, W. H. Growth hormone and the somatomedins. In: Endocrine Control of Growth, edited by W. H. Daughaday. New York: Elsevier, 1981, p. 1–24.
 24. Daughaday, W. H., K. Hall, M. S. Raben, W. D. Salmon, Jr., J. L. van den Brande, and J. J. Van Wyk. Somatomedin: proposed designation for sulphation factor. Nature 235: 107, 1972.
 25. Daughaday, W. H., and P. Rotwein. Insulin‐like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr. Rev. 10: 68–91, 1989.
 26. Daughaday, W. H., and B. Trivedi. Absence of serum growth hormone binding protein in patients with growth hormone receptor deficiency (Laron dwarfism). Proc. Natl. Acad. Sci. USA 84: 4636–4640, 1987.
 27. DeChiara, T. M., A. Efstratiadis, and E. J. Robertson. A growth‐deficiency phenotype in heterozygous mice carrying an insulin‐like growth factor II gene disrupted by targeting. Nature 345: 78–80, 1990.
 28. Degerblad, M., B. A. Bengtsson, M. Bramnert, O. Johnell, P. Manhem, T. Rosen, and M. Thoren. Reduced bone mineral density in adults with growth hormone (GH) deficiency: increased bone turnover during 12 months of GH substitution therapy. Eur. J. Endocrinol. 133: 180–188, 1995.
 29. Degerblad, M., N. Elgindy, K. Hall, H. E. Sjoberg, and M. Thoren. Potent effect of recombinant growth hormone on bone mineral density and body composition in adults with panhypopituitarism. Acta Endocrinol. (Copenh.) 126: 387–393, 1992.
 30. Demarquay, D., M. F. Dumontier, J. Bourguignon, R. L. Hintz, and M. T. Corvol. Stimulation by GH of IGF1 proforms synthesized by rabbit chondrocytes cultured with bFGF in serum‐free medium. Exp. Cell Res. 202: 412–422, 1992.
 31. Demarquay, D., M. F. Dumontier, L. Tsagris, J. Bourguignon, V. Nataf, and M. T. Corvol. In vitro insulin‐like growth factor I interaction with cartilage cells derived from postnatal animals. Horm. Res. 33: 111–114, 1990.
 32. Eden, S., O. G. Isaksson, K. Madsen, and U. Friberg. Specific binding of growth hormone to isolated chondrocytes from rabbit ear and epiphyseal plate. Endocrinology 112: 1127–1129, 1983.
 33. Ernst, M., and E. R. Froesch. Growth hormone dependent stimulation of osteoblast‐like cells in serum‐free cultures via local synthesis of insulin‐like growth factor I. Biochem. Biophys. Res. Commun. 151: 142–147, 1988.
 34. Ewton, D. Z., and J. R. Florini. Effects of the somatomedins and insulin on myoblast differentiation in vitro. Dev. Biol. 86: 31–39, 1981.
 35. Ezzat, S., S. Melmed, D. Endres, D. R. Eyre, and F. R. Singer. Biochemical assessment of bone formation and resorption in acromegaly. J. Clin. Endocrinol. Metab. 76: 1452–1457, 1993.
 36. Fielder, P., D. Mortensen, P. Mallet, B. Carlsson, R. Baxter, and R. Clark. Differential long‐term effects of insulin‐like growth factor‐I (IGF‐I), growth hormone (GH), and IGF‐I plus GH on body growth and IGF binding proteins in hypophysectomized rats. Endocrinology 137: 1913–1920, 1996.
 37. Florini, J. R., M. L. Nicholson, and N. C. Dulak. Effects of peptide anabolic hormones on growth of myoblasts in culture. Endocrinology 101: 32–41, 1977.
 38. Garcia‐Aragon, J., P. E. Lobie, G. E. Muscat, K. S. Gobius, G. Norstedt, and M. J. Waters. Prenatal expression of the growth hormone (GH) receptor/binding protein in the rat: a role for GH in embryonic and fetal development? Development 114: 869–876, 1992.
 39. Godowski, P. J., D. W. Leung, L. R. Meacham, J. P. Galgani, R. Hellmiss, R. Keret, P. S. Rotwein, J. S. Parks, Z. Laron, and W. I. Wood. Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron‐type dwarfism. Proc. Natl. Acad. Sci. USA 86: 8083–8087, 1989.
 40. Golde, D. W., N. Bersch, and C. H. Li. Growth hormone: species‐specific stimulation of erythropoiesis in vitro. Science 196: 1112–1113, 1977.
 41. Green, H., and O. Kehinde. Spontaneous heritable changes leading to increased adipose conversion in 3T3 cells. Cell 7: 105–113, 1976.
