EXCESS IGFBP-3 PROTEOLYSIS IS PARTLY RESPONSIBLE FOR THE ACCELERATED GROWTH IN CONSTITUTIONALLY TALL CHILDREN

Abstract

Serum IGF-I levels in constitutionally tall children and adolescents are above normal on average, but variations between individuals are wide. However these cannot be interpreted without consideration of the IGFBPS, and IGFBP-3 in particular, to which serum IGFs are bound. Recent data from our laboratory indicate that limited proteolysis of IGFBP-3, first described in pregnancy serum, is a physiological mechanism occuring in the normal state, which seems to be essential in controlling IGF bioavailability. Western blot analyses were done of serum IGFBPs in 34 pre-pubertal, constitutionally tall children (1 to 10 years old) using 125I-IGF (ligand blot) and a polyclonal anti-IGFBP-3 antibody with a highly sensitive detection technique (immunoblot). Ligand blotting results were inconsistent. In 60% of cases, IGFBP-3 quantities based on size and density of the 42-39-kDa doublet were appropriate to IGF-I levels, whereas in 40%, they were abnormally low. In the latter, bands of 21.5 20 and 16 kDa were sometimes detectable, resembling the proteolytic fragments in pregnancy serum. With immunoblotting, the relative amounts of 42-39-kDa doublet were similar to those seen with ligand blotting. In all normal and tall children, a 30-kDa band corresponding to the major proteolytic fragment of IGFBP-3 was present. Its intensity was inversely related to that of the 42-39-kDa doublet. The smaller fragments sometimes seen by ligand blotting were more often detectable by immunoblotting in the tall children. These findings suggest that excess proteolysis of IGFBP-3 which increases the bioavailability of IGF-I (whose levels are generally high) may contribute towards the excessive growth in constitutionally tall children.