The anabolic effects of GH/IGF systems on bone

Current Pharmaceutical Design

Volumn 10, Issue 21, 2004, Pages 2577-2592

  Kasukawa, Yuji ^a   Miyakoshi, Naohisa ^a   Mohan, Subburaman ^b,c  

^a AKITA UNIVERSITY SCHOOL OF MEDICINE   (Japan)

^b VETERANS AFFAIRS MEDICAL CENTER   (United States)

^c LOMA LINDA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Bone formation; Growth hormone (GH); IGF receptors; IGF binding proteins (IGFBPs); IGFBP protease; Insulin growth factors (IGFs); Osteoporosis; Somatomedin hypothesis

Indexed keywords

CALCITRIOL; CALCIUM; ENZYME ACTIVATOR; ENZYME INHIBITOR; ESTRADIOL; GLUCOCORTICOID; GROWTH HORMONE; GROWTH HORMONE RELEASING FACTOR; GROWTH HORMONE SECRETAGOGUE; INSULIN RECEPTOR SUBSTRATE 1; INSULIN RECEPTOR SUBSTRATE 2; JANUS KINASE 2; LIGAND; PARATHYROID HORMONE; PROTEINASE; RECOMBINANT SOMATOMEDIN C; SEX HORMONE; SOMATOMEDIN; SOMATOMEDIN B; SOMATOMEDIN BINDING PROTEIN; SOMATOMEDIN BINDING PROTEIN 2; SOMATOMEDIN BINDING PROTEIN 3; SOMATOMEDIN BINDING PROTEIN 4; SOMATOMEDIN BINDING PROTEIN 5; SOMATOMEDIN C; SOMATOMEDIN RECEPTOR; SOMATOSTATIN; STAT PROTEIN; UNINDEXED DRUG; VITAMIN D;

AGING; BONE DENSITY; BONE DISEASE; BONE GROWTH; BONE MASS; BONE METABOLISM; BONE MINERAL; BONE REMODELING; CLINICAL STUDY; CLINICAL TRIAL; CORTICOSTEROID INDUCED OSTEOPOROSIS; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; ELDERLY CARE; EXPERIMENTATION; GROWTH HORMONE DEFICIENCY; GROWTH HORMONE RELEASE; HORMONAL REGULATION; HORMONE ACTION; HUMAN; IDIOPATHIC OSTEOPOROSIS; IN VITRO STUDY; IN VIVO STUDY; NONHUMAN; NUTRITIONAL STATUS; OSSIFICATION; OSTEOLYSIS; OSTEOPENIA; OSTEOPOROSIS; PHYSICAL ACTIVITY; POSTMENOPAUSE OSTEOPOROSIS; PRIORITY JOURNAL; PROTEIN DEFICIENCY; PROTEIN EXPRESSION; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; TRANSGENIC MOUSE; TREATMENT PLANNING;

ANIMALS; BONE DEVELOPMENT; BONE DISEASES; GROWTH HORMONE; HUMAN GROWTH HORMONE; HUMANS; INSULIN-LIKE GROWTH FACTOR BINDING PROTEINS; INSULIN-LIKE GROWTH FACTOR I; INSULIN-LIKE GROWTH FACTOR II; MICE; MICE, TRANSGENIC; RECEPTOR, IGF TYPE 1; RECEPTOR, IGF TYPE 2; SIGNAL TRANSDUCTION; SOMATOMEDINS;

EID: 3242877269     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/1381612043383764     Document Type: Review

References (263)

1. Veldhuis JD, Anderson SM, Shah N, Bray M, Vick T, Gentili A, et al. Neurophysiological regulation and target-tissue impact of the pulsatile mode of growth hormone secretion in the human. Growth Horm IGF Res 2001; 11: S25-37.
2. Spagnoli A, Rosenfeld RG. The mechanisms by which growth hormone brings about growth. The relative contributions of growth hormone and insulin-like growth factors. Endocrinol Metab Clin North Am 1996; 25: 615-31.
3. Cohick WS, Clemmons DR. The insulin-like growth factors. Annu Rev Physiol 1993; 55: 131-53.
4. Stewart CE, Rotwein P. Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors. Physiol Rev 1996; 76: 1005-26.
5. Mohan S, Baylink DJ. IGF system components and their role in bone metabolism. In IGFs in Health and Disease, pp 457-496. Eds RG Rosen feld & CT Roberts. New Jersey: Humana Press.
6. Mohan S, Baylink DJ, Pettis JL. Insulin-like growth factor (IGF)-binding proteins in serum - do they have additional roles besides modulating the endocrine IGF actions? J Clin Endocrinol Metab 1996; 81: 3817-20.
7. Butler AA, LeRoith D. Minireview: tissue-specific versus generalized gene targeting of the igf1 and igf1 r genes and their roles in insulin-like growth factor physiology. Endocrinology 2001; 142: 1685-8.
8. Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995; 16: 3-34.
9. Clark RG, Carlsson LM, Robinson IC. Growth hormone secretory profiles in conscious female rats. J Endocrinol 1987; 114: 399-407.
10. Eden S. Age- and sex-related differences in episodic growth hormone secretion in the rat. Endocrinology 1979; 105: 555-60.
11. Saunders A, Terry LC, Audet J, Brazeau P, Martin JB. Dynamic studies of growth hormone and prolactin secretion in the female rat. Neuroendocrinology 1976; 21: 193-203.
12. Spiess J, Rivier J, Vale W. Characterization of rat hypothalamic growth hormone-releasing factor. Nature 1983; 303: 532-5.
13. Ling N, Esch F, Bohlen P, Wehrenberg WB, Guillemin R. Isolation, primary structure, and synthesis of human hypothalamic somatocrinin: growth hormone-releasing factor. Proc Natl Acad Sci USA 1984; 81: 4302-6.
14. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 1973; 179: 77-9.
15. Smith RG, Pong SS, Hickey G, Jacks T, Cheng K, Leonard R, et al. Modulation of pulsatile GH release through a novel receptor in hypothalamus and pituitary gland. Recent Prog Horm Res 1996; 51: 261-85.
16. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996; 273: 974-7.
17. Muggeo M, Tiengo A, Fedele D, Crepaldi G. The influence of plasma triglycerides on human growth hormone response to arginine and insulin: a study in hyperlipemics and normal subjects. Horm Metab Res 1975; 7: 367-74.
18. Imaki T, Shibasaki T, Shizume K, Masuda A, Hotta M, Kiyosawa Y, et al. The effect of free fatty acids on growth hormone (GH)-releasing hormone-mediated GH secretion in man. J Clin Endocrinol Metab 1985; 60, 290-3.
19. Carro E, Senaris R, Considine RV, Casanueva FF, Dieguez C. Regulation of in vivo growth hormone secretion by leptin. Endocrinology 1997; 138: 2203-6.
20. Tannenbaum GS, Gurd W, Lapointe M. Leptin is a potent stimulator of spontaneous pulsatile growth hormone (GH) secretion and the GH response to GH-releasing hormone. Endocrinology 1998; 139: 3871-5.
21. Vuagnat BA, Pierroz DD, Lalaoui M, Englaro P, Pralong FP, Blum WF, et al. Evidence for a lepti-neuropeptide Y axis for the regulation of growth hormone secretion in the rat. Neuroendocrinology 1998; 67: 291-300.
22. Smith RG, Van der Ploeg LH, Howard AD, Feighner SD, Cheng K, Hickey GJ, et al. Peptidomimetic regulation of growth hormone secretion. Endocr Rev. 1997; 18: 621-45.
23. Dehgenghi R, Cananzi MM, Torsello A, Battisti C, Muller FE, Locatelli V. GH-releasing activity of Hexarelin, a new growth hormone releasing peptide, in infant and adult rats. Life Sci. 1994; 18: 1321-8.
24. Patchett AA, Nargund RP, Tata JR, Chen M-H, Barakat KJ, Johnston DBR, et al. Design and biological activities of L 163, 191(MK-0677), a potent, orally active growth hormone secretagogue. Proc Natl Acad Sci USA 1995; 92: 7001-5.
