insulin like growth factor binding protein 4


Summary: One of the six homologous soluble proteins that bind insulin-like growth factors (SOMATOMEDINS) and modulate their mitogenic and metabolic actions at the cellular level.

Top Publications

  1. Ryan A, Napoletano S, Fitzpatrick P, Currid C, O Sullivan N, Harmey J. Expression of a protease-resistant insulin-like growth factor-binding protein-4 inhibits tumour growth in a murine model of breast cancer. Br J Cancer. 2009;101:278-86 pubmed publisher
    ..Bioavailability of IGF1 is modulated by IGF-binding proteins (IGFBPs). IGFBP4 inhibits IGF1 activity but cleavage by pregnancy-associated plasma protein-A (PAPP-A) protease releases active IGF1...
  2. Zhu W, Shiojima I, Ito Y, Li Z, Ikeda H, Yoshida M, et al. IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. Nature. 2008;454:345-9 pubmed publisher
    ..IGFBP-4 is therefore an inhibitor of the canonical Wnt signalling required for cardiogenesis and provides a molecular link between IGF signalling and Wnt signalling. ..
  3. Conover C, Bale L, Overgaard M, Johnstone E, Laursen U, Füchtbauer E, et al. Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development. Development. 2004;131:1187-94 pubmed
    ..These results provide the first direct evidence that PAPPA is an essential growth regulatory factor in vivo, and suggest a novel mechanism for regulated IGF bioavailability during early fetal development. ..
  4. Nichols T, Busby W, Merricks E, Sipos J, Rowland M, Sitko K, et al. Protease-resistant insulin-like growth factor (IGF)-binding protein-4 inhibits IGF-I actions and neointimal expansion in a porcine model of neointimal hyperplasia. Endocrinology. 2007;148:5002-10 pubmed
    ..The findings support the hypothesis that inhibiting IGFBP-4 proteolysis in the lesion microenvironment could be an effective means for regulating neointimal expansion. ..
  5. Lewinski A, Marcinkowska M, Brzezianska E, Jeziorowska A, Włoch J, Brzezinski J. Expression of insulin-like growth factor I (IGF-I) gene and of genes for IGF-binding proteins 1, 2, 3, 4 (IGFBP-1-IGFBP-4) in non-neoplastic human thyroid cells and in certain human thyroid cancers. Effect of exogenous IGF-I on this expression. Endocr Res. 2004;30:47-59 pubmed
    ..These facts indicate an important role of IGF-I in the pathogenesis and invasiveness of the analyzed malignant neoplasms. ..
  6. Durai R, Davies M, Yang W, Yang S, Seifalian A, Goldspink G, et al. Biology of insulin-like growth factor binding protein-4 and its role in cancer (review). Int J Oncol. 2006;28:1317-25 pubmed
    ..The effect of altered expression of IGFBP-4 in vivo in colon and other cancers needs to be explored as locally available IGFs appear to stimulate mitogenesis. ..
  7. Bunn R, Green L, Overgaard M, Oxvig C, Fowlkes J. IGFBP-4 degradation by pregnancy-associated plasma protein-A in MC3T3 osteoblasts. Biochem Biophys Res Commun. 2004;325:698-706 pubmed
    ..These results demonstrate for the first time that PAPP-A is the IGFBP-4 protease in MC3T3-E1 cells, a widely used model for osteoblast development, and that PAPP-A may regulate IGF release throughout osteoblast differentiation. ..
  8. Overgaard M, Haaning J, Boldt H, Olsen I, Laursen L, Christiansen M, et al. Expression of recombinant human pregnancy-associated plasma protein-A and identification of the proform of eosinophil major basic protein as its physiological inhibitor. J Biol Chem. 2000;275:31128-33 pubmed
    ..Inhibition of PAPP-A by proMBP represents a novel inhibitory mechanism with the enzyme irreversibly bound to its inhibitor by disulfide bonds. ..
  9. Laursen L, Overgaard M, Søe R, Boldt H, Sottrup Jensen L, Giudice L, et al. Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A. FEBS Lett. 2001;504:36-40 pubmed
    ..We thus conclude that IGF enhances proteolysis by binding to IGFBP-4, not by interaction with PAPP-A, which could not previously be ruled out. ..

