Insulin-like growth factor-I molecular pathways in osteoblasts: Potential targets for pharmacological manipulation

Current Molecular Pharmacology

Volumn 5, Issue 2, 2012, Pages 143-152

  Govoni, Kristen E ^a  

^a UNIVERSITY OF CONNECTICUT   (United States)

Author keywords

Anabolic agents; Bone; Insulin like growth factor binding proteins; Insulin like growth factor I; Insulin like growth factor I receptor; Osteoblast

Indexed keywords

BONE MORPHOGENETIC PROTEIN; GROWTH HORMONE RELEASING FACTOR; PARATHYROID HORMONE; PREGNANCY ASSOCIATED PLASMA PROTEIN A; PROTEIN TYROSINE PHOSPHATASE SHP 2; SOMATOMEDIN BINDING PROTEIN 1; SOMATOMEDIN BINDING PROTEIN 2; SOMATOMEDIN BINDING PROTEIN 3; SOMATOMEDIN BINDING PROTEIN 4; SOMATOMEDIN BINDING PROTEIN 5; SOMATOMEDIN BINDING PROTEIN 6; SOMATOMEDIN C; SOMATOMEDIN C RECEPTOR; VITRONECTIN; WNT PROTEIN;

BONE DENSITY; BONE REMODELING; CELL ACTIVITY; CELL ADHESION; CELL COUNT; CELL DIFFERENTIATION; CELL FUNCTION; CELL MIGRATION; CELL PROLIFERATION; DRUG MEGADOSE; DRUG TARGETING; HUMAN; NONHUMAN; OSTEOBLAST; OSTEOLYSIS; OSTEOPOROSIS; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; PROTEIN SYNTHESIS; RECEPTOR BINDING; REVIEW; SIGNAL TRANSDUCTION;

EID: 84861734326     PISSN: 18744672     EISSN: 18744702     Source Type: Journal    
DOI: 10.2174/1874467211205020143     Document Type: Review

References (98)

1. Mohan, S.; Baylink, D.J. Insulin-like growth factor system components and the coupling of bone formation to resorption. Horm. Res., 1996, 45(Suppl. 1), 59-62.
2. Govoni, K.E.; Lee, S.K.; Chung, Y.S.; Behringer, R.R.; Wergedal, J.E.; Baylink, D.J.; Mohan, S. Disruption of insulin-like growth factor-I expression in type IIalphaI collagen-expressing cells reduces bone length and width in mice. Physiol. Genomics, 2007, 30, 354-362.
3. Govoni, K.E.; Wergedal, J.E.; Florin, L.; Angel, P.; Baylink, D.J.; Mohan, S. Conditional deletion of insulin-like growth factor-I in collagen type 1alpha2-expressing cells results in postnatal lethality and a dramatic reduction in bone accretion, Endocrinology, 2007, 148, 5706-5715.
4. Bikle, D.D.; Sakata, T.; Leary, C.; Elalieh, H.; Ginzinger, D.; Rosen, C.J.; Beamer, W.; Majumdar, S.; Halloran, B.P. Insulin-like growth factor I is required for the anabolic actions of parathyroid hormone on mouse bone. J. Bone Miner. Res., 2002, 17, 1570-1578.
5. Kasukawa, Y.; Baylink, D.J.; 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, 2003, 144, 3950-3957.
6. Mohan, S.; Baylink, D.J. Impaired skeletal growth in mice with haploinsufficiency of IGF-I: genetic evidence that differences in IGF-I expression could contribute to peak bone mineral density differences. J. Endocrinol., 2005, 185, 415-420.
7. Mohan, S.; Richman, C.; Guo, R.; Amaar, Y.; Donahue, L.R.; Wergedal, J.; Baylink, D.J. Insulin-like growth factor regulates peak bone mineral density in mice by both growth hormonedependent and-independent mechanisms. Endocrinology, 2003, 144, 929-36.