25. Ghigo E, Arvat E, Gianotti L, Imbimbo BP, Lenaerts V, Deghenghi R, et al. Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal and oral administration in man. J Clin Endocrinol Metab 1994; 78: 693-8.
26. Howard AD, Feighner SD, Cully DF, Arena JF, Liberator PA, Rosenblum CI, et al. Cloning of a G-protein coupled receptor for the growth hormone-releasing peptide (GHRP-6) and non-peptidyl growth hormone secretagogues. Science 1996; 273: 974-7.
27. Kojima M, Hosoda H, Date Y, Nakazato M, Matsui H, Kangawa K. Ghrelin is a growth hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656-60.
28. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 2000; 141: 4325-8.
29. Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, et al. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 2000; 85: 4908-11.
30. Ho KK, O'Sullivan AJ, Weissberger AJ, Kelly JJ. Sex steroid regulation of growth hormone secretion and action. Horm Res 1996; 45: 67-73.
31. Baumann G, Stolar MW, Amburn K, Barsano CP, DeVries BC. A specific growth hormone-binding protein in human plasma: initial characterization. J Clin Endocrinol Metab 1986; 62: 134-41.
32. Leung DW, Spencer SA, Cachianes G, Hammonds RG, Collins C, Henzel R, et al. Growth hormone receptor and serum binding protein: purification, cloning and expression. Nature 1987; 330: 537-43.
33. Carter-Su C, Smit LS. Signaling via JAK tyrosine kinases: growth hormone receptor as a model system. Recent Prog Horm Res 1998; 53: 61-82.
34. Takeda K, Akira S. STAT family of transcription factors in cytokine-mediated biological responses. Cytokine Growth Factor Rev 2000; 11: 199-207.
35. Leonard WJ, O'Shea JJ. Jaks and STATs: biological implications. Annu Rev Immunol 1998; 16: 293-322.
36. Argetsinger LS, Norstedt G, Billestrup N, White MF, Carter-Su C. Growth hormone, interferon-gamma, and leukemia inhibitory factor utilize insulin receptor substrate-2 in intracellular signaling. J Biol Chem 1996; 271: 29415-21.
37. Carter-Su C, King AP, Argetsinger LS, Smit LS, Vanderkuur J, Campbell GS. Signalling pathway of GH. Endocr J 1996; 43: S65-70.
38. Souza SC, Frick GP, Yip R, Lobo RB, Tai LR, Goodman HM. Growth hormone stimulates tyrosine phosphorylation of insulin receptor substrate-1. J Biol Chem 1994; 269: 30085-8.
39. Billestrup N, Moldrup A, Serup P, Mathews LS, Norstedt G, Nielsen JH. Introduction of exogenous growth hormone receptors augments growth hormone-responsive insulin biosynthesis in rat insulinoma cells. Proc Natl Acad Sci USA 1990; 265: 8686-90.
40. Anderson NG. Growth hormone activates mitogen-activated protein kinase and S6 kinase and promotes intracellular tyrosine phosphorylation in 3T3-F442A preadipocytes. Biochem J 1992; 284: 649-52.
41. Campbell GS, Pang L, Miyasaka T, Saltiel AR, Carter-Su C. Stimulation by growth hormone of MAP kinase activity in 3T3-F442A fibroblasts. J Biol Chem 1992; 267: 6074-80.
42. Smal J, De Meyts P. Role of kinase C in the insulin-like effects of human growth hormone in rat adipocytes. Biochem Biophys Res Common 1987; 147: 1232-40.
43. Krebs DL, Hilton DJ. SOCS: physiological suppressors of cytokine signaling. J Cell Sci 2000; 113: 2813-9.
44. Tollet-Egnell P, Flores-Morales A, Stavreus-Evers A, Sahlin L, Norstedt G. Growth hormone regulation of SOCS-2, SOCS-3, and CIS messenger ribonucleic expression in the rat. Endocrinology 1999; 140: 3693-704.
45. Ram PA, Waxman DJ. SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. J Biol Chem 1999; 274: 35553-61.
46. Metcalf D, Greenhalgh CJ, Viney E, Willson TA, Starr R, Nicola NA, et al. Gigantism in mice lacking suppressor of cytokine signaling-2. Nature 2000; 405: 1069-73.
47. Horvat S, Medrano JF. Lack of SOCS-2 expression causes the high-growth phenotype in mice. Genomics 2001; 72: 209-12.
48. Greenhalgh CJ, Metcalf D, Thaus AL, Corbin JE, Uren R, Morgan PO, et al. Biological evidence that SOCS-2 can act either as an enhancer or suppressor of growth hormone signaling. J Biol Chem 2002; 277: 40181-4.
49. Mohan S, Jennings JC, Linkhart TA, Baylink DJ. Primary structure of human skeletal growth factor: homology with human insulin-like growth factor-II. Biochim Biophys Acta 1988; 966: 44-55.
50. Canalis E, Pash JM, Verghese S. Skeletal growth facotors. Crit Rev Euk Gene Expr 1993; 3: 155-66.
51. Baylink DJ, Finkelman RD, Mohan S. Growth factors to stimulate bone formation. J Bone Miner Res 1993; 8: S565-72.
52. Shinar DM, Endo N, Halperin D, Rodan GA, Weinreb M. Differential expression of insulin-like growth factor-I (IGF-I) and IGF-II messenger ribonucleic acid in growing rat bone. Endocrinology 1993; 132: 1158-67.
53. McCarthy TL, Ji C, Shu H, Casinghino S, Crothers K, Rotwein P, et al. 17 beta-estradiol potently suppresses cAMP-induced insulin-like growth factor-I gene activation in primary rat osteoblast cultures. J Biol Chem 1997; 272: 18132-9.
54. Ernst M, Rodan GA. Estradiol regulation of insulin-like growth factor-I expression in osteoblastic cells: evidence for transcriptional control. Mol Endocrinol 1991; 5: 1081-9.
55. Gray TK, Mohan S, Linkhart TA, Baylink DJ. Estradiol stimulates in vitro the secretion of insulin-like growth factors by the clonal osteoblastic cell line, UMR106. Biochem, Biophys Res Commun 1989; 20: 23-32.
56. McCarthy TL, Centrella M, Canalis E. Cyclic AMP induces insulin-like growth factor-I synthesis in osteoblast-enriched cultures. J Biol Chem 1990; 265: 15353-6.
57. Thomas MJ, Umayahara Y, Shu H, Centrella M, Rotwein P, McCarthy TL. Identification of the cAMP response element that controls transcriptional activation of the insulin-like growth factor-I gene by prostaglandin E2 in osteblasts. J Biol Chem 1996; 271: 21835-41.
58. Chen TL, Chang LY, Bates RL, Perlman AJ. Dexamethasone and 1,25-dihydroxuvitamine D3 modulation of insulin-like growth factor-binding proteins in rat osteoblast-like cell cultures. Endocrinology 1991; 128: 73-80.
59. Canalis E. Mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis. J Clin Endocrinol Metab 1996; 81: 3441-7.
60. Scharla SH, Strong DD, Mohan S, Baylink DJ, Linkhart TA. 1,25-Dihydroxyvitamin D3 differentially regulates the production of insulin-like growth factor I (IGF-I) and IGF-binding protein-4 in mouse osteoblasts. Endocrinology 1991; 129: 3139-46.
61. Linkhart TA, MacCharles DC. Interleukin-1 stimulates release of insulin-like growth factor-I from neonatal mouse calvaria by a prostaglandin synthesis-dependent mechanism. Endocrinology 1992; 131: 2297-305.
62. Gabbitas B, Pash J, Canalis E. Regulation of insulin-like growth factor-II synthesis in bone cell cultures by skeletal growth factors. Endocrinology 1994; 135: 284-9.
63. Zhang X, Sobue T, Hurley MM. FGF-2 increases colony formation, PTH receptor, and IGF-I mRNA in mouse marrow stromal cells. Biochem Biophys Res Commun 2002; 290: 526-31.
