CIRCULATING INSULIN-LIKE GROWTH-FACTORS (IGFS), IGF-BINDING PROTEINS (IGFBPS) AND TISSUE MESSENGER-RNA LEVELS OF IGFBP-2 AND IGFBP-4 IN THEOVINE FETUS

The IGF-binding proteins (IGFBPs) are a family of at least six structu rally related proteins, which bind the IGFs and modulate their actions , including the regulation of pre- and postnatal growth. In this study we have examined the relationship between circulating and tissue mRNA levels of IGFBPs and related this to circulating IGFs in the fetal sh eep over the gestational period when rapid growth and development occu rs, Circulating IGFBP-2, as measured by Western ligand blot (WLB), inc reases between early and mid gestation, remains high, then declines th roughout late gestation (P=0.0002). Circulating IGFBP-3 increases thro ughout gestation, as measured by WLB or RIA (P=0.04 and P=0.0001 respe ctively), as does circulating IGFBP-4 (P=0.004). These ontogenic chang es in circulating IGFBPs-2 and -4 are paralleled by changes in liver m RNA for these proteins and, for IGFBP-2, by those in kidney IGFBP-2 mR NA also. This suggests that liver and kidney may be the primary contri butors to circulating IGFBP-2 and the liver to circulating IGFBP-4. IG FBP-2 mRNA is present in the heart and lung in early gestation but bar ely detectable in these tissues after approximately 60 days gestation. IGFBP-4 mRNA is also present in the heart in early but not late gesta tion, but is abundant in the lung throughout gestation. These results demonstrate tissue specific and developmental regulation of IGFBPs-2 a nd -4 at the mRNA level. To assess any role the circulating IGFs may p lay in mediating these changes in IGFBPs, or vice versa, both plasma I GF-I and IGF-II were measured by RIA. Circulating IGF-I increases as g estation progresses (P=0.0001), while circulating IGF-II increases bet ween early and mid gestation, remains high (P=0.01), then declines. Ci rculating 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=0.0 1). Circulating IGF-II positively correlates with circulating IGFBP-2 (r=0.48, P=0.02) throughout gestation and at 1 day postnatally. These relationships are consistent with circulating IGF-I influencing IGFBPs -3 and -4, and similarly, IGF-II determining IGFBP-2, or vice versa. A lternatively, these correlations may reflect coordinate regulation of IGF and IGFBP by a common factor.