8. Rutter, M.M.; Markoff, E.; Clayton, L.; Akeno, N.; Zhao, G.; Clemens, T.L.; Chernausek, S.D. Osteoblast-specific expression of insulin-like growth factor-1 in bone of transgenic mice induces insulin-like growth factor binding protein-5. Bone, 2005, 36, 224-231.
9. Sjogren, K.; Sheng, M.; Moverare, S.; Liu, J.L.; Wallenius, K.; Tornell, J.; Isaksson, O.; Jansson, J.O.; Mohan, S.; Ohlsson, C. Effects of liver-derived insulin-like growth factor I on bone metabolism in mice. J. Bone Miner. Res., 2002, 17, 1977-1987.
10. Wang, J.; Zhou, J.; Bondy, C.A. Igf1 promotes longitudinal bone growth by insulin-like actions augmenting chondrocyte hypertrophy. FASEB J., 1999, 13, 1985-1990.
11. Yakar, S.; Rosen, C.J.; Beamer, W.G.; Ackert-Bicknell, C.L.; Wu, Y.; Liu, J.L.; Ooi, G.T.; Setser, J.; Frystyk, J.; Boisclair, Y.R.; LeRoith, D. Circulating levels of IGF-1 directly regulate bone growth and density. J. Clin. Invest., 2002, 110, 771-781.
12. Zhang, M.; Xuan, S.; Bouxsein, M.L.; von Stechow, D.; Akeno, N.; Faugere, M.C.; Malluche, H.; Zhao, G.; Rosen, C.J.; Efstratiadis, A.; Clemens, T.L. Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J. Biol. Chem., 2002, 277, 44005-44012.
13. Zhao, G.; Monier-Faugere, M.C.; Langub, M.C.; Geng, Z.; Nakayama, T.; Pike, J.W.; Chernausek, S.D.; Rosen, C.J.; Donahue, L.R.; Malluche, H.H.; Fagin, J.A.; Clemens, T.L. Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation, Endocrinology, 2000, 141, 2674-2682.
14. Yakar, S.; Canalis, E.; Sun, H.; Mejia, W.; Kawashima, Y.; Nasser, P.; Courtland, H.W.; Williams, V.; Bouxsein, M.; Rosen, C.; Jepsen, K.J. Serum IGF-1 determines skeletal strength by regulating subperiosteal expansion and trait interactions, J. Bone Miner. Res., 2009, 24, 1481-1492.
15. Mohan, S.; Baylink, D.J. IGF system components and their role in bone metabolism, 1999, 457-496.
16. Rosen, C.J.; Donahue, L.R. Insulin-like growth factors and bone: the osteoporosis connection revisited. Proc. Soc. Exp. Biol. Med., 1998, 219, 1-7.
17. Hock, J.M.; Centrella, M.; Canalis, E. Insulin-like growth factor I has independent effects on bone matrix formation and cell replication. Endocrinology, 1988, 122, 254-260.
18. Gazzerro, E.; Canalis, E. Skeletal actions of insulin-like growth factors. Expert Rev. Endocrinol. Metab., 2006, 1, 47.
19. Cao, J.J.; Kurimoto, P.; Boudignon, B.; Rosen, C.; Lima, F.; Halloran, B.P. Aging impairs IGF-I receptor activation and induces skeletal resistance to IGF-I. J. Bone Miner. Res., 2007, 22, 1271-1279.
20. Niu, T.; Rosen, C.J. The insulin-like growth factor-I gene and osteoporosis: a critical appraisal. Gene, 2005, 361, 38-56.
21. Canalis, E. Growth factor control of bone mass. J. Cell. Biochem., 2009, 108, 769-777.
22. Giustina, A.; Mazziotti, G.; Canalis, E. Growth hormone, insulinlike growth factors, and the skeleton. Endocr. Rev., 2008, 29, 535-559.
23. Rosen, C.J.; Niu, T. Principles of bone biology, 3rd edn. 2008, 1061-1086.
24. Le Roith, D.; Bondy, C.; Yakar, S.; Liu, J.L.; Butler, A. The somatomedin hypothesis: 2001. Endocr. Rev., 2001, 22, 53-74.