 42. Green, H., M. Morikawa, and T. Nixon. A dual effector theory of growth‐hormone action. Differentiation 29: 195–198, 1985.
 43. Guevara‐Aguirre, J., O. Vasconez, V. Martinez, A. L. Martinez, A. L. Rosenbloom, F. B. Diamond, Jr., S. E. Gargosky, L. Nonoshita, and R. G. Rosenfeld. A randomized, double blind, placebo‐controlled trial on safety and efficacy of recombinant human insulin‐like growth factor‐I in children with growth hormone receptor deficiency. J. Clin. Endocrinol. Metab. 80: 1393–1398, 1995.
 44. Guler, H. P., J. Zapf, E. Scheiwiller, and E. R. Froesch. Recombinant human insulin‐like growth factor I stimulates growth and has distinct effects on organ size in hypophysectomized rats. Proc. Natl. Acad. Sci. USA 85: 4889–4893, 1988.
 45. Halse, J., and J. O. Gordeladze. Total and non‐dialyzable urinary hydroxyproline in acromegalics and control subjects. Acta Endocrinol. (Copenh.) 96: 451–457, 1981.
 46. Halse, J., F. Melsen, and L. Mosekilde. Iliac crest bone mass and remodelling in acromegaly. Acta Endocrinol. (Copenh.) 97: 18–22, 1981.
 47. Han, V. K., A. J. D'Ercole, and P. K. Lund. Cellular localization of somatomedin (insulin‐like growth factor) messenger RNA in the human fetus. Science 236: 193–197, 1987.
 48. Harper, J. M., J. B. Soar, and P. J. Buttery. Changes in protein metabolism of ovine primary muscle cultures on treatment with growth hormone, insulin, insulin‐like growth factor I or epidermal growth factor. J. Endocrinol. 112: 87–96, 1987.
 49. Hazel, S. J., C. M. Gillespie, R. J. Moore, R. G. Clark, K. F. Jureidini, and A. A. Martin. Enhanced body growth in uremic rats treated with IGF‐I and growth hormone in combination. Kidney Int. 46: 58–68, 1994.
 50. Heinrichs, C., H. L. Vis, P. Bergmann, P. Wilton, and J. P. Bourguignon. Effects of 17 months treatment using recombinant insulin‐like growth factor‐I in two children with growth hormone insensitivity (Laron) syndrome. Clin. Endocrinol. (Oxf.) 38: 647–651, 1993.
 51. Holder, A. T., E. M. Spencer, and M. A. Preece. Effect of bovine growth hormone and a partially pure preparation of somatomedin on various growth parameters in hypopituitary dwarf mice. J. Endocrinol. 89: 275–282, 1981.
 52. Hunziker, E. B., J. Wagner, and J. Zapf. Differential effects of insulin‐like growth factor I and growth hormone on developmental stages of rat growth plate chondrocytes in vivo. J. Clin. Invest. 93: 1078–1086, 1994.
 53. Hyer, S. L., D. A. Rodin, J. H. Tobias, A. Leiper, and S. S. Nussey. Growth hormone deficiency during puberty reduces adult bone mineral density. Arch. Dis. Child 67: 1472–1474, 1992.
 54. Isaksson, O. G., J. O. Jansson, and I. A. Gause. Growth hormone stimulates longitudinal bone growth directly. Science 216: 1237–1239, 1982.
 55. Isaksson, O. G., A. Lindahl, A. Nilsson, and J. Isgaard. Mechanism of the stimulatory effect of growth hormone on longitudinal bone growth. Endocr. Rev. 8: 426–438, 1987.
 56. Isgaard, J., L. Carlsson, O. G. Isaksson, and J. O. Jansson. Pulsatile intravenous growth hormone (GH) infusion to hypophysectomized rats increases insulin‐like growth factor I messenger ribonucleic acid in skeletal tissues more effectively than continuous GH infusion. Endocrinology 123: 2605–2610, 1988.
 57. Isgaard, J., C. Moller, O. G. Isaksson, A. Nilsson, L. S. Mathews, and G. Norstedt. Regulation of insulin‐like growth factor messenger ribonucleic acid in rat growth plate by growth hormone. Endocrinology 122: 1515–1520, 1988.
 58. Isgaard, J., A. Nilsson, A. Lindahl, J. O. Jansson, and O. G. Isaksson. Effects of local administration of GH and IGF‐1 on longitudinal bone growth in rats. Am. J. Physiol. 250 (Endocrinol. Metab. 13): E367–E372, 1986.