More Information


  1. Miyakoshi N, Qin X, Kasukawa Y, Richman C, Srivastava A, Baylink D, 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 pubmed
    ..This study demonstrates that systemic administration of IGFBP-4 increases bone formation parameters in mice by increasing IGF bioavailability in the circulation via an IGFBP-4 protease-dependent mechanism. ..
  2. Zhang M, Smith E, Kuroda H, Banach W, Chernausek S, Fagin J. Targeted expression of a protease-resistant IGFBP-4 mutant in smooth muscle of transgenic mice results in IGFBP-4 stabilization and smooth muscle hypotrophy. J Biol Chem. 2002;277:21285-90 pubmed
    ..Thus, IGFBP-4.7A results in greater growth inhibition than equivalent levels of native IGFBP-4 in vivo, demonstrating a role for IGFBP-4 proteolysis in the regulation of IGF-I action. ..
  3. Durai R, Yang S, Sales K, Seifalian A, Goldspink G, Winslet M. Insulin-like growth factor binding protein-4 gene therapy increases apoptosis by altering Bcl-2 and Bax proteins and decreases angiogenesis in colorectal cancer. Int J Oncol. 2007;30:883-8 pubmed
    ..This experiment shows that IGFBP-4 gene therapy increases tumour apoptosis via altering the expressions of Bcl-2 and Bax and decreasing the angiogenesis in colorectal cancer. ..
  4. Rehault S, Monget P, Mazerbourg S, Tremblay R, Gutman N, Gauthier F, et al. Insulin-like growth factor binding proteins (IGFBPs) as potential physiological substrates for human kallikreins hK2 and hK3. Eur J Biochem. 2001;268:2960-8 pubmed
    ..Our results suggest that the prostatic kallikreins hK2 and hK3 may influence specifically the tumoral growth of prostate cells through the degradation of IGFBPs, to increase IGF bioavailability. ..
  5. Wright R, Holly J, Galea R, Brincat M, Mason H. Insulin-like growth factor (IGF)-independent effects of IGF binding protein-4 on human granulosa cell steroidogenesis. Biol Reprod. 2002;67:776-81 pubmed
    ..No similar effects were seen with IGFBP-2. These reasults are the first evidence of IGF-independent IGFBP-4 actions and the first evidence of IGF-independent actions of any IGFBPs in the ovary. ..
  6. Hendriksen P, Gadella B, Vos P, Mullaart E, Kruip T, Dieleman S. Follicular dynamics around the recruitment of the first follicular wave in the cow. Biol Reprod. 2003;69:2036-44 pubmed
    ..The first newly recruited follicles do not reach the size of 3 mm before 31 h after the preovulatory FSH surge. At that time, the larger follicles are already competing for dominance. ..
  7. Price W, Moats Staats B, Stiles A. Pro- and anti-inflammatory cytokines regulate insulin-like growth factor binding protein production by fetal rat lung fibroblasts. Am J Respir Cell Mol Biol. 2002;26:283-9 pubmed
    ..These results demonstrate that cytokines regulate IGFBP production and clearance by fetal lung cells and suggest a mechanism by which cytokines regulate cell proliferation following lung injury. ..
  8. Armstrong D, McEvoy T, Baxter G, Robinson J, Hogg C, Woad K, et al. Effect of dietary energy and protein on bovine follicular dynamics and embryo production in vitro: associations with the ovarian insulin-like growth factor system. Biol Reprod. 2001;64:1624-32 pubmed
  9. Byun D, Mohan S, Yoo M, Sexton C, Baylink D, Qin X. Pregnancy-associated plasma protein-A accounts for the insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) proteolytic activity in human pregnancy serum and enhances the mitogenic activity of IGF by degrading IGFBP-4 in vitro. J Clin Endocrinol Metab. 2001;86:847-54 pubmed
  10. Kalousova M, Hodkova M, Dusilova Sulkova S, Uhrova J, Tesar V, Zima T. Effect of hemodiafiltration on pregnancy-associated plasma protein A (PAPP-A) and related parameters. Ren Fail. 2006;28:715-21 pubmed
    ..Studies aimed at a long-term effect of both procedures on these parameters would be needed to further evaluate these therapeutical strategies. ..