25. Govoni, K.E.; Baylink, D.J.; Mohan, S. The multi-functional role of insulin-like growth factor binding proteins in bone. Pediatr. Nephrol., 2005, 20, 261-268.
26. Rajaram, S.; Baylink, D.J.; Mohan, S. Insulin-like growth factorbinding proteins in serum and other biological fluids: regulation and functions. Endocr. Rev., 1997, 18, 801-831.
27. Jones, J.I.; Clemmons, D.R. Insulin-like growth factors and their binding proteins: biological actions. Endocr. Rev., 1995, 16, 3-34.
28. Boisclair, Y.R.; Rhoads, R.P.; Ueki, I.; Wang, J.; Ooi, G.T. The acid-labile subunit (ALS) of the 150 kDa IGF-binding protein complex: an important but forgotten component of the circulating IGF system. J. Endocrinol., 2001, 170, 63-70.
29. Rechler, M.M. Insulin-like growth factor binding proteins. Vitam. Horm., 1993, 47, 1-114.
30. Miyakoshi, N.; Richman, C.; Qin, X.; Baylink, D.J.; Mohan, S. Effects of recombinant insulin-like growth factor-binding protein-4 on bone formation parameters in mice. Endocrinology, 1999, 140, 5719-5728.
31. Mohan, S.; Nakao, Y.; Honda, Y.; Landale, E.; Leser, U.; Dony, C.; Lang, K.; Baylink, D.J. 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, 20424-20431.
32. Mukherjee, A.; Rotwein, P. Insulin-like growth factor-binding protein-5 inhibits osteoblast differentiation and skeletal growth by blocking insulin-like growth factor actions. Mol. Endocrinol., 2008, 22, 1238-1250.
33. Jehle, P.M.; Schulten, K.; Schulz, W.; Jehle, D.R.; Stracke, S.; Manfras, B.; Boehm, B.O.; Baylink, D.J.; Mohan, S. Serum levels of insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-1 to-6 and their relationship to bone metabolism in osteoporosis patients. Eur. J. Intern. Med., 2003, 14, 32-38.
34. Amaar, Y.G.; Thompson, G.R.; Linkhart, T.A.; Chen, S.T.; Baylink, D.J.; 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, 12053-12060.
35. Nicolas, V.; Mohan, S.; Honda, Y.; Prewett, A.; Finkelman, R.D.; Baylink, D.J.; Farley, J.R. An age-related decrease in the concentration of insulin-like growth factor binding protein-5 in human cortical bone. Calcif. Tissue Int., 1995, 57, 206-212.
36. Schleicher, I.; Parker, A.; Leavesley, D.; Crawford, R.; Upton, Z.; Xiao, Y. Surface modification by complexes of vitronectin and growth factors for serum-free culture of human osteoblasts. Tissue Eng., 2005, 11, 1688-1698.
37. Mukherjee, A.; Rotwein, P. Insulin-like growth factor binding protein-5 in osteogenesis: facilitator or inhibitor? Growth Horm. IGF Res., 2007, 17, 179-185.
38. Malpe, R.; Baylink, D.J.; Linkhart, T.A.; Wergedal, J.E.; 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, 423-430.
39. Govoni, K.E.; Amaar, Y.G.; Kramer, A.; Winter, E.; Baylink, D.J.; Mohan, S. Regulation of insulin-like growth factor binding protein-5, four and a half lim-2, and a disintegrin and metalloprotease-9 expression in osteoblasts. Growth Horm. IGF Res., 2006, 16, 49-56.
40. Birnbaum, R.S.; Wiren, K.M. Changes in insulin-like growth factor-binding protein expression and secretion during the proliferation, differentiation, and mineralization of primary cultures of rat osteoblasts. Endocrinology, 1994, 135, 223-230.
41. Conover, C.A.; Kiefer, M.C. Regulation and biological effect of endogenous insulin-like growth factor binding protein-5 in human osteoblastic cells. J. Clin. Endocrinol. Metab., 1993, 76, 1153-1159.