64. Kveiborg M, Flyvbjerg A, Eriksen EF, Kassem M. Transforming growth factor-beta 1 stimulates the production of insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in human bone marrow stromal osteoblast progenitors. J Endocrinol. 2001; 169: 549-61.
65. Malpe R, Baylink DJ, Linkhart TA, Wergedal JE, Mohan S. Insulin-like growth factor (IGF)-I, -II, IGF binding proteins (IGFBP)-3, -4, and-5 levels in the conditioned media of normal human bone cells are skeletal site-dependent. J Bone Miner Res 1997; 12: 423-30.
66. Okazaki R, Durham SK, Riggs BL, Conover CA. Transforming growth factor-beta and forskolin increase all classes of insulin-like growth factor-I transcripts in normal human osteoblast-like cells. Biochem Biophys Res Commun 1995; 207: 963-70.
67. Strom P, Ljunghall S, Melhus H. Adult human osteoblast-like cells do not express insulin-like growth factor-I. Biochem Biophys Res Common 1994; 199: 78-82.
68. Tremollieres FA, Strong DD, Baylink DJ, Mohan S. Progesterone and promegestone stimulate human bone cell proliferation and insulin-like growth factor-2 production. Acta Endocrinol 1992; 126: 329-37.
69. Cheng SL, Zhang SF, Mohan S, Lecanda F, Fausto A, Hunt AH, et al. Regulation of insulin-like growth factors I and II and their binding proteins in human bone marrow stromal cells by dexamethasone. J Cell Biochem. 1998; 71: 449-58.
70. Slootweg MC, Hoogerbrugge CM, de Poorter TL, Duursma SA, van Buul-Offers SC. The presence of classical insulin-like growth factor (IGF) type-I and -II receptors on mouse osteoblasts: autocrine/paracrine growth effect of IGFs? J Endocrinol 1990; 125: 271-7.
71. Linkhart TA, Jennings JC, Mohan S, Wakley GK, Baylink DJ. Characterization of mitogenic activities extracted from bovine bone matrix. Bone 1986; 7: 479-87.
72. Canalis E, Centrella M, Burch W, McCarthy TL. Insulin-like growth factor I mediates selective anabolic effects of parathyroid hormone in bone cultures. J Clin Invest 1989; 83: 60-5.
73. Langdahl BL, Kassem M, Moller MK, Eriksen EF. The effects of IGF-I and IGF-II on proliferation and differentiation of human osteoblasts and interactions with growth hormone. Eur J Clin Invest. 1998; 28: 176-83.
74. Canalis E, Rydziel S, Delany AM, Varghese S, Jeffrey JJ. Insulin-like growth factors inhibit interstitial collagenase synthesis in bone cell cultures. Endocrinology 1995; 136: 1348-54.
75. Strong DD, Beachler AL, Wergedal JE, Linkhart TA. Insulin-like growth factor II and transforming growth factor beta regulate collagen expression in human osteoblastlike cells in vitro. J Bone Miner Res 1991; 6: 15-23.
76. Rydziel S, Delany AM, Canalis E. Insulin-like growth factor I inhibits the transcription of collagenase 3 in osteoblast cultures. J Cell Biochem 1997; 67: 176-83.
77. Thomas T, Gori F, Spelsberg TC, Khosla S, Riggs BL, Conover CA. Response of bipotential human marrow stromal cells to insulin-like growth factors: effect on binding protein production, proliferation, and commitment to osteoblasts and adipocytes. Endocrinology 1999; 140: 5036-44.
78. Kasukawa Y, Stabnov L, Miyakoshi N, Baylink DJ, Mohan S. Insulin-like growth factor I effect on the number of osteoblast progenitors is impaired in ovariectomized mice. J Bone Miner Res 2002; 17: 1579-87.
79. Jia D, Heersche JN. Insulin-like growth factor-I and -II stimulate osteoprogenitor proliferation and differentiation and adipocyte formation in cell populations derived from adult rat bone. Bone 2000; 27: 785-94.
80. Eriksen EF, Kassem M, Langdahl B. Growth hormone, insulin-like growth factors and bone remodeling. Eur J Clin Invest 1996; 26: 525-34.
81. Rosen CJ. GH, insulin-like growth factors, and the senescent skeleton: Ponce de Leon's Fountain revisited? J Cell Biochem 1994; 56: 348-56.
82. Ammann P, Rizzoli R, Muller K, Slosman D, Bonjour JP. IGF-I and pamidronate increase bone mineral density in ovariectomized adult rats. Am J Physiol 1993; 265: E770-6.
83. Machwate M, Zerath E, Holy X, Pastoureau P, Marie PJ. Insulin-like growth Factor-I increases trabecular bone formation osteoblastic cell proliferation in unloaded rats. Endocrinology 1994; 134: 1031-8.
84. Spencer EM, Liu CC, Si EC, Howard GA. In vivo actions of insulin-like growth factor-I (IGF-I) on bone formation and resorption in rats. Bone 1991; 12: 21-6.
85. Zapf J, Froesch ER. Insulin-like growth factors/somatomedins: structure, secretion, biological actions and physiological role. Horm Res 1986; 24: 121-30.
86. Mueller K, Cortesi R, Modrowski D, Marie PJ. Stimulation of trabecular bone formation by insulin-like growth factor I in adult ovariectomized rats. AM J Physiol 1994; 267: E1-E6.
87. Verhaeghe J, van Bree R, Van Herck E, Thomas H, Skottner A, Dequeker J, et al. Effects of recombinant human growth hormone and insulin-like growth factor-I, with or without 17 beta-estradiol, on bone and mineral homeostasis of aged ovariectomized rats. J Bone Miner Res 1996; 11: 1723-35.
88. Narusawa K, Nakamura T, Suzuki K, Matsuoka Y, Lee LJ, Tanaka H, et al. The effects of recombinant human insulin-like growth factor (rhIGF)-I and rhIGF-I/IGF binding protein-3 administration on rat osteopenia induced by ovariectomy with concomitant bilateral sciatic neurectomy. J Bone Miner Res 1995; 10: 1853-64.
89. Wakisaka A, Tanaka H, Barnes J, Liang CT. Effect of locally infused IGF-I on femoral gene expression and bone turnover activity in old rats. J Bone Miner Res 1998; 13: 13-9.
90. Tanaka H, Wakisaka A, Ogasa H, Kawai S, Liang CT. Effect of IGF-I and PDGF administered in vivo on the expression of osteoblast-related genes in old rats. J Endocrinol 2002; 174: 63-70.
91. Walsh S, Jefferiss CM, Stewart K, Beresford JN. IGF-I does not affect the proliferation or early osteogenic differentiation of human marrow stromal cells. Bone 2003; 33: 80-9.
92. Raile K, Hille R, Laue S, Schulz A, Pfeifer G, Horn F, et al. Insulin-like growth factor I (IGF-I) stimulates proliferation but also increases caspase-3 activity, Annexin-V binding, and DNA-fragmentation in human MG63 osteosarcoma cells: co-activation of pro- and anti-apoptotic pathway by IGF-I. Horm Metab Res 2003; 35: 786-93.
93. Kawakami A, Nakashima T, Tsuboi M, Urayama S, Matsuoka N, Ida H, et al. Insulin-like growth factor I stimulates proliferation and Fas-mediated apoptosis of human osteoblasts. Biochem Biophys Res Commun 1998; 247: 46-51.
94. Herzlieb N, Gallaher BM, Berthold A, Hille R, Kiess W. Insulin-like growth factor-I inhibits the progression of human U-2 OS osteosarcoma cells towards programmed cell death through interaction with the IGF-I receptor. Cell Mol Biol 2000; 46: 71-7.
95. Schmid C, Ghirlanda-Keller C, Zapf J. Effeects of IGF-I and -II, IGF binding protein-3 (IGFBP-3), and transforming growth factor-beta (TGF-beta) on growth and apoptosis of human osteosarcoma Saos-2/B-10 cells: lack of IGF-independent IGFBP-3 effects. Eur J Endocrinol 2001; 168: 41-51.