  11. Fridman A, Rosati R, Li Q, Tainsky M. Epigenetic and functional analysis of IGFBP3 and IGFBPrP1 in cellular immortalization. Biochem Biophys Res Commun. 2007;357:785-91 pubmed
    ..Analysis of how IGFBPs regulate immortalization will lead to a better understanding of this process and may lead to novel methods for the prevention and treatment of cancer. ..
  12. Lewis M, Fournier M, Storer T, Bhasin S, Porszasz J, Ren S, et al. Skeletal muscle adaptations to testosterone and resistance training in men with COPD. J Appl Physiol (1985). 2007;103:1299-310 pubmed
    ..Our data suggest that the combined interventions produced an enhanced local anabolic milieu driven in large part by the muscle IGF system, despite potentially negative biochemical influences present in COPD patients. ..
  13. Wegmann B, Schöneberger H, Kiefer P, Jaques G, Brandscheid D, Havemann K. Molecular cloning of IGFBP-5 from SCLC cell lines and expression of IGFBP-4, IGFBP-5 and IGFBP-6 in lung cancer cell lines and primary tumours. Eur J Cancer. 1993;29A:1578-84 pubmed
    ..IGFBP-6 was not detected in northern analysis of any tested SCLC cell line but it was expressed in nine out of 11 NSCLC cell lines and in nine out of 11 human lung cancer specimens and in normal lung. ..
  14. Conover C, Mason M, Bale L, Harrington S, Nyegaard M, Oxvig C, et al. Transgenic overexpression of pregnancy-associated plasma protein-A in murine arterial smooth muscle accelerates atherosclerotic lesion development. Am J Physiol Heart Circ Physiol. 2010;299:H284-91 pubmed publisher
    ..These data provide further evidence for the importance of PAPP-A in the cardiovascular system and suggest PAPP-A as a potential therapeutic target in the control of atherosclerosis. ..
  15. Fleming J, Leibowitz B, Kerr D, Cohick W. IGF-I differentially regulates IGF-binding protein expression in primary mammary fibroblasts and epithelial cells. J Endocrinol. 2005;186:165-78 pubmed
  16. Ghosh M, Shanker S, Siwanowicz I, Mann K, Machleidt W, Holak T. Proteolysis of insulin-like growth factor binding proteins (IGFBPs) by calpain. Biol Chem. 2005;386:85-93 pubmed
    ..We therefore conclude that calpains seem not to recognize amino acid sequences, but instead cleave with low sequence specificity at unstructured or solvent-exposed fragments that connect folded, stable domains of target proteins. ..
  17. Oesterreicher S, Blum W, Schmidt B, Braulke T, Kubler B. Interaction of insulin-like growth factor II (IGF-II) with multiple plasma proteins: high affinity binding of plasminogen to IGF-II and IGF-binding protein-3. J Biol Chem. 2005;280:9994-10000 pubmed
  18. Yamaguchi T, Kanatani M, Yamauchi M, Kaji H, Sugishita T, Baylink D, et al. Serum levels of insulin-like growth factor (IGF); IGF-binding proteins-3, -4, and -5; and their relationships to bone mineral density and the risk of vertebral fractures in postmenopausal women. Calcif Tissue Int. 2006;78:18-24 pubmed
  19. Rivera G, Fortune J. Proteolysis of insulin-like growth factor binding proteins -4 and -5 in bovine follicular fluid: implications for ovarian follicular selection and dominance. Endocrinology. 2003;144:2977-87 pubmed
  20. Bethel C, Vitullo J, Miller R, Aron D. Molecular cloning of mouse insulin-like growth factor binding protein 4 (IGFBP4) cDNA and expression of a fusion protein with IGF-binding activity. Biochem Mol Biol Int. 1994;34:385-92 pubmed
    ..7 kD. An IGFBP-4/maltose binding protein fusion peptide expression in the pMal-p2 vector produced a fusion protein exhibiting both IGFBP immunoreactivity and IGF-I binding activity with specificity characteristic of IGFBPs. ..
  21. Schuller A, van Neck J, Beukenholdt R, Zwarthoff E, Drop S. IGF, type I IGF receptor and IGF-binding protein mRNA expression in the developing mouse lung. J Mol Endocrinol. 1995;14:349-55 pubmed
    ..A possible role for IGFBPs-2, -4 and -5 is to participate in the regulation of cell-specific IGF responses during mouse lung development. ..