42. Gabbitas, B.; Canalis, E. Insulin-like growth factors sustain insulinlike growth factor-binding protein-5 expression in osteoblasts. Am. J. Physiol., 1998, 275, E222-E228.
43. Richman, C.; Baylink, D.J.; 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, 4699-4705.
44. Andress, D.L. IGF-binding protein-5 stimulates osteoblast activity and bone accretion in ovariectomized mice. Am. J. Physiol. Endocrinol. Metab., 2001, 281, E283-8.
45. Bauss, F.; Lang, K.; Dony, C.; Kling, L. The complex of recombinant human insulin-like growth factor-I (rhIGF-I) and its binding protein-5 (IGFBP-5) induces local bone formation in murine calvariae and in rat cortical bone after local or systemic administration. Growth Horm. IGF Res., 2001, 11, 1-9.
46. Lotinun, S.; Sibonga, J.D.; Turner, R.T. Differential effects of intermittent and continuous administration of parathyroid hormone on bone histomorphometry and gene expression. Endocrine, 2002, 17, 29-36.
47. Devlin, R.D.; Du, Z.; Buccilli, V.; Jorgetti, V.; Canalis, E. Transgenic mice overexpressing insulin-like growth factor binding protein-5 display transiently decreased osteoblastic function and osteopenia. Endocrinology, 2002, 143, 3955-3962.
48. Zhang, M.; Faugere, M.C.; Malluche, H.; Rosen, C.J.; Chernausek, S.D.; Clemens, T.L. Paracrine overexpression of IGFBP-4 in osteoblasts of transgenic mice decreases bone turnover and causes global growth retardation. J. Bone Miner. Res., 2003, 18, 836-843.
49. Qin, X.; Strong, D.D.; Baylink, D.J.; Mohan, S. Structure-function analysis of the human insulin-like growth factor binding protein-4. J. Biol. Chem., 1998, 273, 23509-23516.
50. Miyakoshi, N.; Richman, C.; Kasukawa, Y.; Linkhart, T.A.; Baylink, D.J.; Mohan, S. Evidence that IGF-binding protein-5 functions as a growth factor. J. Clin. Invest., 2001, 107, 73-81.
51. DeMambro, V.E.; Clemmons, D.R.; Horton, L.G.; Bouxsein, M.L.; Wood, T.L.; Beamer, W.G.; Canalis, E.; Rosen, C.J. Genderspecific changes in bone turnover and skeletal architecture in igfbp-2-null mice. Endocrinology, 2008, 149, 2051-2061.
52. Conover, C.A.; Khosla, S. Role of extracellular matrix in insulinlike growth factor (IGF) binding protein-2 regulation of IGF-II action in normal human osteoblasts. Growth Horm. IGF Res., 2003, 13, 328-335.
53. Eckstein, F.; Weusten, A.; Schmidt, C.; Wehr, U.; Wanke, R.; Rambeck, W.; Wolf, E.; Mohan, S. Longitudinal in vivo effects of growth hormone overexpression on bone in transgenic mice. J. Bone Miner. Res., 2004, 19, 802-810.
54. Campbell, P.G.; Novak, J.F. Insulin-like growth factor binding protein (IGFBP) inhibits IGF action on human osteosarcoma cells. J. Cell. Physiol., 1991, 149, 293-300.
55. Mohan, S.; Bautista, C.M.; Wergedal, J.; Baylink, D.J. Isolation of an inhibitory insulin-like growth factor (IGF) binding protein from bone cell-conditioned medium: a potential local regulator of IGF action, Proc. Natl. Acad. Sci. USA, 1989, 86, 8338-8342.
56. Yan, T.; Wergedal, J.; Zhou, Y.; Mohan, S.; Baylink, D.J.; Strong, D.D. Inhibition of human osteoblast marker gene expression by retinoids is mediated in part by insulin-like growth factor binding protein-6. Growth Horm. IGF Res., 2001, 11, 368-377.