 59. Isgaard, J., A. Nilsson, K. Vikman, and O. G. Isaksson. Growth hormone regulates the level of insulin‐like growth factor‐I mRNA in rat skeletal muscle. J. Endocrinol. 120: 107–112, 1989.
 60. Jennische, E., and G. L. Andersson. Expression of GH receptor mRNA in regenerating skeletal muscle of normal and hypophysectomized rats. An in situ hybridization study. Acta Endocrinol. (Copenh.) 125: 595–602, 1991.
 61. Johansson, A. G., E. Lindh, and S. Ljunghall. Insulin‐like growth factor I stimulates bone turnover in osteoporosis. Lancet 339: 1619, 1992.
 62. Johansson, G., T. Rosen, I. Bosaeus, L. Sjöström, and B. Bengtsson. Two years of growth hormone treatment increases bone mineral content and density in hyopopituitary patients with adult‐onset growth hormone deficiency. J. Clin. Endocrinol. Metab. 81: 2865–2873, 1996.
 63. Jones, K. L., J. F. Villela, and U. J. Lewis. The growth of cultured rabbit articular chondrocytes is stimulated by pituitary growth factors but not by purified human growth hormone or ovine prolactin. Endocrinology 118: 2588–2593, 1986.
 64. Kassem, M., W. Blum, J. Ristelli, L. Mosekilde, and E. F. Eriksen. Growth hormone stimulates proliferation and differentiation of normal human osteoblast‐like cells in vitro. Calcif. Tissue Int. 52: 222–226, 1993.
 65. Kassem, M., K. Brixen, L. Mosekilde, and E. F. Eriksen. Human marrow stromal osteoblast‐like cells do not show reduced responsiveness to in vitro stimulation with growth hormone in patients with postmenopausal osteoporosis. Calcif. Tissue Int. 54: 1–6, 1994.
 66. Kassem, M., L. Mosekilde, and E. F. Eriksen. Growth hormone stimulates proliferation of normal human bone marrow stromal osteoblast precursor cells in vitro. Growth Regul. 4: 131–135, 1994.
 67. Kawamura, M., D. F. Jensen, E. V. Wancewicz, L. L. Joy, J. C. Khoo, and D. Steinberg. Hormone‐sensitive lipase in differentiated 3T3–L1 cells and its activation by cyclic AMP‐dependent protein kinase. Proc. Natl. Acad. Sci. USA 78: 732–736, 1981.
 68. Kember, N. F. Growth hormone and cartilage cell division in hypophysectomized rats. Cell Tissue Kinet. 4: 193–199, 1971.
 69. Kember, N. F. Cell population kinetics of bone growth: the first ten years of autoradiographic studies with tritiated thymidine. Clin. Orthop. 76: 213–230, 1971.
 70. Kember, N. F. Cell kinetics and the control of growth in long bones. Cell Tissue Kinet. 11: 477–485, 1978.
 71. Kember, N. F, and K. V. Walker. Control of bone growth in rats. Nature 229: 428–429, 1971.
 72. Klinger, B, and Z. Laron. Three year IGF‐I treatment of children with Laron syndrome. J. Pediatr. Endocrinol. Metab. 8: 149–158, 1995.
 73. Kostyo, J. L., and D. F. Nutting. Growth hormone and protein metabolism. In: Handbook of Physiology. Endocrinology, edited by E. Knobil and W. H. Sawyer. Washington, DC: Am. Physiol. Soc., Sect. 7, vol. IV, 1974, p. 187–199.
 74. Kupfer, S. R., L. E. Underwood, R. C. Baxter, and D. R. Clemmons. Enhancement of the anabolic effects of growth hormone and insulin‐like growth factor I by use of both agents simultaneously. J. Clin. Invest. 91: 391–396, 1993.
 75. Laron, Z., S. Anin, Y. Klipper‐Aurbach, and B. Klinger. Effects of insulin‐like growth factor on linear growth, head circumference, and body fat in patients with Laron‐type dwarfism. Lancet 339: 1258–1261, 1992.
 76. Laron, Z, and B. Klinger. IGF‐I treatment of adult patients with Laron syndrome: preliminary results. Clin. Endocrinol. (Oxf.) 41: 631–638, 1994.
 77. LeRoith, D. Insulin‐like growth factors and binding proteins. Baillieres Clin. Endocrinol. Metab. 10: 49–73, 1996.
 78. Lewinson, D., P. Shenzer, and Z. Hochberg. Growth hormone involvement in the regulation of tartrate‐resistant acid phosphatase‐positive cells that are active in cartilage and bone resorption. Calcif. Tissue Int. 52: 216–221, 1993.