  22. Jehle P, Ostertag A, Schulten K, Schulz W, Jehle D, Stracke S, et al. Insulin-like growth factor system components in hyperparathyroidism and renal osteodystrophy. Kidney Int. 2000;57:423-36 pubmed
    ..Therefore, IGFBP-5 may gain significance as a serological marker for osteopenia and low bone turnover in long-term dialysis patients. ..
  23. Price W. PDGF-BB regulates IGF-mediated IGFBP-4 proteolysis in fetal lung fibroblasts. Exp Lung Res. 2001;27:655-74 pubmed
    ..These studies demonstrate that PDGF-BB increases the accumulation of ICFBP-4 in fetal rat lung fibroblasts CM through increased production and by inhibiting IGF-mediated IGFBP-4 proteolysis. ..
  24. Laursen L, Overgaard M, Nielsen C, Boldt H, Hopmann K, Conover C, et al. Substrate specificity of the metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) assessed by mutagenesis and analysis of synthetic peptides: substrate residues distant from the scissile bond are critical for proteolysis. Biochem J. 2002;367:31-40 pubmed
  25. Mohan S, Farley J, Baylink D. 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 pubmed
  26. Benbassat C, Lazarus D, Cichy S, Evans T, Moldawer L, Lowry S, et al. Interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor alpha (TNF alpha) regulate insulin-like growth factor binding protein-1 (IGFBP-1) levels and mRNA abundance in vivo and in vitro. Horm Metab Res. 1999;31:209-15 pubmed
    ..Additional studies are required to identify specific mechanisms mediating effects of cytokines on hepatic production of IGFBP-1. ..
  27. Wex H, Ahrens D, Hohmann B, Redlich A, Mittler U, Vorwerk P. Insulin-like growth factor-binding protein 4 in children with acute lymphoblastic leukemia. Int J Hematol. 2005;82:137-42 pubmed
    ..IGFBP-4 was exclusively expressed in cell lines derived either from B-cells or from myelomonocytic cells, whereas IGFBP-4 was not expressed in T-cell lines. ..
  28. Monitto C, Berkowitz D, Lee K, Pin S, Li D, Breslow M, et al. Differential gene expression in a murine model of cancer cachexia. Am J Physiol Endocrinol Metab. 2001;281:E289-97 pubmed
    ..The roles of a number of these genes in known metabolic pathways identify them as potential participants in the induction of cachexia...
  29. Amaar Y, Thompson G, Linkhart T, Chen S, Baylink D, 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 pubmed
    ..The role of FHL2 as an intracellular mediator of the effects of IGFBP-5 and other osteoregulatory agents in osteoblasts will need to be verified in future studies. ..
  30. Tanaka Y, Kobayashi H, Suzuki M, Hirashima Y, Kanayama N, Terao T. Genetic downregulation of pregnancy-associated plasma protein-A (PAPP-A) by bikunin reduces IGF-I-dependent Akt and ERK1/2 activation and subsequently reduces ovarian cancer cell growth, invasion and metastasis. Int J Cancer. 2004;109:336-47 pubmed
    ..IGF-I-induced IGFBP-4 proteolysis by PAPP-A may enhance cell growth and invasion through IGF-I-dependent Akt and ERK1/2 activation and subsequently upregulation of uPA. ..
  31. Green J, Goldberg R, Maor G. PTH ameliorates acidosis-induced adverse effects in skeletal growth centers: the PTH-IGF-I axis. Kidney Int. 2003;63:487-500 pubmed
    ..This study lends further credence to the notion that under certain conditions, PTH or PTHrP can exert anabolic effects in the skeleton. These findings may be of clinical-therapeutic significance in children and patients with CMA. ..
  32. Søe R, Overgaard M, Thomsen A, Laursen L, Olsen I, Sottrup Jensen L, et al. Expression of recombinant murine pregnancy-associated plasma protein-A (PAPP-A) and a novel variant (PAPP-Ai) with differential proteolytic activity. Eur J Biochem. 2002;269:2247-56 pubmed
    ..Importantly, these data support the development of the mouse as a model organism for the study of PAPP-A, which must take into account the differences between the mouse and the human. ..
