BIOACTIVITY OF A 29-KILODALTON INSULIN-LIKE-GROWTH-FACTOR BINDING PROTEIN-3 FRAGMENT PRESENT IN EXCESS IN CHRONIC-RENAL-FAILURE SERUM

Children with chronic renal failure (CRF) have normal or high serum le vels of GH, IGF-I, and IGF-II. Despite this, the serum of CRF patients has low IGF bioactivity, which may contribute to CRF growth failure. Recent studies suggest that excess IGF binding proteins (IGFBPs) in th e similar to 35-kD fractions of CRF serum contribute to this low IGF b ioactivity. This report characterizes a 29-kD form of IGFBP-3, IGFBP-3 (29), which accumulates in the similar to 35-kD fractions of CRF serum and peritoneal dialysate. Deglycosylation and [I-125]IGF ligand blot studies show that IGFBP-3(29) is a glycosylated IGFBP-3 fragment with low affinity for IGF peptides. Using an IGFBP-3 antibody column, IGFBP -3(29) was purified to homogeneity from the similar to 35-kD fractions of peritoneal dialysate from children with CRF. Compared with native IGFBP-3, pure IGFBP-3(29) has a 4-10-fold lower affinity for IGF-II an d a 200-fold lower affinity for IGF-I. Consistent with the binding dat a, IGFBP-3(29) inhibited IGF-II-stimulated thymidine incorporation in chondrosarcoma cells, but was a less potent inhibitor than native IGFB P-3; also, native IGFBP-3 clearly inhibited IGF-I-stimulated thymidine incorporation in chondrosarcoma cells and potentiated IGF-I-stimulate d aminoisobutyric acid uptake in bovine fibroblasts, but higher concen trations of IGFBP-3(29) had no effect on these IGF-I actions. Thus, th e 29-kD IGFBP-3 form that accumulates in CRF serum and extravascular s paces is an IGFBP-3 fragment that may modulate IGF-II, but not IGF-I, effects on target tissues. Whether IGFBP-3(29) plays any role in the g rowth failure of children with CRF remains to be determined.