 79. Lindahl, A., J. Isgaard, L. Carlsson, and O. G. Isaksson. Differential effects of growth hormone and insulin‐like growth factor I on colony formation of epiphyseal chondrocytes in suspension culture in rats of different ages. Endocrinology 121: 1061–1069, 1987.
 80. Lindahl, A., J. Isgaard, and O. G. Isaksson. Growth hormone in vivo potentiates the stimulatory effect of insulin‐like growth factor‐1 in vitro on colony formation of epiphyseal chondrocytes isolated from hypophysectomized rats. Endocrinology 121: 1070–1075, 1987.
 81. Lindahl, A., J. Isgaard, A. Nilsson, and O. G. Isaksson. Growth hormone potentiates colony formation of epiphyseal chondrocytes in suspension culture. Endocrinology 118: 1843–1848, 1986.
 82. Lindahl, A., A. Nilsson, and O. G. Isaksson. Effects of growth hormone and insulin‐like growth factor‐I on colony formation of rabbit epiphyseal chondrocytes at different stages of maturation. J. Endocrinol. 115: 263–271, 1987.
 83. Liu, J. P., J. Baker, A. S. Perkins, E. J. Robertson, and A. Efstratiadis. Mice carrying null mutations of the genes encoding insulin‐like growth factor I (Igf‐1) and type 1 IGF receptor (Igf1r). Cell 75: 59–72, 1993.
 84. Madsen, K., U. Friberg, P. Roos, S. Eden, and O. Isaksson. Growth hormone stimulates the proliferation of cultured chondrocytes from rabbit ear and rat rib growth cartilage. Nature 304: 545–547, 1983.
 85. Madsen, K., A. M. Makower, U. Friberg, S. Eden, and O. Isaksson. Effect of human growth hormone on proteoglycan synthesis in cultured rat chondrocytes. Acta Endocrinol (Copenh.). 108: 338–342, 1985.
 86. Makower, A. M., A. Skottner, and J. Wroblewski. Binding of insulin‐like growth factor‐I (IGF‐I) to primary cultures of chondrocytes from rat rib growth cartilage. Cell Biol. Int. Rep. 13: 655–665, 1989.
 87. Makower, A. M., J. Wroblewski, and A. Pawlowski. Effects of IGF‐I, EGF, and FGF on proteoglycans synthesized by fractionated chondrocytes of rat rib growth plate. Exp. Cell Res. 179: 498–506, 1988.
 88. Maor, G., Z. Hochberg, and M. Silbermann. Growth hormone stimulates the growth of mouse neonatal condylar cartilage in vitro. Acta Endocrinol (Copenh.). 120: 526–532, 1989.
 89. Mathews, L. S., B. Enberg, and G. Norstedt. Regulation of rat growth hormone receptor gene expression. J. Biol. Chem. 264: 9905–9910, 1989.
 90. Mathews, L. S., R. E. Hammer, R. R. Behringer, A. J. D'Ercole, G. I. Bell, R. L. Brinster, and R. D. Palmiter. Growth enhancement of transgenic mice expressing human insulin‐like growth factor I. Endocrinology 123: 2827–2833, 1988.
 91. Merchav, S., Z. Graif, and A. Skottner. In‐vitro response of erythroid progenitors from children with thalassaemia major to human growth hormone and insulin‐like growth factor I. Clin. Endocrinol. (Oxf.) 39: 207–211, 1993.
 92. Mertani, H. C., and G. Morel. In situ gene expression of growth hormone (GH) receptor and GH binding protein in adult male rat tissues. Mol. Cell. Endocrinol. (Oxf.) 109: 47–61, 1995.
 93. Morel, G., P. Chavassieux, B. Barenton, P. M. Dubois, P. J. Meunier, and G. Boivin. Evidence for a direct effect of growth hormone on osteoblasts. Cell Tissue Res. 273: 279–286, 1993.
 94. Morikawa, M. Sensitivity of preadipose 3T3 cells to growth hormone. J. Cell. Physiol. 128: 293–298, 1986.
 95. Morikawa, M., H. Green, and U. J. Lewis. Activity of human growth hormone and related polypeptides on the adipose conversion of 3T3 cells. Mol. Cell. Biol. 4: 228–231, 1984.
 96. Morikawa, M., T. Nixon, and H. Green. Growth hormone and the adipose conversion of 3T3 cells. Cell 29: 783–789, 1982.
 97. Nilsson, A., B. Carlsson, J. Isgaard, O. G. Isaksson, and L. Rymo. Regulation by GH of insulin‐like growth factor‐I mRNA expression in rat epiphyseal growth plate as studied with in‐situ hybridization. J. Endocrinol. 125: 67–74, 1990.