  33. Mazerbourg S, Callebaut I, Zapf J, Mohan S, Overgaard M, Monget P. Up date on IGFBP-4: regulation of IGFBP-4 levels and functions, in vitro and in vivo. Growth Horm IGF Res. 2004;14:71-84 pubmed
    ..In this review, we have provided an update on IGFBP-4 research and we have summarized our current understanding of the regulation of levels and actions of IGFBP-4 and proteolytic fragments both in vitro and in vivo. ..
  34. van Doorn J, Cornelissen A, Van Buul Offers S. Plasma levels of insulin-like growth factor binding protein-4 (IGFBP-4) under normal and pathological conditions. Clin Endocrinol (Oxf). 2001;54:655-64 pubmed
    ..The possibility of quantifying IGFBP-4 by RIA will facilitate further in vitro and in vivo studies on its regulation and function in humans. ..
  35. Mita K, Zhang Z, Ando Y, Toyama T, Hamaguchi M, Kobayashi S, et al. Prognostic significance of insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5 expression in breast cancer. Jpn J Clin Oncol. 2007;37:575-82 pubmed
  36. Olney R, Mougey E. Expression of the components of the insulin-like growth factor axis across the growth-plate. Mol Cell Endocrinol. 1999;156:63-71 pubmed
    ..Since IGF-I and -II are potent stimulators of proliferation, the down-regulation of these genes may be necessary in order for hypertrophy to proceed. ..
  37. Sitar T, Popowicz G, Siwanowicz I, Huber R, Holak T. Structural basis for the inhibition of insulin-like growth factors by insulin-like growth factor-binding proteins. Proc Natl Acad Sci U S A. 2006;103:13028-33 pubmed
  38. Xu Q, Li S, Zhao Y, Maures T, Yin P, Duan C. Evidence that IGF binding protein-5 functions as a ligand-independent transcriptional regulator in vascular smooth muscle cells. Circ Res. 2004;94:E46-54 pubmed
    ..These results suggest that IGFBP-5 is localized in VSMC nucleus and possesses transcription-regulatory activity that is IGF independent. ..
  39. Llewellyn S, Fitzpatrick R, Kenny D, Murphy J, Scaramuzzi R, Wathes D. Effect of negative energy balance on the insulin-like growth factor system in pre-recruitment ovarian follicles of post partum dairy cows. Reproduction. 2007;133:627-39 pubmed
  40. Ehrnborg C, Ohlsson C, Mohan S, Bengtsson B, Rosen T. Increased serum concentration of IGFBP-4 and IGFBP-5 in healthy adults during one month's treatment with supraphysiological doses of growth hormone. Growth Horm IGF Res. 2007;17:234-41 pubmed
  41. van Kleffens M, Groffen C, Dits N, Lindenbergh Kortleve D, Schuller A, Bradshaw S, et al. Generation of antisera to mouse insulin-like growth factor binding proteins (IGFBP)-1 to -6: comparison of IGFBP protein and messenger ribonucleic acid localization in the mouse embryo. Endocrinology. 1999;140:5944-52 pubmed
    ..The overlapping mRNA and protein localization for IGFBP-2 and -4, on the other hand, may indicate that these IGFBPs also function in an auto- or paracrine manner. ..
  42. Durham S, Kiefer M, Riggs B, Conover C. 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 pubmed
    ..However, pretreatment of cultured hOB with IGF-II enhanced IGF-I-stimulated [3H]thymidine incorporation threefold.(ABSTRACT TRUNCATED AT 250 WORDS) ..
  43. Hastie P, Haresign W. Modulating peripheral gonadotrophin levels affects follicular expression of mRNAs encoding insulin-like growth factor binding proteins in sheep. Anim Reprod Sci. 2010;119:198-204 pubmed publisher
    ..These data highlight that FSH and LH are involved, at least in part, in mediating the proliferative and differentiative changes in intrafollicular IGFBP levels that are observed during follicular growth and atresia in the sheep. ..