57. Zhou, Y.; Mohan, S.; Linkhart, T.A.; Baylink, D.J.; Strong, D.D. Retinoic acid regulates insulin-like growth factor-binding protein expression in human osteoblast cells. Endocrinology, 1996, 137, 975-983.
58. Mohan, S.; Thompson, G.R.; Amaar, Y.G.; Hathaway, G.; Tschesche, H.; Baylink, D.J. ADAM-9 is an insulin-like growth factor binding protein-5 protease produced and secreted by human osteoblasts. Biochemistry (N.Y.), 2002, 41, 15394-15403.
59. Qin, X.; Wergedal, J.E.; Rehage, M.; Tran, K.; Newton, J.; Lam, P.; Baylink, D.J.; Mohan, S. Pregnancy-associated plasma protein (PAPP)-A increases osteoblast proliferation in vitro and bone formation in vivo. Endocrinology, 2006, 147(12), 5653-5661.
60. Conover, C.A.; Chen, B.K.; Resch, Z.T. Regulation of pregnancyassociated plasma protein-A expression in cultured human osteoblasts. Bone, 2004, 34, 297-302.
61. Turner, R.T.; Wronski, T.J.; Zhang, M.; Kidder, L.S.; Bloomfield, S.A. Sibonga, J.D. Effects of ethanol on gene expression in rat bone: transient dose-dependent changes in mRNA levels for matrix proteins, skeletal growth factors, and cytokines are followed by reductions in bone formation. Alcohol. Clin. Exp. Res., 1998, 22, 1591-1599.
62. Schumacher, R.; Mosthaf, L.; Schlessinger, J.; Brandenburg, D.; Ullrich, A. Insulin and insulin-like growth factor-1 binding specificity is determined by distinct regions of their cognate receptors. J. Biol. Chem., 1991, 266, 19288-19295.
63. LeRoith, D.; Werner, H.; Neuenschwander, S.; Kalebic, T.; Helman, L.J. The role of the insulin-like growth factor-I receptor in cancer. Ann. N.Y. Acad. Sci., 1995, 766, 402-408.
64. Hsu, D.; Knudson, P.E.; Zapf, A.; Rolband, G.C.; Olefsky, J.M. NPXY motif in the insulin-like growth factor-I receptor is required for efficient ligand-mediated receptor internalization and biological signaling. Endocrinology, 1994, 134, 744-750.
65. Butler, A.A.; Yakar, S.; Gewolb, I.H.; Karas, M.; Okubo, Y.; LeRoith, D. Insulin-like growth factor-I receptor signal transduction: at the interface between physiology and cell biology. Comp. Biochem. Physiol. B. Biochem. Mol. Biol., 1998, 121, 19-26.
66. Kato, H.; Faria, T.N.; Stannard, B.; Roberts, C.T. Jr.; LeRoith, D. Role of tyrosine kinase activity in signal transduction by the insulin-like growth factor-I (IGF-I) receptor. Characterization of kinase-deficient IGF-I receptors and the action of an IGF-I-mimetic antibody (alpha IR-3). J. Biol. Chem., 1993, 268, 2655-2661.
67. Ogata, N.; Chikazu, D.; Kubota, N.; Terauchi, Y.; Tobe, K.; Azuma, Y.; Ohta, T.; Kadowaki, T.; Nakamura, K.; Kawaguchi, H. Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover. J. Clin. Invest., 2000, 105, 935-943.
68. Chook, Y.M.; Gish, G.D.; Kay, C.M.; Pai, E.F.; Pawson, T. The Grb2-mSos1 complex binds phosphopeptides with higher affinity than Grb2. J. Biol. Chem., 1996, 271, 30472-30478.
69. Kyriakis, J.M.; App, H.; Zhang, X.F.; Banerjee, P.; Brautigan, D.L.; Rapp, U.R.; Avruch, J. Raf-1 activates MAP kinase-kinase. Nature, 1992, 358, 417-421.
70. LeRoith, D. Insulin-like growth factor I receptor signaling--overlapping or redundant pathways? Endocrinology, 2000, 141, 1287-1288.
