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Endocrine Reviews 18 (6): 801-831
Copyright © 1997 by The Endocrine Society

Insulin-Like Growth Factor-Binding Proteins in Serum and Other Biological Fluids: Regulation and Functions1

Sujatha Rajaram, David J. Baylink and Subburaman Mohan

Mineral Metabolism Laboratory (D.J.B., S.M.), Jerry L. Pettis Memorial Veterans Administration Medical Center, Department of Nutrition (S.R.), School of Public Health, Departments of Medicine, Biochemistry, and Physiology, School of Medicine (D.J.B., S.M), Loma Linda University, Loma Linda, California 92357

I. Introduction
II. Characteristics of the IGFBPs
III. Target Cell Actions of the IGFBPs
A. To modulate IGF actions
B. To facilitate storage of IGFs in extracellular matrices
C. To exert IGF-independent effects
IV. IGF-IGFBP Complexes in Biological Fluids
A. Serum
B. Milk
C. Urine
D. Cerebrospinal fluid (CSF)
E. Follicular fluid
F. Amniotic fluid
G. Lymph
H. Seminal fluid
I. Other biological fluids
V. Assays for Circulating Levels of IGFBP
A. Western ligand blotting
B. Western immunoblotting
C. RIA
D. Immunoradiometric assay (IRMA)
VI. Relative Distribution of IGFBPs in Serum
VII. Regulation of Serum IGFBPs
A. Physiological conditions
B. Development and aging
C. Hormonal effects: mechanisms
D. Pathological conditions
VIII. IGFBP Proteases in Circulation
A. Proteases under normal conditions
B. Pregnancy-associated proteases
C. Proteases under catabolic and disease states
IX. Endocrine Functions of IGFBPs in Serum
A. To prevent insulin-like effects
B. To increase the half-lives of IGFs
C. To control the transport of IGFs from the vascular space
X. Conclusions




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K. Nosho, H. Yamamoto, H. Taniguchi, Y. Adachi, Y. Yoshida, Y. Arimura, T. Endo, Y. Hinoda, and K. Imai
Interplay of Insulin-Like Growth Factor-II, Insulin-Like Growth Factor-I, Insulin-Like Growth Factor-I Receptor, COX-2, and Matrix Metalloproteinase-7, Play Key Roles in the Early Stage of Colorectal Carcinogenesis
Clin. Cancer Res., December 1, 2004; 10(23): 7950 - 7957.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
M. Dehoux, R. Van Beneden, N. Pasko, P. Lause, J. Verniers, L. Underwood, J.-M. Ketelslegers, and J.-P. Thissen
Role of the Insulin-Like Growth Factor I Decline in the Induction of Atrogin-1/MAFbx during Fasting and Diabetes
Endocrinology, November 1, 2004; 145(11): 4806 - 4812.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
K.-C. Leung, G. Johannsson, G. M. Leong, and K. K. Y. Ho
Estrogen Regulation of Growth Hormone Action
Endocr. Rev., October 1, 2004; 25(5): 693 - 721.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
P. A. Pennisi, J. J. Kopchick, S. Thorgeirsson, D. LeRoith, and S. Yakar
Role of Growth Hormone (GH) in Liver Regeneration
Endocrinology, October 1, 2004; 145(10): 4748 - 4755.
[Abstract] [Full Text] [PDF]

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 ReproductionHome page
E D Watson, S-E Bae, R Thomassen, S R M Thomson, K Woad, and D G Armstrong
Insulin-like growth factors-I and -II and insulin-like growth factor-binding protein-2 in dominant equine follicles during spring transition and the ovulatory season
Reproduction, September 1, 2004; 128(3): 321 - 329.
[Abstract] [Full Text] [PDF]

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 IOVSHome page
J. L. King and C. Guidry
Insulin-Like Growth Factor Binding Proteins Modulate Muller Cell Responses to Insulin-Like Growth Factors
Invest. Ophthalmol. Vis. Sci., August 1, 2004; 45(8): 2848 - 2855.
[Abstract] [Full Text] [PDF]