96. Bikle D, Majumdar S, Laib A, Powell-Braxton L, Rosen C, Beamer W, et al. The skeletal structure of insulin-like growth factor I-deficient mice. J Bone Miner Res 2001; 16: 2320-9.
97. Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (IGF-I) and type I IGF receptor (IGF-IR). Cell 1993; 75: 59-72.
98. Powell-Braxton L, Hollingshead P, Warburton C, Dowd M, Pitts-Meek S, Dalton D, et al. IGF-I is required for normal embryonic growth in mice. Genes Dev 1993; 7: 2609-17.
99. Woods KA, Camacho-Hubner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Eng J Med 1996; 335: 1363-7.
100. Wang J, Zhou J, Bondy CA. Igf1 promotes longitudinal bone growth by insulin-like actions augmenting chondrocyte hypertrophy. FASEB J 1999; 13: 1985-90.
101. Shinar DM, Endo N, Halperin D, Rodan GA, Weinreb M. Differential expression of insulin-like growth factor-I (IGF-I) and IGF-II messenger ribonucleic acid in growing rat bone. Endocrinology 1993; 132: 1158-67.
102. Wang E, Wang J, Chin E, Zhou J, Bondy CA. Cellular patterns of insulin-like growth factor system gene expression in murine chondrogenesis and osteogenesis. Endcrinology 1995; 136: 2741-51.
103. Sjogren K, Liu JL, Blad K, Skrtic S, Vidal O, Wallenius V, et al. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc Natl Acad Sci USA 1999; 96: 7088-92.
104. Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, et al. Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci USA 1999; 96: 7324-9.
105. Sjogren K, Wallenius K, Liu JL, Bohlooly-Y M, Pacini G, Svensson L, et al. Live-derived IGF-I is of importance for normal carbohydrate and lipid metabolism. Diabetes 2001; 50: 1539-45.
106. Sjogren K, Sheng M, Moverare S, Liu JL, Wallenius K, Tornell J, et al. Effects of liver-derived insulin-like growth factor I on bone metabolism in mice. J Bone Miner Res 2002; 17: 1977-87.
107. Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y, Liu JL, et al. Circulating levels of IGF-I directly regulate bone growth and density. J Clin Invest 2002; 110: 771-81.
108. LeRoith D, Werner H, Beitner-Johanson D, Robert CT. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 1995; 16: 143-63.
109. Steele-Perkins G, Turner J, Edman JC, Hari J, Pierce SB, Stover C, et al. Expression and characterization of a functional human insulin-like growth factor I receptor. J Biol Chem 1988; 263: 11486-92.
110. Sasaki N, Rees-Jones RW, Zick Y, Nissley SP, Rechler MM. Characterization of insulin-like growth factor I-stimulated tyrosine kinase activity associated with the beta-subunit of type I insulin-like growth factor receptors of rat live cells. J Biol Chem 1985; 260: 9793-804.
111. Centrella M, McCarthy TL, Canalis E. Receptors for insulin-like growth factors-I and -II in osteoblast-enriched cultures from fetal rat bone. Endocrinology 1990; 126: 39-44.
112. Raile K, Hoflich A, Kessler U, Yang Y, Pfuender M, Blum WF, et al. Human osteosarcoma (U-2 OS) cells express both insulin-like growth factor-I (IGF-I) receptors and insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptors and synthesize IGF-II: autocrine growth stimulation by IGF-II via the IGF-I receptor. J Cell Physiol 1994; 159: 531-41.
113. Kadowaki T, Tobe K, Honda-Yamamoto R, Tamemoto H, Kaburagi Y, Momomura K, et al. Signal transduction mechanism of insulin and insulin-like growth factor-I. Endocr J 1996; 43: S33-S41.
114. Ogata N, Chikazu D, Kubota N, Terauchi Y, Tobe K, Azuma Y, et al. Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover. J Clin Invest 2000; 105: 935-43.
115. Akune T, Ogata N, Hoshi K, Kubota N, Terauchi Y, Tobe K, et al. Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts. J Cell Biol 2002; 159: 147-56.
116. Shimoaka T, Kamekura S, Chikuda H, Hoshi K, Chung UI, Akune T, et al. Impairment of bone healing by insulin receptor substrate-1 deficiency. J Biol Chem 2004; Epub ahead of print.
117. LaTour D, Mohan S, Linkhart TA, Baylink DJ, Strong DD. Inhibitory insulin-like growth factor-binding protein: cloning, complete sequence, and physiological regulation. Mol Endocrinol 1990; 4: 1806-14.
118. Conover CA, Bale LK, Clarkson JT, Torring O. Regulation of insulin-like growth factor binding protein-5 messenger ribonucleic acid expression and protein availability in rat osteoblast-like cells. Endocrinology 1993; 132: 2525-30.
119. Honda Y, Landale EC, Strong DD, Baylink DJ, Mohan S. Recombinant synthesis of insulin-like growth factor-binding protein-4 (IGFBP-4): development, validation, and application of a radioimmunoassay for IGFBP-4 in human serum and other biological fluids. J Clin Endocrinol Metab 1996; 81: 1389-96.
120. Scharla SH, Strong DD, Mohan S, Chevalley T, Linkhart TA. Effect of tumor necrosis factor-alpha on the expression of insulin-like growth factor I and insulin-like growth factor binding protein 4 in mouse osteoblasts. Eur J Endocrinol 1994; 131: 293-301.
121. Scharla SH, Strong DD, Rosen C, Mohan S, Holick M, Baylink DJ, et al. 1,25-dihydroxyvitamin D3 increases secretion of insulin-like growth factor binding protein-4 (IGFBP-4) by human osteoblast-like cells in vitro and elevates IGFBP-4 serum levels in vivo. J Clin Endocrinol Metab 1993; 77: 1190-7.
122. Kveiborg M, Flyvbjerg A, Eriksen EF, Kassen M. 1,25-Dihydroxyvitamin D3 stimulates the production of insulin-like growth factor-binding proteins-2, -3, and -4 in human bone marrow stromal cells. Eur J Endocrinol 2001; 144: 549-57.
123. Kassem M, Okazaki R, De Leon D, Harris SA, Robinson JA, Spelsberg TC, et al. Potential mechanism of estrogen-mediated decrease in bone formation: estrogen increases production of inhibitory insulin-like growth factor-binding protein-4. Proc Assoc Am Physicians 1996; 108: 155-64.
124. Okazaki R, Riggs BL, Conover CA. Glucocorticoid regulation of insulin-like growth factor-binding protein expression in normal human osteoblast-like cells. Endocrinology 1994; 134: 126-32.
125. Gabbitas B, Canalis E. Cortisol enhances the transcription of insulin-like growth factor binding protein-6 in skeletal cells. J Cell Physiol 1996, 169: 15-22.
126. Chevalley T, Strong DD, Mohan S, Baylink DJ, Linkhart TA. Evidence for a role for insulin-like growth factor binding proteins in glucocorticoid inhibition of normal human osteoblast-like cell proliferation. Eur J Endocrinol 1996; 134: 591-601.
127. Gabbitas B, Canalis E. Retinoic acid stimulates the transcription of insulin-like growth factor binding protein-6 in skeletal cells. J Cell Physiol 1996; 169: 15-22.
128. Zhou Y, Mohan S, Linkhart TA, Baylink DJ, Strong DD. Retinoic acid regulates insulin-like growth factor-binding protein expression in human osteoblast cells. Endocrinology 1996; 137: 975-83.
129. Kanzaki S, Hilliker S, Baylink DJ, Mohan S. Evidence that human bone cells in culture produce insulin-like growth factor-binding protein-4 and -5 proteases. Endocrinology 1994; 134: 383-92.
130. Knutsen R, Honda Y, Strong DD, Sampath TK, Baylink DJ, Mohan S. Regulation of insulin-like growth factor system components by osteogenic protein-1 in human bone cells. Endocrinology 1995; 136: 857-65.