71. Carpenter, G. PLC and PKC: a tale of two messengers. Receptormediated stimulation of phosphoinositide metabolism and protein kinase C, Sixth International Symposium on Cellular Endocrinology sponsored by the W. Alton Jones Cell Science Center, Lake Placid, NY, USA, August 12-15, 1990. New Biol., 1990, 2, 965-969.
72. Marte, B.M.; Downward, J. PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem. Sci., 1997, 22, 355-358.
73. Grey, A.; Chen, Q.; Xu, X.; Callon, K.; Cornish, J. Parallel phosphatidylinositol-3 kinase and p42/44 mitogen-activated protein kinase signaling pathways subserve the mitogenic and antiapoptotic actions of insulin-like growth factor I in osteoblastic cells. Endocrinology, 2003, 144, 4886-4893.
74. Clemmons, D.R.; Maile, L.A. Interaction between insulin-like growth factor-I receptor and alphaVbeta3 integrin linked signaling pathways: cellular responses to changes in multiple signaling inputs. Mol. Endocrinol., 2005, 19, 1-11.
75. Kapur, S.; Mohan, S.; Baylink, D.J.; Lau, K.H. Fluid shear stress synergizes with insulin-like growth factor-I (IGF-I) on osteoblast proliferation through integrin-dependent activation of IGF-I mitogenic signaling pathway. J. Biol. Chem., 2005, 280, 20163-20170.
76. Canalis, E. Update in new anabolic therapies for osteoporosis. J. Clin. Endocrinol. Metab., 2010, 95, 1496-1504.
77. Grinspoon, S.; Baum, H.; Lee, K.; Anderson, E.; Herzog, D.; Klibanski, A. Effects of short-term recombinant human insulin-like growth factor I administration on bone turnover in osteopenic women with anorexia nervosa. J. Clin. Endocrinol. Metab., 1996, 81, 3864-3870.
78. Kawai, M.; Rosen, C.J. Insulin-like growth factor-I and bone: lessons from mice and men. Pediatr. Nephrol., 2009, 24, 1277-1285.
79. Fujita, T.; Azuma, Y.; Fukuyama, R.; Hattori, Y.; Yoshida, C.; Koida, M.; Ogita, K.; Komori, T. Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K-Akt signaling. J. Cell Biol., 2004, 166, 85-95.
80. Qiao, M.; Shapiro, P.; Kumar, R.; Passaniti, A. Insulin-like growth factor-1 regulates endogenous RUNX2 activity in endothelial cells through a phosphatidylinositol 3-kinase/ERK-dependent and Aktindependent signaling pathway. J. Biol. Chem., 2004, 279, 42709-42718.
81. Mukherjee, A.; Rotwein, P. Akt promotes BMP2-mediated osteoblast differentiation and bone development. J. Cell. Sci., 2009, 122, 716-726.
82. Mukherjee, A.; Wilson, E.M.; Rotwein, P. Selective signaling by Akt2 promotes bone morphogenetic protein 2-mediated osteoblast differentiation. Mol. Cell. Biol., 2010, 30, 1018-1027.
83. Ghosh-Choudhury, N.; Abboud, S.L.; Nishimura, R.; Celeste, A.; Mahimainathan, L.; Choudhury, G.G. Requirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and Smad-dependent BMP-2 gene transcription. J. Biol. Chem., 2002, 277, 33361-33368.
84. Raucci, A.; Bellosta, P.; Grassi, R.; Basilico, C.; Mansukhani, A. Osteoblast proliferation or differentiation is regulated by relative strengths of opposing signaling pathways. J. Cell. Physiol., 2008, 215, 442-451.
85. Boonen, S.; Rosen, C.; Bouillon, R.; Sommer, A.; McKay, M.; Rosen, D.; Adams, S.; Broos, P.; Lenaerts, J.; Raus, J.; Vanderschueren, D.; Geusens, P. Musculoskeletal effects of the recombinant human IGF-I/IGF binding protein-3 complex in osteoporotic patients with proximal femoral fracture: a doubleblind, placebo-controlled pilot study. J. Clin. Endocrinol. Metab., 2002, 87, 1593-1599.