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 J. Histochem. Cytochem.Home page
A. De Luca, M. De Falco, V. Fedele, L. Cobellis, A. Mastrogiacomo, V. Laforgia, I. L. Tuduce, M. Campioni, D. Giraldi, M. G. Paggi, et al.
The Serine Protease HtrA1 Is Upregulated in the Human Placenta During Pregnancy
J. Histochem. Cytochem., July 1, 2004; 52(7): 885 - 892.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
D. Vanderschueren, L. Vandenput, S. Boonen, M. K. Lindberg, R. Bouillon, and C. Ohlsson
Androgens and Bone
Endocr. Rev., June 1, 2004; 25(3): 389 - 425.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
C. H. Lang, R. A. Frost, E. Svanberg, and T. C. Vary
IGF-I/IGFBP-3 ameliorates alterations in protein synthesis, eIF4E availability, and myostatin in alcohol-fed rats
Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E916 - E926.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
C. Y. Bowers, R. Granda, S. Mohan, J. Kuipers, D. Baylink, and J. D. Veldhuis
Sustained Elevation of Pulsatile Growth Hormone (GH) Secretion and Insulin-Like Growth Factor I (IGF-I), IGF-Binding Protein-3 (IGFBP-3), and IGFBP-5 Concentrations during 30-Day Continuous Subcutaneous Infusion of GH-Releasing Peptide-2 in Older Men and Women
J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2290 - 2300.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
L. J. Spicer
Proteolytic Degradation of Insulin-Like Growth Factor Binding Proteins by Ovarian Follicles: A Control Mechanism for Selection of Dominant Follicles
Biol Reprod, May 1, 2004; 70(5): 1223 - 1230.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
J. Ayuk, R. N. Clayton, G. Holder, M. C. Sheppard, P. M. Stewart, and A. S. Bates
Growth Hormone and Pituitary Radiotherapy, But Not Serum Insulin-Like Growth Factor-I Concentrations, Predict Excess Mortality in Patients with Acromegaly
J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1613 - 1617.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
K. Wolk, S. C. Larsson, B. Vessby, A. Wolk, and K. Brismar
Metabolic, Anthropometric, and Nutritional Factors as Predictors of Circulating Insulin-Like Growth Factor Binding Protein-1 Levels in Middle-Aged and Elderly Men
J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1879 - 1884.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
Z. T. Resch, B.-K. Chen, L. K. Bale, C. Oxvig, M. T. Overgaard, and C. A. Conover
Pregnancy-Associated Plasma Protein A Gene Expression as a Target of Inflammatory Cytokines
Endocrinology, March 1, 2004; 145(3): 1124 - 1129.
[Abstract] [Full Text] [PDF]

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 Clin. Cancer Res.Home page
S. Baron-Hay, F. Boyle, A. Ferrier, and C. Scott
Elevated Serum Insulin-Like Growth Factor Binding Protein-2 as a Prognostic Marker in Patients with Ovarian Cancer
Clin. Cancer Res., March 1, 2004; 10(5): 1796 - 1806.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
S. R. Ravelich, B. H. Breier, S. Reddy, J. A. Keelan, D. N. Wells, A. J. Peterson, and R. S.F. Lee
Insulin-Like Growth Factor-I and Binding Proteins 1, 2, and 3 in Bovine Nuclear Transfer Pregnancies
Biol Reprod, February 1, 2004; 70(2): 430 - 438.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
S.'i. Miyamoto, K. Yano, S. Sugimoto, G. Ishii, T. Hasebe, Y. Endoh, K. Kodama, M. Goya, T. Chiba, and A. Ochiai
Matrix Metalloproteinase-7 Facilitates Insulin-Like Growth Factor Bioavailability through Its Proteinase Activity on Insulin-Like Growth Factor Binding Protein 3
Cancer Res., January 15, 2004; 64(2): 665 - 671.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
F. Haddad and G. R. Adams
Inhibition of MAP/ERK kinase prevents IGF-I-induced hypertrophy in rat muscles
J Appl Physiol, January 1, 2004; 96(1): 203 - 210.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
D. Nemet, P. H. Connolly, A. M. Pontello-Pescatello, C. Rose-Gottron, J. K. Larson, P. Galassetti, and D. M. Cooper
Negative energy balance plays a major role in the IGF-I response to exercise training
J Appl Physiol, January 1, 2004; 96(1): 276 - 282.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
S. R. Edmondson, S. P. Thumiger, G. A. Werther, and C. J. Wraight
Epidermal Homeostasis: The Role of the Growth Hormone and Insulin-Like Growth Factor Systems
Endocr. Rev., December 1, 2003; 24(6): 737 - 764.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
Y. Matsumoto, Y. Oda, M. Uryu, and Y. Hayakawa
Insect Cytokine Growth-blocking Peptide Triggers a Termination System of Cellular Immunity by Inducing Its Binding Protein
J. Biol. Chem., October 3, 2003; 278(40): 38579 - 38585.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
J. A. Clowes, H. C. Allen, D. M. Prentis, R. Eastell, and A. Blumsohn
Octreotide Abolishes the Acute Decrease in Bone Turnover in Response to Oral Glucose
J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4867 - 4873.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
X. Wu, S.-T. Pang, L. Sahlin, A. Blanck, G. Norstedt, and A. Flores-Morales
Gene Expression Profiling of the Effects of Castration and Estrogen Treatment in the Rat Uterus
Biol Reprod, October 1, 2003; 69(4): 1308 - 1317.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
B. C. Nindl, J. W. Castellani, A. J. Young, J. F. Patton, M. J. Khosravi, A. Diamandi, and S. J. Montain
Differential responses of IGF-I molecular complexes to military operational field training
J Appl Physiol, September 1, 2003; 95(3): 1083 - 1089.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
B.-K. Chen, K. M. Leiferman, M. R. Pittelkow, M. T. Overgaard, C. Oxvig, and C. A. Conover
Localization and Regulation of Pregnancy-Associated Plasma Protein A Expression in Healing Human Skin
J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4465 - 4471.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
C. H. Lang, T. C. Vary, and R. A. Frost
Acute in Vivo Elevation of Insulin-Like Growth Factor (IGF) Binding Protein-1 Decreases Plasma Free IGF-I and Muscle Protein Synthesis
Endocrinology, September 1, 2003; 144(9): 3922 - 3933.
[Abstract] [Full Text] [PDF]