131. Hayden JM, Strong DD, Baylink DJ, Powell DR, Sampath TK, Mohan S. Osteogenic protein-1 stimulates production of insulin-like growth factor binding protein-3 nuclear transcripts in human osteosarcoma cells. Endocrinology 1997; 138: 4240-7.
132. Conover CA. Insulin-like growth factor binding protein proteolysis in bone cell models. Prog Growth Factor Res 1995; 6: 301-9.
133. Mohan S, Nakao Y, Honda Y, Landale E, Leser U, Dolly C, et al. Studies on the mechanisms by which insulin-like growth factor (IGF) binding protein-4 (IGFBP-4) and IGFBP-5 modulate IGF actions in bone cells. J Biol Chem 1995; 270: 20424-31.
134. Qin X, Strong DD, Baylink DJ, Mohan S. Structure-function analysis of the human insulin-like growth factor binding protein-4. J Biol Chem 1998; 273: 23509-16.
135. Andress DL, Birnbaum RS. Human osteoblast-derived insulin-like growth factor (IGF) binding protein-5 stimulates osteoblast mitogenesis and potentiates IGF action. J Biol Chem 1992; 267: 22467-72.
136. Amaar YG, Thompson GR, Linkhart TA, Chen ST, Baylink DJ, Mohan S. Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2). J Biol Chem 2002; 277: 12053-60.
137. Miyakoshi N, Richman C, Qin X, Baylink DJ, Mohan S. Effects of recombinant insulin-like growth factor-binding protein-4 on bone formation parameters in mice. Endocrinology 1999; 140: 5719-28.
138. Miyakoshi N, Qin X, Kasukawa Y, Richman C, Srivastava AK, Baylink DJ, et al. Systemic administration of insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) increases bone formation parameters in mice by increasing IGF bioavailability via an IGFBP-4 protease-dependent mechanism. Endocrinology 2001; 142: 2641-8.
139. Wang J, Niu W, Witte DP, Chernausek SD, Nikiforov YE, Clemens TL, et al. Overexpression of insulin-like growth factor-binding protein-4 (IGFBP-4) in smooth muscle cells of transgenic mice through a smooth muscle alpha-actin-IGFBP-4 fusion gene induces smooth muscle hypoplasia. Endocrinology 1998; 139: 2605-14.
140. Rajaram S, Baylink D.L Mohan S. Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr Rev 1997; 18: 801-31.
141. Richman C, Baylink DJ, Lang K, Dony C, Mohan S. Recombinant human insulin-like growth factor-binding protein-5 stimulates bone formation parameters in vitro and in vivo. Endocrinology 1999; 140: 4699-705.
142. Miyakoshi N, Richman C, Kasukawa Y, Linkhart TA, Baylink DJ, Mohan S. Evidence that IGF-binding protein-5 functions as a growth factor. J Clin Invest 2001; 107: 73-81.
143. Hoeflich A, Wu M, Mohan S, Foll J, Wanke R, Froehlich T, et al. Overexpression of insulin-like growth factor-binding protein-2 in transgenic mice reduces postnatal body weight gain. Endocrinology 1999; 140: 5488-96.
144. Eckstein F, Pavicic T, Nedbal S, Schmidt C, Wehr U, Rambeck W, et al. Insulin-like growth factor-binding protein-2 (IGFBP-2) overexpression negatively regulates bone size and mass, but not density, in the absence and presence of growth hormone/IGF-I excess in transgenic mice. Anat Embryol 2002; 206: 139-48.
145. Silha JV, Mishra S, Rosen CJ, Beamer WG, Turner RT, Powell DR, et al. Perturbations in bone formation and resorption in insulin-like growth factor binding protein-3 transgenic mice. J Bone Miner Res 2003; 18: 1834-41.
146. Zhang M, Faugere MC, Malluche H, Rosen CJ, Chernausek SD, Clemens TL. Paracrine overexpression of IGFBP-4 in osteoblasts of transgenic mice decreases bone turnover and causes global growth retardation. J Bone Miner Res 2003; 18: 836-43.
147. Devlin RD, Du Z, Buccilli V, Jorgetti V, Canalis F. Transgenic mice overexpression insulin-like growth factor binding protein-5 display transiently decreased osteoblastic function and osteopenia. Endocrinology 2002; 143: 3955-62, .
148. Ueki I, Ooi GT, Tremblay ML, Hurst KR, Bach LA, Boisclair YR. Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system. Proc Nat Acad Sci USA 2000; 97: 6868-73.
149. Durham SK, Kiefer MC, Riggs BL, Conover CA. Regulation of insulin-like growth factor binding protein 4 by a specific insulin-like growth factor binding protein 4 proteinase in normal human osteoblast-like cells: implications in bone cell physiology. J Bone Miner Res 1994; 9: 111-7.
150. Durham SK, De Leon DD, Okazaki R, Riggs BL, Conover CA. Regulation of insulin-like growth factor (IGF)-binding protein-4 availability in normal human osteoblast-like cells: role of endogenous IGFs. J Clin Endocrinol Metab 1995; 80: 104-10.
151. Ortiz CO, Chen BK, Bale LK, Overgaard MT, Oxvig C, Conover CA. Transforming growth factor-beta regulation of the insulin-like growth factor binding protein-4 proteases system in cultured human osteoblasts. J Bone Miner Res 2003; 18: 1066-72.
152. Conover CA, Durham SK, Zapf J, Masiarz FR, Kiefer MC. Cleavage analysis of insulin-like growth factor (IGF)-dependent IGF-binding protein-4 proteolysis and expression of protease-resistant IGF-binding protein-4 mutants. J Biol Chem 1995; 270: 4395-400.
153. Thraikill KM, Siddhanti SR, Fowlkes JL, Quarles LD. Differentiation of MC3T3-E1 osteoblasts is associated with temporal changes in the expression of IGF-I and IGFBPs. Bone 1995; 17: 307-13.
154. Mohan S, Thompson GR, Amaar YG, Hathaway G, Tschesche H, Baylink DJ. ADAM-9 is an insulin-like growth factor binding protein-5 protease produced and secreted by human osteoblasts. Biochemistry 2002; 41: 15394-403.
155. Thrailkill KM, Quarles LD, Nagase H, Suzuki K, Serra DM, Fowlkes JL. Characterization of insulin-like growth factor-binding protein 5-degrading proteases produced throughout murine osteoblast differentiation. Endocrinology 1995; 136: 3527-33.
156. Overgaard MT, Boldt HB, Laursen LS, Sottrup-Jensen L, Conover CA, Oxvig C. Pregnancy-associated plasma protein-A2 (PAPP-A2), a novel insulin-like growth factor-binding protein-5 proteinase. J Biol Chem 2001; 276: 21849-53.
157. Murphy WR, Daughaday WH, Hartnett C. The effect of hypophysectomy and growth hormone on the incorporation of labeled sulfate into tibial epiphyseal and nasal cartilage of the rat. J Lab Clin Med 1956; 47: 715-22.
158. Salmon WD, Daughaday WH. A hormonally controlled serum factor which stimulates sulfate incorporation by cartilage in vitro. J Lab Clin Med 1957; 49: 825-6.
159. Denko CW, Bergenstal DM. The effect of hypophysectomy and growth hormone on cartilage sulfate metabolism. Proc Soc Exp Biol Med 1955; 47: 715-22.
160. Garland JT, Lottes ME, Kozak S, Daughaday WH. Stimulation of DNA synthesis in isolated chondrocytes by sulfation factor. Endocrinology 1972; 90: 1086-90.
161. Daughaday WH, Hall K, Raben MS, Salmon WD, van den Brande JL, van Wyk JJ. Somatomedin: porposed designation for sulphation factor. Nature 1972; 235: 107.
162. Klapper DG, Svoboda ME, Van Wyk JJ. Sequence and analysis of somatomedin-C: confirmation or identify with insulin-like growth factor I. Endocrinology 1983; 112: 2215-7.
163. Rinderknecht E, Humbel RE. The amino acid sequence of human insulin-like growth factor I and it structural homology with proinsulin. J Biol Chem 1978; 253: 2769-76.