86. Salih, D.A.; Mohan, S.; Kasukawa, Y.; Tripathi, G.; Lovett, F.A.; Anderson, N.F.; Carter, E.J.; Wergedal, J.E.; Baylink, D.J.; Pell, J.M. Insulin-like growth factor-binding protein-5 induces a genderrelated decrease in bone mineral density in transgenic mice. Endocrinology, 2005, 146, 931-940.
87. Phang, D.; Rehage, M.; Bonafede, B.; Hou, D.; Xing, W.; Mohan, S.; Wergedal, J.E.; Qin, X. Inactivation of insulin-like-growth factors diminished the anabolic effects of pregnancy-associated plasma protein-A (PAPP-A) on bone in mice. Growth Horm. IGF Res., 2010, 20, 192-200.
88. Cantley, L.C.; Neel, B.G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc. Natl. Acad. Sci. USA, 1999, 96, 4240-4245.
89. Liu, X.; Bruxvoort, K.J.; Zylstra, C.R.; Liu, J.; Cichowski, R.; Faugere, M.C.; Bouxsein, M.L.; Wan, C.; Williams, B.O.; Clemens, T.L. Lifelong accumulation of bone in mice lacking Pten in osteoblasts. Proc. Natl. Acad. Sci. USA, 2007, 104, 2259-2264.
90. Piters, E.; Boudin, E.; Van Hul, W. Wnt signaling: a win for bone. Arch. Biochem. Biophys., 2008, 473, 112-116.
91. Westendorf, J.J.; Kahler, R.A.; Schroeder, T.M. Wnt signaling in osteoblasts and bone diseases. Gene, 2004, 341, 19-39.
92. Canalis, E.; Giustina, A.; Bilezikian, J.P. Mechanisms of anabolic therapies for osteoporosis N. Engl. J. Med., 2007, 357, 905-916.
93. Chen, J.; Wu, A.; Sun, H.; Drakas, R.; Garofalo, C.; Cascio, S.; Surmacz, E.; Baserga, R. Functional significance of type 1 insulin like growth factor-mediated nuclear translocation of the insulin receptor substrate-1 and beta-catenin. J. Biol. Chem., 2005, 280, 29912-29920.
94. Jin, T.; George Fantus, I.; Sun, J. Wnt and beyond Wnt: multiple mechanisms control the transcriptional property of beta-catenin. Cell. Signal., 2008, 20, 1697-1704.
95. Desbois-Mouthon, C.; Cadoret, A.; Blivet-Van Eggelpoel, M.J.; Bertrand, F.; Cherqui, G.; Perret, C.; Capeau, J. Insulin and IGF-1 stimulate the beta-catenin pathway through two signalling cascades involving GSK-3beta inhibition and Ras activation. Oncogene, 2001, 20, 252-259.
96. Satyamoorthy, K.; Li, G.; Vaidya, B.; Patel, D.; Herlyn, M. Insulinlike growth factor-1 induces survival and growth of biologically early melanoma cells through both the mitogen-activated protein kinase and beta-catenin pathways. Cancer Res., 2001, 61, 7318-7324.
97. Playford, M.P.; Bicknell, D.; Bodmer, W.F.; Macaulay, V.M. Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of beta-catenin. Proc. Natl. Acad. Sci. USA, 2000, 97, 12103-12108.
98. Sunters, A.; Armstrong, V.J.; Zaman, G.; Kypta, R.M.; Kawano, Y.; Lanyon, L.E.; Price, J.S. Mechano-transduction in osteoblastic cells involves strain-regulated estrogen receptor alpha-mediated control of insulin-like growth factor (IGF) I receptor sensitivity to Ambient IGF, leading to phosphatidylinositol 3-kinase/AKTdependent Wnt/LRP5 receptor-independent activation of betacatenin signaling. J. Biol. Chem., 2010, 285, 8743-8758.