 98. Nilsson, A., B. Carlsson, L. Mathews, and O. G. Isaksson. Growth hormone regulation of the growth hormone receptor mRNA in cultured rat epiphyseal chondrocytes. Mol. Cell. Endocrinol. 70: 237–246, 1990.
 99. Nilsson, A., J. Isgaard, A. Lindahl, A. Dahlstrom, A. Skottner, and O. G. Isaksson. Regulation by growth hormone of number of chondrocytes containing IGF‐I in rat growth plate. Science 233: 571–574, 1986.
 100. Nilsson, A., J. Isgaard, A. Lindahl, L. Peterson, and O. Isaksson. Effects of unilateral arterial infusion of GH and IGF‐I on tibial longitudinal bone growth in hypophysectomized rats. Calcif. Tissue Int. 40: 91–96, 1987.
 101. Nilsson, A., A. Lindahl, S. Eden, and O. G. Isaksson. Demonstration of growth hormone receptors in cultured rat epiphyseal chondrocytes by specific binding of growth hormone and immunohistochemistry. J. Endocrinol. 122: 69–77, 1989.
 102. Nilsson, A., D. Swolin, S. Enerback, and C. Ohlsson. Expression of functional growth hormone receptors in cultured human osteoblast‐like cells. J. Clin. Endocrinol. Metab. 80: 3483–3488, 1995.
 103. Nishiyama, K., T. Sugimoto, H. Kaji, M. Kanatani, T. Kobayashi, and K. Chihara. Stimulatory effect of growth hormone on bone resorption and osteoclast differentiation. Endocrinology 137: 35–41, 1996.
 104. Nixon, B. T., and H. Green. Growth hormone promotes the differentiation of myoblasts and preadipocytes generated by azacytidine treatment of 10T1/2 cells. Proc. Natl. Acad. Sci. USA 81: 3429–3432, 1984.
 105. Nixon, T., and H. Green. Properties of growth hormone receptors in relation to the adipose conversion of 3T3 cells. J. Cell. Physiol. 115: 291–296, 1983.
 106. Nixon, T, and H. Green. Contribution of growth hormone to the adipogenic activity of serum. Endocrinology 114: 527–532, 1984.
 107. Ohlsson, C., B. A. Bengtsson, O. G. Isaksson, T. T. Andreassen, M. C. Slootweg. Growth hormone and bone. Endocr. Rev. 19: 55–79, 1998.
 108. Ohlsson, C., O. Isaksson, and A. Lindahl. Clonal analysis of rat tibia growth plate chondrocytes in suspension culture—differential effects of growth hormone and insulin‐like growth factor I. Growth Regul. 4: 1–7, 1994.
 109. Ohlsson, C., J. Isgaard, J. Tornell, A. Nilsson, O. G. Isaksson, and A. Lindahl. Endocrine regulation of longitudinal bone growth. Acta Paediatr. Suppl. 391: 33–40, 1993.
 110. Ohlsson, C., and E. Jennische. Effects in skeletal muscle of supraphysiological growth hormone stimulation. Eur. J. Endocrinol. 133: 678–679, 1995.
 111. Ohlsson, C., K. Lovstedt, P. V. Holmes, A. Nilsson, L. Carlsson, and J. Tornell. Embryonic stem cells express growth hormone receptors: regulation by retinoic acid. Endocrinology 133: 2897–2903, 1993.
 112. Ohlsson, C., A. Nilsson, O. G. Isaksson, and A. Lindahl. Effect of growth hormone and insulin‐like growth factor‐I on DNA synthesis and matrix production in rat epiphyseal chondrocytes in monolayer culture. J. Endocrinol. 133: 291–300, 1992.
 113. Ohlsson, C., A. Nilsson, O. Isaksson, and A. Lindahl. Growth hormone induces multiplication of the slowly cycling germinal cells of the rat tibial growth plate. Proc. Natl. Acad. Sci. USA 89: 9826–9830, 1992.
 114. Okazaki, R., C. A. Conover, S. A. Harris, T. C. Spelsberg, and B. L. Riggs. Normal human osteoblast‐like cells consistently express genes for insulin‐like growth factors I and II but transformed human osteoblast cell lines do not. J. Bone Miner. Res. 10: 788–795, 1995.
 115. Pairault, J., and H. Green. A study of the adipose conversion of suspended 3T3 cells by using glycerophosphate dehydrogenase as differentiation marker. Proc. Natl. Acad. Sci. USA 76: 5138–5142, 1979.