164. LeRoith D, Bondy C, Yakar S, Liu JL, Butler A. The somatomedin hypothesis: 2001. Endocr Rev 2001; 22: 53-74.
165. Berelowitz M, Szabo M, Frohman LA, Firestone S, Chu L, Hintz RL. Somatomedin-C mediates growth hormone negative feedback by effects on both the hypothalamus and the pituitary. Science 1981; 212: 1279-81.
166. D'Ercole AJ, Applewhite GT, Underwood LE. Evidence that somatomedin is synthesized by multiple tissues in the fetus. Dev Biol 1980; 75: 315-28.
167. Roberts CT Jr, Lasky SR, Lowe WL Jr, Seaman WT, LeRoith D. Molecular cloning of rat insulin-like growth factor I complementary deoxyribonucleic acids: differential messenger ribonucleic acid processing regulation by growth hormone in extrahepatic tissues. Mol Endocrinol 1987; 1: 243-8.
168. Han VK, Lund PK, Lee DC, D'Ercole AJ. Expression of somatomedin/insulin-like growth factor messenger ribonucleic acids in the human fetus: identification, characterization and tissue distribution. J Clin Endocrinol Metab 1988; 66: 422-9.
169. Lowe WL Jr, Roberts CT Jr, Lasky SR, LeRoith D. Differential expression of alternative 5′ untranslated regions in mRNA encoding rat insulin-like growth factor I. Proc Natl Acad Sci USA 1987; 84: 8946-50.
170. Lowe WL Jr, Lasky SR, LeRoith D, Roberts CT Jr. Distribution and regulation of rat insulin-like growth factor I messenger ribonucleic acids encoding alternative carboxyterminal E-peptides: evidence for differential processing and regulation in liver. Mol Endocrinol 1988; 2: 528-35.
171. Isaksson OG, Jansson JO, Gause IA. Growth hormone stimulates longitudinal bone growth directly. Science 1982; 216: 1237-9.
172. Russell SM, Spencer EM. Local injections of human or rat growth hormone or of purified human somatomedin-C stimulate unilateral tibial epiphyseal growth in hypophysectomized rats. Endocrinology 1985; 116: 2563-7.
173. Schlechter NL, Russell SM, Spancer EM, Nicoll CS. Evidence suggesting that the direct growth-promoting effect of growth hormone on cartilage in vivo is mediated by local production of somatomedin. Proc Natl Acad Sci USA 1986; 83: 7932-4.
174. Green H, Morikawa M, Nixon T. A dual effector theory of growth-hormone action. Differentiation 1985; 29: 195-8.
175. Rubin CS, Hirsch A, Fung C, Rosen OM. Development of hormone receptors and hormonal responsiveness in vitro. Insulin receptors and insulin sensitivity in the preadipocyte and adipocyte forms of 3T3-L1 cells. J Biol Chem 1978; 253: 7570-8.
176. Reed BC, Lane MD. Insulin receptor synthesis and turnover in differentiating 3T3-L1 preadipocytes. Proc Natl Acad Sci USA 1980; 77: 285-9.
177. Nixon T, Green H. Properties of growth hormone receptors in relation to the adipose conversion of 3T3 cells. J Cell Physiol 1983; 115: 291-6.
178. Isaksson OG, Lindahl A, Nilsson A, Isgaard J. Mechanism of the stimulatory effect of growth hormone on longitudinal bone growth. Endocr Rev 1987; 8: 426-38.
179. Ohlsson C, Bengtsson BA, Isaksson OG, Andreassen TT, Slootweg MC. Growth hormone and bone. Endocr Rev 1998; 19: 55-79.
180. Hunziker EB, Wagner J, Zapf J. Differential effects of insulin-like growth factor I and growth hormone on developmental stages of rat growth plate chondrocytes in vivo. J Clin Invest 1994; 93: 1078-86.
181. Wang J, Zhou J, Bondy CA. Igf1 promotes longitudinal bone growth by insulin-like actions augmenting chondrocyte hypertrophy. FASEB J 1999; 13: 1985-90.
182. Saggese G, Federico G, Cinquanta L. Plasma growth hormone-binding protein activity, insulin-like growth factor I, and its binding protein levels in patients with Turner's syndrome: effect of short- and long-term recombinant human growth hormone administration. Pediatr Res 1995; 37: 106-11.
183. Eisman JA. Genetics of osteoporosis. Endocr Rev 1999; 20: 788-804.
184. Richman C, Kutilek S, Miyakoshi N, Srivastava AK, Beamer WG, Donahue LR, et al. Postnatal and pubertal skeletal changes contribute predominantly to the differences in peak bone density between C3H/HeJ and C57BL/6J mice. J Bone Miner Res 2001; 16: 386-397.
185. Bouillon R, Prodonova A. Growth and hormone deficiency and peak bone mass. J Pediatr Endocrinol Metab 2000; 13: 1327-36.
186. Rosen CJ, Donahue LR. Insulin-like growth factors and bone: the osteoporosis connection revisited. Proc Soc Exp Biol Med 1998; 219: 1-7.
187. Simpson H, Savine R, Sonksen P, Bengtsson BA, Carlsson L, Christiansen JS, et al. Growth hormone replacement therapy for adults: into the new millennium. Growth Horm IGF Res 2002; 12: 1-33.
188. Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet SM. Reduced bone mineral density in patients with adult onset growth hormone deficiency. J Clin Endocrinol Metab 1994; 78: 669-74.
189. de Boer H, Blok GJ, van Lingen A, Teule A, Lips P, van der Veen EA. Consequences of childhood-onset growth hormone deficiency for adult bone mass. J Bone Miner Res 1994; 9: 1319-26.
190. Degerblad M, Bengtsson BA, Bramnert M, Johnell O, Manhem P, Rosen T, et al. Reduced bone mineral density in adults with growth hormone (GH) deficiency: increased bone turnover during 12 months of GH substitution therapy. Euu J Endocrinol 1995; 133: 180-8.
191. Rosen T, Wilhelmsen L, Landin-Wilhelmsen K, Lappas G, Bengtsson BA. Increased fracture frequency in adult patients with hypopituitarism and GH deficiency. Eur J Endocrinol 1997; 137: 240-5.
192. Libanati C, Baylink DJ, Lois-Wenzel E, Srinvasan N, Mohan S. Studies on the potential mediators of skeletal changes occurring during puberty in girls. J Clin Endocrinol Metab 1999; 84: 2807-14.
193. Rose SR, Municchi G, Barnes KM, Kamp GA, Uriarte MM, Ross JL, et al. Spontaneous growth hormone secretion increases during puberty in normal girls and boys. J Clin Endocrinol Metab 1991; 73: 428-35.
194. Saban J, Schneider GB, Bolt D, King D. Erythroid-specific expression of human growth hormone affects bone morphology in transgenic mice. Bone 1996; 18: 47-52.
195. Sjogren K, Bohlooly YM, Olsson B, Coschigano K, Tornell J, Mohan S, et al. Disproportional skeletal growth and markedly decreased bone mineral content in growth hormone receptor -/- mice. Biochem Biophys Res Commun 2000; 267: 603-8.
196. Sims NA, Clement-Lacroix P, Da Ponte F, Bouali Y, Binart N, Moriggl R, et al. Bone homeostasis in growth hormone receptor-null mice is restored by IGF-I but independent of Stat5. J Clin Invest 2000; 106: 1095-103.
197. Mohan S, Richman C, Guo R, Amaar Y, Donahue LR, Wergedal J, et al. Insulin-like growth factor regulates peak bone mineral density in mice by both growth hormone-dependent and -independent mechanisms. Endocrinology 2003; 144: 929-36.
198. Amato G, Carella C, Fazio S, La Montagna G, Cittadini A, Sabatini D, et al. Body composition, bone metabolism, and heart structure and function in growth hormone (GH)-deficient adults before and after GH replacement therapy at low doses. J Clin Endocrinol Metab 1993; 77: 1671-6.
