Disease relevance of IGFBP-3

• Hepatic IGF-I mRNA and plasma IGFBP-3 content were reduced by 140 d when body weight was reduced in prenatal T-treated fetuses [1].
• Circulating IGF-I is positively correlated with fetal weight (r = 0.66, P = 0.03), circulating IGFBP-3 (r = 0.54, P = 0.01) and IGFBP-4 (r = 0.52, P = 0.01) [2].
• Thus, chronic hypoxemia in the newborn is associated with a decrease in IGF-I and IGFBP-3 in the face of normal GH [3].
• The response of maternal plasma IGFBP-3 and IGF-I to undernutrition did not depend on the level of periconceptual nutrition [4].
• Tf treatment blocked IGFBP-3-induced cell proliferation in bladder smooth muscle cells, and IGFBP-3-induced apoptosis in prostate cancer cells [5].

High impact information on IGFBP-3

• As an independent confirmation of this interaction, using a yeast two-hybrid system, we cloned Tf from a human liver complementary DNA library as an IGFBP-3 protein partner [5].
• Plasma IGFBP-2 content was significantly reduced in prenatal T-treated newborns, but by 4 months these females had significantly higher circulating IGF-I and IGFBP-3 concentrations and faster growth rates than control females [1].
• There was a transient increase in plasma IGF-I and IGFBP-3 concentrations at fetal 90 d in prenatal T-treated fetuses [1].
• C-terminal, but not N-terminal, proteolytic fragments derived from IGFBP-3 (aa 161-264), as well as heparin-binding domain-containing peptides derived from the C-terminal domain of IGFBP-3 and -5 also induced the inhibition of IGFBP-4 proteolytic degradation [6].
• Furthermore, IGFBP-3, mutated on its heparin-binding domain, was not able to inhibit IGFBP-4 proteolytic degradation [6].

Biological context of IGFBP-3

• To determine if there was any difference in plasma IGF-I and IGFBP-3 concentrations in growth-retarded fetal sheep with altered renal status, concentrations were measured by specific radioimmunoassay from bilaterally nephrectomized fetal sheep between Days 113 and 135 gestation [7].
• IGFBP-3 was the major postnatal binding protein, while in the fetus IGFBP-2, IGFBP-3 and the circulating IGF type 2 receptor fragment each contributed 25-30% of total IGF binding capacity [8].
• There was no change in plasma IGFBP-3 concentration with gestational age in either experimental group [7].
• Neither insulin nor rhIGF-I treatment had an effect on hepatic IGFBP-3 gene expression [9].
• The different affinities of des(1-3)IGF-I for IGFBP-3, -2, and -1 lead us to suggest that IGFBP-2 and/or -1 are present in the deep stroma and glands, whereas IGFBP-3 may be responsible for the additional binding sites in the myometrium and blood vessel walls [10].

Anatomical context of IGFBP-3

• In the intercotyledonary endometrium, IGFBP-3, IGFBP-5 and uterine milk protein (UTMP) mRNA were all expressed in the glandular epithelium [11].
• Neither granulosa nor theca cell cultures produced significant quantities of IGFBP-3, and the source of this binding protein in the follicular fluid from large ovine follicles is probably the circulation [12].
• We conclude that inhibition of thyroid iodide uptake and its organification, stimulation of iodocompound secretion and stimulation of IGFBP-2 and IGFBP-3 secretion may be effected through the modulation of a limited number of PKC isozymes and possibly initially, only through PKC beta 1 [13].
• In the fetal trophoblast, IGFBP-3 mRNA expression was higher in the MH group [14].
• Nutritionally related changes in IGFBP expression within the placentome and intercotyledonary endometrium may explain these findings, with IGFBP-3 expression in the luminal epithelium and caruncular stroma of the placentome villi being inversely correlated to placentome number and the total placentome weight respectively [15].

Associations of IGFBP-3 with chemical compounds

• Ethanol exposure did not alter maternal or fetal plasma concentrations of IGFBP-2 and IGFBP-3, measured by Western ligand blotting [16].
• Estradiol increased serum IGF-I, IGFBP-3, and IGFBP-4 throughout the treatment period, but it did not influence other IGFBPs in serum [17].
• While circulating IGF-II/M6P receptor and IGFBP-4 levels were increased following the fetal insulin or glucose infusion, IGFBP-3 was unchanged and increased only after 48 h of maternal refeeding [18].
• In fetal plasma, the circulating IGF-II/mannose-6-phosphate (M6P) receptor, IGFBP-3 and IGFBP-4 were reduced during starvation [18].
• On PNDs 14 and 56, IGFBP-3 mRNA was decreased in the uterus of EV-treated ewes, but IGF-1R and IGFBP-4 mRNAs were not affected [19].

Physical interactions of IGFBP-3

• This inhibition might be partly mediated by direct interaction of IGFBP-4 proteinase(s) and heparin-binding domain within the C-terminal region from IGFBP-3 and -5 [6].
• Serial blood samples were taken at 15-min intervals for 12 h for the determination of GH and IGF-I content by radioimmunoassay and for IGF-binding protein-3 (IGFBP-3) levels by Western blotting [20].

Regulatory relationships of IGFBP-3

• IGFBP-2 was suppressed (P less than 0.05) by day 55 and IGFBP-3 and 4 did not change [21].

Other interactions of IGFBP-3

• These data show that each of the IGF carrier proteins is sensitive of changes in nutrition, either acutely, such as IGFBP-1, or chronically, as for IGFBP-3 [18].
• The co-ordinate maximum expression of mRNA for both IGF-I and IGF-II, the type 1 IGF receptor and IGFBP-3 during the period when the gametes and embryo are in transit suggests a role for IGF-I and possibly IGF-II peptides in providing an oviductal environment propitious to conception and early embryonic growth and metabolism [22].
• No difference was found in IGF-1, IGF-2 or IGFBP-3 levels between the NR and C groups at either gestational age [23].
• A possible role of IGFBP-3 proteolysis in the ovine ULF may be to selectively increase the bioavailability of IGF-1 in the uterine microenvironment, which may be crucial for the rapid elongation of trophoblast that begins during days 12-15 after mating [24].

Analytical, diagnostic and therapeutic context of IGFBP-3

• Maternal plasma IGFBP-3 concentrations did not differ between the bilateral nephrectomy group (3.11 +/- 0.09 micrograms mL-1, n = 7) and the control group (3.25 +/- 0.11 micrograms mL-1, n = 7) and showed no change within groups over the experimental period [7].
• Fetal plasma insulin-like growth factor-binding protein-3 concentrations are elevated following bilateral nephrectomy in fetal sheep [7].
• Western blot data indicate that changes in either maternal or fetal plasma IGFBP-3 concentrations were not the result of increased proteolytic activity [4].
• In situ hybridization of endometrial tissue sections localized the IGFBP-3 mRNA to the luminal epithelial cell layer, areas of the stromal tissue and in some glandular epithelial cells [25].
• Immunoblotting with an IGFBP-3 antibody revealed these to be proteolytic fragments of IGFBP-3 [24].

References