 116. Palmiter, R. D., R. L. Brinster, R. E. Hammer, M. E. Trumbauer, M. G. Rosenfeld, N. C. Birnberg, and R. M. Evans. Dramatic growth of mice that develop from eggs microinjected with metallothionein‐growth hormone fusion genes. Nature 300: 611–615, 1982.
 117. Postel‐Vinay, M. C., M. T. Corvol, F. Lang, F. Fraud, H. Guyda, and B. Posner. Receptors for insulin‐like growth factors in rabbit articular and growth plate chondrocytes in culture. Exp. Cell Res. 148: 105–116, 1983.
 118. Powell‐Braxton, L., P. Hollingshead, C. Warburton, M. Dowd, S. Pitts‐Meek, D. Dalton, N. Gillett, and T. A. Stewart. IGF‐I is required for normal embryonic growth in mice. Genes Dev. 7: 2609–2617, 1993.
 119. Ranke, M., M. Savage, P. Chatelain, M. Preece, R. Rosenfeld, W. Blum, and P. Wilton. Insulin‐like growth factor I improves height in growth hormone insensitivity: two years' result. Harm. Res. 44: 253–264, 1995.
 120. Rapaport, R., I. N. Sills, L. Green, P. Barrett, J. Labus, K. A. Skuza, A. Chartoff, L. Goode, M. Stene, and B. H. Petersen. Detection of human growth hormone receptors on IM‐9 cells and peripheral blood mononuclear cell subsets by flow cytometry: correlation with growth hormone–binding protein levels. J. Clin. Endocrinol. Metab. 80: 2612–2619, 1995.
 121. Riggs, B. L., R. V. Randall, H. W. Wahner, J. Jowsey, P. J. Kelly, and M. Singh. The nature of the metabolic bone disorder in acromegaly. J. Clin. Endocrinol. Metab. 34: 911–918, 1972.
 122. Rinderknecht, E., and R. E. Humbel. Polypeptides with non‐suppressible insulin‐like and cell‐growth promoting activities in human serum: isolation, chemical characterization, and some biological properties of forms I and II. Proc. Natl. Acad. Sci. USA 73: 2365–2369, 1976.
 123. Rinderknecht, E., and R. E. Humbel. The amino acid sequence of human insulin‐like growth factor I and its structural homology with proinsulin. J. Biol. Chem. 253: 2769–2776, 1978.
 124. Rinderknecht, E., and R. E. Humbel. Primary structure of human insulin‐like growth factor II. FEBS Lett. 89: 283–286, 1978.
 125. Rosen, T., T. Hansson, H. Granhed, J. Szucs, and B. A. Bengtsson. Reduced bone mineral content in adult patients with growth hormone deficiency. Acta Endocrinol. (Copenh.) 129: 201–206, 1993.
 126. Rosen, T., L. Wilhemsen, K. Landin‐Wilhemsen, G. Lappas, G. Lindstedt, and B. Bengtsson. Increased fracture rate in growth hormone (GH) deficient adults program, The Endocrine Society, 77th Meeting, Washington, DC, 1995.
 127. Russell, S. M., and E. M. Spencer. Local injections of human or rat growth hormone or of purified human somatomedin‐C stimulate unilateral tibial epiphyseal growth in hypophysectomized rats. Endocrinology 116: 2563–2567, 1985.
 128. Saggese, G., G. I. Baroncelli, S. Bertelloni, L. Cinquanta, and G. Di Nero. Effects of long‐term treatment with growth hormone on bone and mineral metabolism in children with growth hormone deficiency. J. Pediatr. 122: 37–45, 1993.
 129. Salazar‐Olivo, L. A., F. Castro‐Munozledo, and W. Kuri‐Harcuch. A preadipose 3T3 cell variant highly sensitive to adipogenic factors and to human growth hormone. J. Cell Sci. 108: 2101–2107, 1995.
 130. Salmon, W. D., and W. H. Daughaday. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J. Lab. Clin. Med. 49: 825–836, 1957.
 131. Sandstedt, J., J. Tornell, E. Norjavaara, O. Isaksson, and C. Ohlsson. Elevated levels of growth hormone increase bone mineral content in normal young mice, but not in ovariectomized mice. Endocrinology 137: 3368–3374, 1996.
 132. Scheven, B. A., and N. J. Hamilton. Longitudinal bone growth in vitro: effects of insulin‐like growth factor I and growth hormone. Acta Endocrinol. (Copenh. 124: 602–607, 1991.
 133. Schlechter, N. L., S. M. Russell, S. Greenberg, E. M. Spencer, and C. S. Nicoll. A direct growth effect of growth hormone in rat hindlimb shown by arterial infusion. Am. J. Physiol. (Endocrinol. Metab. 13) 250: E231–E235, 1986.