199. Holloway L, Butterfield G, Hintz RL, Gesundheit N, Marcus R. Effects of recombinant human growth hormone on metabolic indices, body composition, and bone turnover in healthy elderly women. J Clin Endocrinol Metab 1994; 79: 470-9.
200. Boot AM, Engels MA, Boerma GJ, Krenning EP, De Muinck Keizer-Schrama SM. Changes in bone mineral density, body composition, and lipid metabolism during growth hormone (GH) treatment in children with GH deficiency. J Clin Endocrinol Metab 1997; 82: 2423-8.
201. Choi HK, Waxman DJ. Plasma growth hormone pulse activation of hepatic JAK-STAT5 signaling: developmental regulation and role in male-specific liver gene expression. Endocrinology 2000; 141: 3245-55.
202. Cowell CT, Woodhead HJ, Brody J. Bone markers and bone mineral density during growth hormone treatment in children with growth hormone deficiency. Horm Res 2000; 54: 44-51.
203. Kasukawa Y, Baylink DJ, Guo R, Mohan S. Evidence that sensitivity to growth hormone (GH) is growth period and tissue type dependent: studies in GH-deficient lit/lit mice. Endocrinology 2002; 144: 3950-7.
204. Javaid MK, Godfrey KM, Taylor P, Shore SR, Breier B, Arden NK, et al. Umbilical venous IGF-I concentration, neonatal bone mass, and body composition. J Bone Miner Res 2004; 19: 56-63.
205. Ricketts WA, Rose DW, Shoelson S, Olefsky JM. Functional roles of the She phosphotyrosine binding and Src homology 2 domains in insulin and epidermal growth factor signaling. J Biol Chem 1996; 271: 26165-9.
206. Sasaoka T, Rose DW, Jhun BH, Saltiel AR, Draznin B, Olefsky JM. Evidence for a functional role of Shc proteins in mitogenic signaling induced by insulin, insulin-like growth factor-I, and epidermal growth factor. J Biol Chem 1994; 269: 13689-94.
207. D'Mello SR, Borodezt K, Soltoff SP. Insulin-like growth factor and potassium depolarization maintain neuronal survival by distinct pathways: possible involvement of PI 3-kinase in IGF-I signaling. J Neurosci 1997; 17: 1548-60.
208. Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocr Rev 1993; 14: 20-39.
209. Muller EE, Locatelli V, Cocchi D. Neuroendocrine control of growth hormone secretion. Physiol Rev 1999; 79: 511-607.
210. Veldhuis JD, Bowers CY. Human GH pulsatility: an ensemble property regulated by age and gender. J Endocrinol Invest 2003; 26: 799-813.
211. Bartke A. Growth hormone and aging. Endocrine 1998; 8: 103-8.
212. Veldhuis JD, Iranmanesh A. Physiological regulation of the human growth hormone (GH)-insulin-like growth factor type I (IGF-I) axis: predominant impact of age, obesity, gonadal function, and sleep. Sleep 1996; 19: S221-4.
213. Misra M, Miller KK, Bjornson J, Hackman A, Aggarwal A, Chung J, et al. Alterations in growth hormone secretory dynamics in adolescent girls with anorexia nervosa and effects on bone metabolism. J Clin Endocrinol Metab 2003; 88: 5615-23.
214. Benbassat CA, Maki KC, Unterman TG. Circulating levels of insulin-like growth factor (IGF) binding protein-1 and -3 in aging men: relationships to insulin, glucose, IGF, and dehydroepiandrosterone sulfate levels and anthropometric measures. J Clin Endocrinol Metab 1997; 82: 1484-91.
215. Seck T, Bretz A, Krempien R, Krempien B, Ziegler R, Pfeilschifter J. Age-related changesin insulin-like growth factor I and II in human femoral cortical bone: lack of correlation with bone mass. Bone 1999; 24: 387-93.
216. Tanaka H, Liang CT. Mitogenic activity but not phenotype expression of rat osteoprogenitor cells in response to IGF-I is impaired in aged rats. Mech Ageing Dev 1996; 92: 1-10.
217. Romagnoli E, Minisola S, Carnevale V, Rosso R, Pacitti MT, Scarda A, et al. Circulating levels of insulin-like growth factor binding protein 3 (IGFBP-3) and insulin-like growth factor I (IGF-I) in perimenopausal women. Osteoporos Int 1994; 4: 305-8.
218. Sugimoto T, Nishiyama K, Kuribayashi F, Chihara K. Serum levels of insulin-like growth factor (IGF) I, IGF-binding protein (IGFBP)-2 and IGFBP-3 in osteoporotic patients with and without spinal fractures. J Bone Miner Res 1997; 12: 1272-9.
219. Munoz-Torres M, Mezquita-Raya P, Lopez-Rodriguez F, Torres-Vela E, de Dios Luna J, Escobar-Jimenez F. The contribution of IGF-I to skeletal integrity in postmenopausal women. Clin Endocrinol (Oxf) 2001; 55: 759-66.
220. Gillberg P, Olofsson H, Mallmin H, Blum WF, Ljunghall S, Nilsson AG. Bone mineral density in femoral neck is positively correlated to circulating insulin-like growth factor (IGF)-I and IGF-binding protein (IGPBP)-3 in Swedish men. Calcif Tissue Int 2002; 70: 22-9.
221. Reed BY, Zerwekh JE, Sakhaee K, Breslau NA, Gottschalk F, Pack CY. Serum IGF-I is low and correlated with osteoblastic surface in idiopathic osteoporosis. J Bone Miner Res 1995; 10: 1218-24.
222. Nicolas V, Prewett A, Bettica P, Mohan S, Finkelman RD, Baylink DJ, et al. Age-related decreases in insulin-like growth factor-I and transforming growth factor-beta in femoral cortical bone from both men and women: implications for bone loss with aging. J Clin Endocrinol Metab 1994; 78: 1011-6.
223. Boonen S, Aerssens J, Dequeker J, Nicholson P, Cheng X, Lowet G, et al. Age-associated decline in human femoral neck cortical and trabecular content of insulin-like growth factor I: potential implications for age-related (type II) osteoporotic fracture occurrence. Calcif Tissue Int 1997; 61: 173-8.
224. Mohan S, Farley JR, Baylink DJ. Age-related changes in IGFBP-4 and IGFBP-5 levels in human serum and bone: implications for bone loss with aging. Prog Growth Factor Res 1995; 6: 465-73.
225. Karasik D, Rosen CJ, Hannan MT, Broe KE, Dawson-Hughes B, Gagnon DR, et al. Insulin-like growth factor biding proteins 4 and 5 and bone mineral density in elderly men and women. Calcif Tissue Int 2002; 71: 323-8.
226. Nicolas V, Mohan S, Honda Y, Prewett A, Finkelman RD, Baylink DJ, et al. An age-related decrease in the concentration of insulin-like growth factor binding protein-5 in human cortical bone. Calcif Tissue Int 1995; 57: 206-12.
227. Kassem M, Brixen K, Blum W, Mosekilde L, Eriksen EF. No evidence for reduced spontaneous or growth-hormone-stimulated serum levels of insulin-like growth factor (IGF)-I, IGF-II or IGF binding protein 3 in women with spinal osteoporosis. Eur J Endocrinol 1994; 131: 150-5.
228. Gillberg P, Johansson AG, Blum WF, Groth T, Ljunghall S. Growth hormone secretion and sensitivity in men with idiopathic osteoporosis. Calcif Tissue Int 2001; 68: 67-73.
229. Martini G, Valenti R, Giovani S, Franci B, Campagna S, Nuti R. Influence of insulin-like growth factor-I and leptin on bone mass in healthy postmenopausal women. Bone 2001; 28: 113-7.
230. Zofkova I, Bahbouh R, Bendlova B. Systemic insulin-like growth factor-I, insulin and vitamin D status in relation to age-associated bone loss in women. Exp Clin Endocrinol Diabetes 2001; 109: 267-72.
231. Seck T, Bretz A, Krempien R, Krempien B, Ziegler R, Pfeilschifter J. Age-related changes in insulin-like growth factor I and II in human femoral cortical bone: lack of correlation with bone mass. Bone 1999; 24: 387-93.