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 LupusHome page
J A Mohammed, A Y. Mok, A Parbtani, and D G Matsell
Increased expression of insulin-like growth factors in progressive glomerulonephritis of the MRL lpr mouse
Lupus, August 1, 2003; 12(8): 584 - 590.
[Abstract] [PDF]

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 EndocrinologyHome page
S. Mohan, G. Masinde, X. Li, and D. J. Baylink
Mapping Quantitative Trait Loci That Influence Serum Insulin-Like Growth Factor Binding Protein-5 Levels in F2 Mice (MRL/MpJ X SJL/J)
Endocrinology, August 1, 2003; 144(8): 3491 - 3496.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
S. N. Sauter, E. Ontsouka, B. Roffler, Y. Zbinden, C. Philipona, M. Pfaffl, B. H. Breier, J. W. Blum, and H. M. Hammon
Effects of dexamethasone and colostrum intake on the somatotropic axis in neonatal calves
Am J Physiol Endocrinol Metab, August 1, 2003; 285(2): E252 - E261.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
T. B. Twickler, M. J. M. Cramer, G. M. Dallinga-Thie, M. J. Chapman, D. W. Erkelens, and H. P. F. Koppeschaar
Adult-Onset Growth Hormone Deficiency: Relation of Postprandial Dyslipidemia to Premature Atherosclerosis
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2479 - 2488.
[Full Text] [PDF]

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 Am J EpidemiolHome page
R. O. Roberts, D. J. Jacobson, C. J. Girman, T. Rhodes, G. G. Klee, M. M. Lieber, and S. J. Jacobsen
Insulin-like Growth Factor I, Insulin-like Growth Factor Binding Protein 3, and Urologic Measures of Benign Prostatic Hyperplasia
Am. J. Epidemiol., May 1, 2003; 157(9): 784 - 791.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
S.-E. Kong, R. C. Baxter, and P. J. D. Delhanty
Age-Dependent Regulation of the Acid-Labile Subunit in Response to Fasting-Refeeding in Rats
Endocrinology, December 1, 2002; 143(12): 4505 - 4512.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
D. B. Speert, S. J. MCClennen, and A. F. Seasholtz
Sexually Dimorphic Expression of Corticotropin-Releasing Hormone-Binding Protein in the Mouse Pituitary
Endocrinology, December 1, 2002; 143(12): 4730 - 4741.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
L. Rosendal, H. Langberg, A. Flyvbjerg, J. Frystyk, H. Orskov, and M. Kjar
Physical capacity influences the response of insulin-like growth factor and its binding proteins to training
J Appl Physiol, November 1, 2002; 93(5): 1669 - 1675.
[Abstract] [Full Text] [PDF]

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 FASEB J.Home page
A. HOEFLICH, M. M. WEBER, T. FISCH, S. NEDBAL, C. FOTTNER, M. W. ELMLINGER, R. WANKE, and E. WOLF
Insulin-like growth factor binding protein 2 (IGFBP-2) separates hypertrophic and hyperplastic effects of growth hormone (GH)/IGF-I excess on adrenocortical cells in vivo
FASEB J, November 1, 2002; 16(13): 1721 - 1731.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
A. Bachelot, P. Monget, P. Imbert-Bollore, K. Coshigano, J. J. Kopchick, P. A. Kelly, and N. Binart
Growth Hormone Is Required for Ovarian Follicular Growth
Endocrinology, October 1, 2002; 143(10): 4104 - 4112.
[Abstract] [Full Text] [PDF]

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 PediatricsHome page
D. Nemet, Y. Oh, H.-S. Kim, M. Hill, and D. M. Cooper
Effect of Intense Exercise on Inflammatory Cytokines and Growth Mediators in Adolescent Boys
Pediatrics, October 1, 2002; 110(4): 681 - 689.
[Abstract] [Full Text] [PDF]

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 Cancer Epidemiol. Biomarkers Prev.Home page
K. J. Hunt, P. Toniolo, A. Akhmedkhanov, A. Lukanova, H. Dechaud, S. Rinaldi, A. Zeleniuch-Jacquotte, R. E. Shore, E. Riboli, and R. Kaaks
Insulin-like Growth Factor II and Colorectal Cancer Risk in Women
Cancer Epidemiol. Biomarkers Prev., September 1, 2002; 11(9): 901 - 905.
[Abstract] [Full Text] [PDF]

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 J. Nutr.Home page
D. A. Khalil, E. A. Lucas, S. Juma, B. J. Smith, M. E. Payton, and B. H. Arjmandi
Soy Protein Supplementation Increases Serum Insulin-Like Growth Factor-I in Young and Old Men but Does Not Affect Markers of Bone Metabolism
J. Nutr., September 1, 2002; 132(9): 2605 - 2608.
[Abstract] [Full Text] [PDF]


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