IGFBP-5 is the most conserved of a family of high affinity proteins that modulate IGF activity. It is upregulated in key lineages during their differentiation and development. In addition to domains associated with IGF binding, IGFBP-5 also possesses motifs that may be involved with its recently demonstrated IGF-independent actions. We have therefore examined the hypothesis that IGFBP-5 is important during development. We have generated mice overexpressing IGFBP-5 using an early, constitutive and active promoter (CMV enhancer/beta actin promoter). The mice are growth retarded by up to 60% both pre- and postnatally and exhibit increased morbity, even in heterozygous animals. This is the most severe phenotype of any IGFBP genetic manipulation and suggests a key function for IGFBP-5. The aim of the current study was to examine the effects of IGFBP-5 overexpression on the circulating IGF axis.
Circulating IGFBP concentrations were inferred in 8 week-old mice by ligand and immunoblotting. A 2- to 40-fold increase in circulating IGFBP-5 was observed in the transgenic mice with a concomitant decrease in IGFBP-3 levels by up to 8-fold; these changes correlated with the severity of growth retardation. Northern analysis revealed that transgenic IGFBP-5 mRNA was present in all tissues investigated; hepatic IGFBP-3 mRNA levels were variably reduced. Even though hepatic IGF-I mRNA levels were decreased by 10% in high IGFBP-5 overexpressing mice, circulating IGF-I concentrations doubled. Changes in circulating IGFBP-3 levels were further investigated between birth and 8 weeks; the consistent presence of IGFBP-5 in serum abolished the developmental increase in circulating IGFBP-3 usually observed. We are investigating the hypothesis that transgenic IGFBP-5 may also form a ternary complex with the ALS, displacing IGFBP-3 and increasing the opportunity for proteolytic degradation of IGFBP-3.
We conclude that overexpression of IGFBP-5 yields a phenotype consistent with inhibition of IGF activity and also disrupts the IGF axis.
08 - 11 Apr 2002
British Endocrine Societies