232. Schlemmer A, Johansen JS, Pedersen SA, Jorgensen JO, Hassager C, Christiansen C. The effect of growth hormone (GH) therapy on urinary pyridinoline cross-links in GH-deficient adults. Clin Endocrinol (Oxf) 1991; 35: 471-6.
233. Saggese G, Baroncelli GI, Bertelloni S, Cinquanta L, Di Nero G. Effects of long-term treatment with growth hormone on bone and mineral metabolism in children with growth hormone deficiency. J Pediatr 1993; 122: 37-45.
234. Johannsson G, Rosen T, Bosaeus I, Sjöström L, Bengtsson B-Å. Two years of growth hormone (GH) treatment increases bone mineral content and density in hypopituitary patients with adult-onset GH deficiency. J Clin Endocrinol Metab 1996; 81: 2865-73.
235. Clanget C, Seck T, Hinke V, Wüste C, Ziegler R, Pfeilschifter J. Effects of 6 years of growth hormone (GH) treatment on bone mineral density in GH-deficient adults. Clin Endocrinol (Oxf) 2001; 55: 93-9.
236. Brixen K, Nielsen HK, Mosekilde L, Flyvbjerg A. A short course of recombinant human growth hormone treatment stimulates osteoblasts and activates bone remodeling in normal human volunteers. J Bone Miner Res 1990; 5: 609-18.
237. Clemmensen B, Overgaard K, Riis B, Christiansen C. Human growth hormone and growth hormone releasing hormone: A double-masked, placebo-controlled study of their effects on bone metabolism in elderly women. Osteoporosis Int 1993; 3: 330-6.
238. Holloway L, Butterfield G, Hintz RL, Gesundheit N, Marcus R. Effects of recombinant human growth hormone on metabolic indices, body composition, and bone turnover in healthy elderly women. J Clin Endocrinol Metab 1994; 79: 470-9.
239. Rudman D, Feller AG, Nagraj HS, Gergans GA, Lalitha PY, Goldberg AF, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med 1990; 323: 1-6.
240. Kassem M, Brixen K, Blum WF, Mosekilde L, Eriksen EF. Normal osteolastic and osteoblastic response to exogenous growth hormone in patients with postmenopausal spinal osteoporosis. J Bone Miner Res 1994; 9: 1365-70.
241. Brixen K, Kassem M, Nielsen HK, Loft AG, Flyvbjerg A, Mosekilde L. Short-term treatment with growth hormone stimulates osteoblastic and osteoclastic activity in osteopenic postmenopausal women: a dose response study. J Bone Miner Res 1995; 10: 1865-74.
242. Saaf M, Hilding A, Thoren M, Troell S, Hall K. Growth hormone treatment of osteoporotic postmenopausal women - a one-year placebo-controlled study. Eur J Endocrinol 1999; 140: 390-9.
243. Kassem M, Brixen K, Mosekilde L Blum WF, Flyvbjerg A. Effects of growth hormone treatment on serum levels of insulin-like growth factors (IGFs) and IGF binding proteins 1-4 in post-menopausal women. Clin Endocrinol (Oxf) 1998; 49: 747-56.
244. Sugimoto T, Nakaoka D, Nasu M, Kanzawa M, Sugishita T, Chihara K. Effect of recombinant human growth hormone in elderly osteoporotic women. Clin Endocrinol (Oxf) 1999; 51: 715-24.
245. Holloway L, Kohlmeier L, Kent K, Marcus R. Skeletal effects of cyclic recombinant human growth hormone and salmon calcitonin in osteopenic postmenopausal women. J Clin Endocrinol Metab 1997; 82: 1111-7.
246. Landin-Wilhelmsen K, Nilsson A, Bosaeus I, Bengtsson BA. Growth hormone increases bone mineral content in postmenopausal osteoporosis: a randomized placebo-controlled trial. J Bone Miner Res 2003; 18: 393-405.
247. Johansson AG, Lidh E, Ljunghall S. Insulin-like growth factor I stimulates bone turnover in osteoporosis. Lancet 1992; 339: 1619.
248. Ebeling PR, Jones JD, O'Fallon WM, Janes CH, Riggs BL. Short-term effects of recombinant human insulin-like growth factor on bone turnover in normal women. J Clin Endocrinol Metab 1993; 77: 1384-7.
249. Johansson AG, Lindh E, Blum WF, Kollerup G, Sorensen OH, Ljunghall S. Effects of growth hormone and insulin-like growth factor-I in men with idiopathic osteoporosis. J Clin Endocrinol Metab 1996; 81: 44-8.
250. Bianda T, Hussain MA, Glatz Y, Bouillon R, Froesch FR, Schmid C. Effects of short-term insulin-like growth factor-I or growth hormone treatment on bone turnover, renal phosphate reabsorption and 1,25-dihydroxyvitamin D3 production in healthy man. J Intern Med 1997; 241: 143-50.
251. Rubin CD, Reed B, Sakhaee K, Pak CY. Treating a patient with the Werner syndrome and osteoporosis using recombinant human insulin-like growth factor. Ann Intern Med 1994; 121: 665-8.
252. Grinspoon SK, Baum HB, Peterson S, Klibanski A. Effects of rhIGF-I administration on bone turnover during short-term fasting. J Clin Invest 1995; 96: 900-6.
253. Johansson G, Lindh E, Kollerup G, Ljunghal S. Dose-dependent effects of IGF-I on metabolism of collagen type I in male osteoporosis. J Bone Miner Res 1995; 10: S393.
254. Ghiron LJ, Thompson JL, Holloway L, Hintz RL, Butterfield GE, Hoffman AR, et al. Effects of recombinant insulin-like growth factor-I and growth hormone on bone turnover in elderly women. J Bone Miner Res 1995; 10: 1844-52.
255. Mauras N, Doi SQ, Shapiro JR. Recombinant human insulin-like growth factor I, recombinant growth hormone, and sex steroids: effects on markers of bone turnover in humans. J Clin Endocrinol Metab 1996; 81: 2222-6.
256. Berneis K, Oehri M, Kraenzlin M, Kellar U. Effects of IGF-I combined with GH on glucocorticoid-induced changes of bone and connective tissue turnover in man. J Endocrinol 1999; 162: 259-64.
257. Boonen S, Rosen C, Bouillon R, Sommer A, McKay M, Rosen D, et al. Musculoskeletal effects of the recombinant human IGF-I/IGF binding protein-3 complex in osteoporotic patients with proximal flemoral fracture: a double-blind, placebo-controlled pilot study. J Clin Endocrinol Metab 2002; 87: 1593-9.
258. Erdtsieck RJ, Pols HA, Valk NK, van Ouwerkerk BM, Lamberts SW, Mulder P, et al. Treatment of post-menopausal osteoporosis with a combination of growth hormone and pamidronate: a placebo controlled trial. Clin Endocrinol (Oxf) 1995; 43: 557-65.
259. Sugimoto T, Kaji H, Nakaoka D, Yamauchi M, Yano S, Sugishita T, et al. Effect of low-dose of recombinant human growth hormone on bone metabolism in elderly women with osteoporosis. Eur J Endocrinol 2002; 147: 339-48.
260. Gillberg P, Mallmin H, Petren-Mallmin M, Ljunghall S, Nilsson AG. Two years of treatment with recombinant human growth hormone increase bone mineral density in men with idiopathic osteoporosis. J Clin Endocrinol Metab 2002; 87: 4900-6.
261. Metcalf CA 3rd, van Schravendijk MR, Dalgamo DC, Sawyer TK. Targeting protein kinases for bone disease: discovery and development of Src inhibitors. Curr Pharm Design 2002; 8(23): 2049-75.
262. Svensson J. The importance of growth hormone (GH) and GH secretagogues for bone mass and density. Curr Pharm Design 2002; 8(23): 2023-32.
263. Woods SC, Seeley RJ, Baskin DG, Schwartz MW. Insulin and the blood-brain barrier. Curr Pharm Design 2003; 9(10): 795-800.