 134. Schlechter, N. L., S. M. Russell, E. M. Spencer, and C. S. Nicoll. Evidence suggesting that the direct growth‐promoting effect of growth hormone on cartilage in vitro is mediated by local production of somatomedin. Proc. Natl. Acad. Sci. USA 83: 7932–7934, 1986.
 135. Schmid, C., M. Ernst, J. Zapf, and E. R. Froesch. Release of insulin‐like growth factor carrier proteins by osteoblasts: stimulation by estradiol and growth hormone. Biochem. Biophys. Res. Commun. 160: 788–794, 1989.
 136. Skottner, A., R. G. Clark, I. C. Robinson, and L. Fryklund. Recombinant human insulin‐like growth factor: testing the somatomedin hypothesis in hypophysectomized rats. J. Endocrinol. 112: 123–132, 1987.
 137. Slootweg, M. C. Growth hormone and bone. Horm. Metab. Res. 25: 335–343, 1993.
 138. Slootweg, M. C., R. P. de Groot, M. P. Herrmann‐Erlee, I. Koornneef, W. Kruijer, and Y. M. Kramer. Growth hormone induces expression of c‐jun and jun B oncogenes and employs a protein kinase C signal transduction pathway for the induction of c‐fos oncogene expression. J. Mol. Endocrinol. 6: 179–188, 1991.
 139. Slootweg, M. C., S. C. van Buul‐Offers, M. P. Herrmann‐Erlee, and S. A. Duursma. Direct stimulatory effect of growth hormone on DNA synthesis of fetal chicken osteoblasts in culture. Acta Endocrinol. (Copenh.) 118: 294–300, 1988.
 140. Slootweg, M. C., S. T. van Genesen, A. P. Otte, S. A. Duursma, and W. Kruijer. Activation of mouse osteoblast growth hormone receptor: c‐fos oncogene expression independent of phosphoinositide breakdown and cyclic AMP. J. Mol. Endocrinol. 4: 265–274, 1990.
 141. Smith, R. L., M. V. Palathumpat, C. W. Ku, and R. L. Hintz. Growth hormone stimulates insulin‐like growth factor I actions on adult articular chondrocytes. J. Orthop. Res. 7: 198–207, 1989.
 142. Spiegelman, B. M., M. Frank, and H. Green. Molecular cloning of mRNA from 3T3 adipocytes. Regulation of mRNA content for glycerophosphate dehydrogenase and other differentiation‐dependent proteins during adipocyte development. J. Biol. Chem. 258: 10083–10089, 1983.
 143. Stracke, H., A. Schulz, D. Moeller, S. Rossol, and H. Schatz. Effect of growth hormone on osteoblasts and demonstration of somatomedin‐C/IGF I in bone organ culture. Acta Endocrinol. (Copenh.) 107: 16–24, 1984.
 144. Swolin, D., C. Brantsing, G. Matejka, and C. Ohlsson. Cortisol decreases IGF‐I mRNA levels in human osteoblast‐like cells. J. Endocrinol. 149: 397–403, 1996.
 145. Tobias, J. H., J. W. Chow, and T. J. Chambers. Opposite effects of insulin‐like growth factor‐I on the formation of trabecular and cortical bone in adult female rats. Endocrinology 131: 2387–2392, 1992.
 146. Trippel, S. B., M. T. Corvol, M. F. Dumontier, R. Rappaport, H. H. Hung, and H. J. Mankin. Effect of somatomedin‐C/insulin‐like growth factor I and growth hormone on cultured growth plate and articular chondrocytes. Pediatr. Res. 25: 76–82, 1989.
 147. Trippel, S. B., J. J. Van Wyk, M. B. Foster, and M. E. Svoboda. Characterization of a specific somatomedin‐C receptor on isolated bovine growth plate chondrocytes. Endocrinology 112: 2128–2136, 1983.
 148. Trippel, S. B., J. J. Van Wyk, and H. J. Mankin. Localization of somatomedin‐C binding to bovine growth‐plate chondrocytes in situ. J. Bone Joint Surg. Am. 68: 897–903, 1986.
 149. Trippel, S. B., J. Wroblewski, A. M. Makower, M. C. Whelan, D. Schoenfeld, and S. R. Doctrow. Regulation of growth‐plate chondrocytes by insulin‐like growth‐factor I and basic fibroblast growth factor. J. Bone. Joint Surg. Am. 75: 177–189, 1993.