  44. Ilvesmaki V, Liu J, Heikkila P, Kahri A, Voutilainen R. Expression of insulin-like growth factor binding protein 1-6 genes in adrenocortical tumors and pheochromocytomas. Horm Metab Res. 1998;30:619-23 pubmed
    ..Our data show that the six IGFBPs 1-6 are expressed at variable level in adrenal tumors and hyperplasias. The low level of IGFBP mRNAs in hormonally active adrenocortical carcinomas was of particular interest. ..
  45. Gu K, Zhang L, Jin T, Rutherford R. Identification of potential modifiers of Runx2/Cbfa1 activity in C2C12 cells in response to bone morphogenetic protein-7. Cells Tissues Organs. 2004;176:28-40 pubmed
    ..In addition, our data revealed for the first time that BMP-7 not only induced the expression of osteoblastic differentiation markers but also stimulated the expression of chondroblastic markers in C2C12 cells. ..
  46. Kiepe D, Andress D, Mohan S, Ständker L, Ulinski T, Himmele R, et al. Intact IGF-binding protein-4 and -5 and their respective fragments isolated from chronic renal failure serum differentially modulate IGF-I actions in cultured growth plate chondrocytes. J Am Soc Nephrol. 2001;12:2400-10 pubmed
    ..IGFBP-5, however, can either stimulate (if it remains intact) or inhibit (if amino-terminal forms predominate) IGF-I-stimulated chondrocyte proliferation. ..
  47. Giudice L, Conover C, Bale L, Faessen G, Ilg K, Sun I, et al. Identification and regulation of the IGFBP-4 protease and its physiological inhibitor in human trophoblasts and endometrial stroma: evidence for paracrine regulation of IGF-II bioavailability in the placental bed during human implantation. J Clin Endocrinol Metab. 2002;87:2359-66 pubmed
    ..Overall, the data underscore potential roles for a complex family of enzyme (PAPP-A), substrate (IGFBP-4), inhibitor (proMBP), and cofactor (IGF-II) in the placental bed during human implantation. ..
  48. Hilleson Gayne C, Clapper J. Effects of decreased estradiol-17beta on the serum and anterior pituitary IGF-I system in pigs. J Endocrinol. 2005;187:369-78 pubmed
    ..These data further support a role for E2 in regulating components of the IGF system in pigs. ..
  49. Glantschnig H, Varga F, Luegmayr E, Klaushofer K. Characterization of the mouse insulin-like growth factor binding protein 4 gene regulatory region and expression studies. DNA Cell Biol. 1998;17:51-60 pubmed
    ..The description of the genomic IGFBP-4 region in the mouse now opens new perspectives for further clarification of the role of IGFBP-4 in growth and development. ..
  50. Hsieh T, Gordon R, Clemmons D, Busby W, Duan C. Regulation of vascular smooth muscle cell responses to insulin-like growth factor (IGF)-I by local IGF-binding proteins. J Biol Chem. 2003;278:42886-92 pubmed
    ..IGFBP-5 not only modulates IGF-I actions, but it also stimulates cell migration by interacting with cell-surface heparan sulfate proteoglycans. ..
  51. Hausman G, Richardson R, Simmen F. Secretion of insulin-like growth factor (IGF)-I and -II and IGF binding proteins (IGFBPs) in fetal stromal-vascular (S-V) cell cultures obtained before and after the onset of adipogenesis in vivo. Growth Dev Aging. 2002;66:11-26 pubmed
  52. Holmin S, Mathiesen T, Langmoen I, Sandberg Nordqvist A. Depolarization induces insulin-like growth factor binding protein-2 expression in vivo via NMDA receptor stimulation. Growth Horm IGF Res. 2001;11:399-406 pubmed
    ..Taken together, these findings indicate that upregulation of IGFBP-2 by depolarization is mediated by NMDA receptors, and, as no neuronal damage was detected, astrocytic NMDA receptors may be responsible for this upregulation. ..
  53. Devine A, Rosen C, Mohan S, Baylink D, Prince R. Effects of zinc and other nutritional factors on insulin-like growth factor I and insulin-like growth factor binding proteins in postmenopausal women. Am J Clin Nutr. 1998;68:200-6 pubmed
    ..These results suggest that low zinc intake is associated with low IGF-I concentrations in healthy postmenopausal women and that the effects of zinc may be independent of protein intake. ..