Insulin-like Growth Factor Binding Protein-1: Recent Findings and New Directions

Abstract

In 1988, insulin-like growth factor-binding protein-1 (IGFBP-1) became the first characterized member of a group of structurally related soluble proteins which specifically bind and modulate the actions of the IGFs. Since then, a wealth of information has accumulated regarding the physiology of this dynamic serum protein. In this review, we update our 1993 summary (Lee PDK et al. Proc Soc Exp Biol Med 204:4-29) of the status of IGFBP-1 research. The IGFBP-1 protein sequence contains 12 N-terminal and 6 C-terminal cysteine residues which are conserved in other mammalian IGFBP-1 sequences and amongst other IGFBPs; both of the cysteine-rich regions are required for optimal IGF binding. The nonconserved IGFBP-1 midregion may act as both a hinge which defines ligand binding characteristics and as a specific target for protease activity. Integrin-binding and phosphorylation sites within the IGFBP-1 sequence have functional significance in vitro, but their physiologic relevance in vivo have not been defined. The human IGFBP-1 and IGFBP-3 genes are contiguous and located in close proximity to the homeobox A (HOXA) gene cluster on chromosome 7. The other IGFBP genes, located on chromosomes 2, 12, and 17, are also associated with HOX clusters, suggesting evolutionary linkage of the IGFBP and HOX gene families. Similarities between the hIGFBP-1 and phosphoenolpyruvate kinase (PEPCK) promoters, including regions conferring insulin, glucocorticoid, and cyclic adenosine-monophosphate responses, are consistent with our previous hypothesis that IGFBP-1 is involved in regulation of glucose metabolism. The tissue-specific patterns of IGFBP-1 gene expression in liver, kidney, decidua, and ovary may be due to stimulation of IGFBP-1 transcription by hepatic nuclear factor 1 (HNF1) proteins. Clinical and basic studies of IGFBP-1 physiology have been aided by several recently developed assay methods. Numerous investigations have confirmed that insulin, via inhibition of IGFBP-1 transcription, is the primary determinant of IGFBP-1 expression both in vitro and in vivo. IGF-I and IGF-II also have specific inhibitory effects on IGFBP-1 expression. Glucocorticoids and cAMP stimulate IGFBP-1 transcription, but these effects are observed only in conditions of low or absent insulin effect. Other stimulants of IGFBP-1 expression include thyroid hormones and epidermal growth factor. Phorbol ester stimulation of IGFBP-1 expression can supersede the effects of insulin in vitro;however, the mechanism and in vivo correlates of this effect have not been determined. Cytokines and, perhaps, growth hormones may affect IGFBP-1 expression, perhaps by altering the regulatory actions of insulin; this effect may have important clinical relevance. IGFBP-1 expression is upregulated in liver and (nonhuman) kidney during postinjury regeneration. The IGF-inhibitory actions of IGFBP-1 has been confirmed by numerous in vitro studies and several in vivo animal investigations, including administration of recombinant IGFBP-1 and IGFBP-1 transgenic models. IGFBP-1 has ...

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

“…IGF‐I promotes mitosis and cell cycle progression and is involved in human postnatal growth and development. Circulating IGF‐I is mainly bound to IGF‐binding proteins (IGFBPs) (Fowlkes, 1997), which affect activity (Lee et al ., 1997) and half‐life of IGF‐I (Guler et al ., 1989). From the clinical point of view, the measurement of IGF‐I and IGFBP‐3 blood concentrations is an important tool in establishing the diagnosis as well as monitoring treatment of GH‐related diseases (Ho & Participants, 2007; Cohen et al ., 2008; Melmed et al ., 2009).…”

Treating Human Meniscal Fibrochondrocytes with hIGF-1 Gene by Liposome

“…Several studies confirm human insulin-like growth factor-1 (hIGF-1) plays a key role in the regulation of chondrocyte proteoglycan metabolism and stimulates cell proliferation [5,12,16,17]. Theoretically, then, human meniscal fibrochondrocytes cultured in vitro may present a positive response to liposome-mediated hIGF-1 gene transfection.…”

“…It also plays an important role in stimulating collagen and proteoglycan synthesis in cartilage through an autocrine feedback mechanism [25]. Since hIGF-1 is a major chondro-enhancing agent, notwithstanding its attenuated effect on aged cartilage, it would appear a logical choice for gene therapy approaches [4,5,7,12,16]. It is a relatively small gene of approximately 45 kb pairs with the transcribed region spanning less than 1 kb, and the DNA sequence is known in most species.…”

“…Human insulin-like growth factor-1 (hIGF-1) stimulates the synthesis and deposition of extracellular matrix components by chondrocytes as well as cell proliferation [5,12,16]. In cell culture, it suppresses chondrocyte dedifferentiation and stabilizes the chondrocyte phenotype [17].…”

Marked differences in the IGF system that are associated with migration in comparable populations of Gujaratis living in Sandwell, UK, and Gujarat, India

“…The IGF system has been implicated in the pathogenesis of hypertension [7], atheromatous vascular disease [8,9], cardiomegaly [10], ischaemic disease [11] and cardiac failure [12,13]. IGF bioactivity is modulated by a series of specific high-affinity IGFBPs [14]. Of the six IGFBPs fully characterised, IGFBP-1 is considered to be the principal hour-to-hour regulator of circulating IGF activity [14], forming the link between dietary ingestion, glucose metabolism and the IGF axis.…”