 150. Van den Brande, J. L., and S. van Buul‐Offers. Effect of growth hormone and peptide fractions containing somatomedin activity on growth and cartilage metabolism of Snell dwarf mice. Acta Endocrinol. (Copenh.) 92: 242–257, 1979.
 151. Vannier, C., D. Gaillard, P. Grimaldi, E. Z. Amri, P. Djian, C. Cermolacce, C. Forest, J. Etienne, R. Negrel, and G. Ailhaud. Adipose conversion of ob17 cells and hormone‐related events. Int. J. Obes. 9 (Suppl. 1): 41–53, 1985.
 152. Verhaeghe, J., A.M. Suiker, W.J. Visser, E. Van Herck, R. Van Bree, and R. Bouillon. The effects of systemic insulin, insulin‐like growth factor‐I and growth hormone on bone growth and turnover in spontaneously diabetic BB rats. J. Endocrinol. 134: 485–492, 1992.
 153. Vetter, U., J. Zapf, W. Heit, G. Helbing, E. Heinze, E. R. Froesch, and W. M. Teller. Human fetal and adult chondrocytes. Effect of insulin‐like growth factors I and II, insulin, and growth hormone on clonal growth. J. Clin. Invest. 77: 1903–1908, 1986.
 154. Vikman, K., B. Carlsson, H. Billig, and S. Eden. Expression and regulation of growth hormone (GH) receptor messenger ribonucleic acid (mRNA) in rat adipose tissue, adipocytes, and adipocyte precursor cells: GH regulation of GH receptor mRNA. Endocrinology 129: 1155–1161, 1991.
 155. Vikman, K., J. Isgaard, and S. Eden. Growth hormone regulation of insulin‐like growth factor‐I mRNA in rat adipose tissue and isolated rat adipocytes. J. Endocrinol. 131: 139–145, 1991.
 156. Walker, J. L., R. C. Baxter, S. Young, J. Pucilowska, D. R. Clemmons, and L. E. Underwood. Effects of recombinant insulin‐like growth factor I on IGF binding proteins and the acid‐labile subunit in growth hormone insensitivity syndrome. Growth Regul. 3: 109–112, 1993.
 157. Walker, J. L., M. Ginalska‐Malinowska, T. E. Romer, J. B. Pucilowska, and L. E. Underwood. Effects of the infusion of insulin‐like growth factor I in a child with growth hormone insensitivity syndrome (Laron dwarfism). N. Engl. J. Med. 324: 1483–1488, 1991.
 158. Walker, J. L., J. J. Van Wyk, and L. E. Underwood. Stimulation of statural growth by recombinant insulin‐like growth factor I in a child with growth hormone insensitivity syndrome (Laron type) [see comments]. J. Pediatr. 121: 641–646, 1992.
 159. Werther, G. A., K. M. Haynes, R. Barnard, and M. J. Waters. Visual demonstration of growth hormone receptors on human growth plate chondrocytes. J. Clin. Endocrinol. Metab. 70: 1725–1731, 1990.
 160. Werther, G. A., K. Haynes, S. Edmonson, S. Oakes, C. J. Buchanan, A. C. Herington, and M. J. Waters. Identification of growth hormone receptors on human growth plate chondrocytes. Acta Paediatr. Suppl. 391: 50–53, 1993.
 161. Wise, L. S., and H. Green. Participation of one isozyme of cytosolic glycerophosphate dehydrogenase in the adipose conversion of 3T3 cells. J. Biol. Chem. 254: 273–275, 1979.
 162. Wuster, C., E. Slenczka, and R. Ziegler. Increased prevalence of osteoporosis and arteriosclerosis in conventionally substituted anterior pituitary insufficiency: need for additional growth hormone substitution? Klin. Wochenschr. 69: 769–773, 1991.
 163. Zadik, Z., Z. Estrov, Y. Karov, T. Hahn, and Y. Barak. The effect of growth hormone and IGF‐I on clonogenic growth of hematopoietic cells in leukemic patients during active disease and during remission—a preliminary report. J. Pediatr. Endocrinol. 6: 79–83, 1993.
 164. Zezulak, K. M., and H. Green. The generation of insulin‐like growth factor‐1‐sensitive cells by growth hormone action. Science 233: 551–553, 1986.

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: The Dual Effector Theory
 

How to Cite

Claes Ohlsson, Anders Lindahl, Jörgen Isgaard, Anders Nilsson, Olle G. P. Isaksson. The Dual Effector Theory. Compr Physiol 2011, Supplement 24: Handbook of Physiology, The Endocrine System, Hormonal Control of Growth: 501-514. First published in print 1999. doi: 10.1002/cphy.cp070516