Insulin-like Growth Factor-binding Protein 3 (IGFBP-3)

Overview:

The insulin-like growth factor (IGF) system plays a critical role in the growth and differentiation of normal and malignant cells. The components of the IGF system include growth hormone (GH), IGF-I and II, type I and II receptors, IGF binding proteins and proteases. IGF binding proteins were first identified for their high affinity interactions with IGF-I and IGF-II.2

IGFBP-3 is the most abundant IGFBP species in circulation and binds 75% to 90% of circulating IGF-I in a ternary complex consisting of IGFBP-3, IGF-I and acid-labile subunit (ALS). IGFBP-3 modulates the activity of IGF-1 and to increase their half lives. It has been postulated that IGFBP-3 is regulated by GH and originates in the liver as low levels were observed in patients with impaired hepatic function.3

IGFBP-3 has historically been used in the investigation of growth hormone deficiency, acromegaly, hypopituitarism and to monitor recombinant GH therapy.4,5 IGFBP-3 is known to modulate the actions of IGFs in circulation as and at the IGF-1 receptor.3 IGFBP-3 has also been shown to exhibit distinct biological effects independent of the IGF/IGF-1 receptor axis.6,7 Recent studies have impaired interaction of IGFBP-3 with a variety of proteins or signaling cascades critical to cell cycle control and apoptosis; however, the actual mechanism of IGFBP-3 action is unclear.6

Several factors influence IGFBP-3 levels, including age, sexual development, nutrition, and hepatic and renal function. IGFBP-3 increases during early childhood and puberty and then decreases slightly in adult life. Levels of this binding protein decrease during fasting and chronic malnutrition. IGFBP-3 levels are decreased in hepatic failure and diabetes mellitus, but are increased in chronic renal failure.

1. Friedrich N, Wolthers OD, Arafat AM, et al. Age- and sex-specific reference intervals across life span for insulin-like growth factor binding protein 3 (IGFBP-3) and the IGF-1 to IGFBP-3 ratio measured by new automated chemiluminescence assays. J Clin Endocrinol Metab. 2014 May; 99(5):1675-1686. PubMed 24483154

2. Ballard J, Baxter R, Binoux M, et al. On the nomenclature of the IGF binding proteins. Acta Endocrinol (Copenh). 1989 Nov; 121(5):751-752. PubMed 2555997

3. Holly JM, Perks CM. Insulin-like growth factor physiology: What we have learned from human studies. Endocrinol Metab Clin North Am. 2012 Jun; 41(2):249-263. PubMed 22682629 4. Blum WF, Ranke MB. Use of insulin-like growth factor binding protein 3 for the evaluation of growth disorders. Horm Res. 990; 33(Suppl 4):31-37. PubMed 1700965

5. Ranke MB, Schweizer R, Elmlinger MW, et al. Significance of basal IGF-I, IGFBP-3 and IGFBP-2. measurements in the diagnostics of short stature in children. Horm Res. 2000; 54(2):60-68. PubMed 11251368

6. Jogie-Brahim S, Feldman D, Oh Y. Unraveling insulin-like growth factor binding protein-3 actions in human disease. Endocr Rev. 2009 Aug; 30(5):417-437. PubMed 19477944

7. Mohan S, Baylink DJ. IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms. J Endocrinol. 2002 Oct; 175(1):19-31. PubMed 12379487

Baxter RC, Martin JL. Radioimmunoassay of growth hormone-dependent insulin-like growth factor binding protein in human plasma. J Clin Invest. 1986 Dec; 78(6):1504-1512. PubMed 2431001

Blum WF, Ranke MB, Kietzmann K, Gauggel E, Zeisel HJ, Bierich JR. A specific radioimmunoassay for the growth hormone (GH)-dependent somatomedin-binding protein: Its use for diagnosis of GH deficiency. J Clin Endocrinol Metab. 1990 May; 70(5):1292-1298. PubMed 1692331

Insulin-like Growth Factor Binding Protein-3 on the IDS iSYS, Device Code IS-4400, IFU Version 2011-11-29 V03. Fountain Hills, Ariz:Immunodiagnostic Systems Inc (IDS Inc). Rosenfeld RG,

Wilson DM, Lee PD, Hintz RL.. Insulin-like growth factors I and II in evaluation of growth retardation. J Pediatr. 1986 Sep; 109(3):428-433. PubMed 3746530