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 levels 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 the ~35-kD fractions of CRF serum contribute to this low IGF bioactivity. This report characterizes a 29-kD form of IGFBP-3, IGFBP-3²⁹, which accumulates in the ~35-kD fractions of CRF serum and peritoneal dialysate. Deglycosylation and [¹²⁵I]IGF ligand blot studies show that IGFBP-3²⁹ is a glycosylated IGFBP-3 fragment with low affinity for IGF peptides. Using an IGFBP-3 antibody column, IGFBP-3²⁹ was purified to homogeneity from the ~35-kD fractions of peritoneal dialysate from children with CRF. Compared with native IGFBP-3, pure IGFBP-3²⁹ has a 4-10-fold lower affinity for IGP-II and a 200-fold lower affinity for IGF-I. Consistent with the binding data, IGFBP-3²⁹ inhibited IGF-II stimulated thymidine incorporation in chondrosarcoma cells, but was a less potent inhibitor than native IGFBP-3; also, native IGFBP-3 clearly inhibited IGF-I-stimulated thymidine incorporation in chondrosarcoma cells and potentiated IGF-I-stimulated aminoisobutyric acid uptake in bovine fibroblasts, but higher concentrations of IGFBP-3²⁹ had no effect on these IGF-I actions. Thus, the 29-kD IGFBP-3 form that accumulates in CRF serum and extravascular spaces is an IGFBP-3 fragment that may modulate IGF-II, but not IGF-I, effects on target tissues. Whether IGFBP-3²⁹ plays any role in the growth failure of children with CRF remains to be determined.