Intact IGF-binding protein-4 and -5 and their respective fragments isolated from chronic renal failure serum differentially modulate IGF-I actions incultured growth plate chondrocytes

Impairment of longitudinal growth among children with chronic renal failure (CRF) may be partly attributable to the inhibition of insulin-like growth factor (IGF) activity by an excess amount of high-affinity IGF-binding prot eins (IGFBP). Elevated levels of immunoreactive IGFBP-4 in CRF serum are in versely correlated with the standardized heights of these children, whereas levels of IGFBP-5, which circulates mainly as proteolyzed fragments, are p ositively correlated with growth parameters. To delineate the respective ef fects of these IGFBP on growth cartilage, the biologic effects of intact an d fragmented forms of IGFBP-4 and IGFBP-5 on rat growth plate chondrocytes in primary cultures were characterized. Intact IGFBP-4 and IGFBP-5 and the amino-terminal fragment IGFBP-5(1-169) were recombinant proteins; the carbo xy-terminal fragments IGFBP-5(144-252) and IGFBP-4(136-237) and the aminote rminal fragment IGFBP-4(1-122) were purified to homogeneity from CRF hemofi ltrates. Intact IGFBP-4 and, to a lesser extent, IGFBP-4(1-122) inhibited l GF-1-induced cell proliferation. In contrast, intact IGFBP-5 was stimulator y in the absence or presence of exogenous IGF-1, whereas the amino-terminal fragment IGFBP-5(1-169) was inhibitory. Studies on the mechanism by which IGFBP-4 and IGFBP-5 exert opposite effects on chondrocyte proliferation dem onstrated that intact IGFBP-4 prevented the binding or I-125-IGF-I to chond rocytes, whereas intact IGFBP-5 enhanced ligand binding and was able to bin d specifically to the cell membrane. These data suggest that intact IGFBP-4 and, to a lesser extent, IGFBP-4(1-122) act exclusively as growth-inhibito ry binding proteins in the growth cartilage. IGFBP-5, however, can either s timulate (if it remains intact) or inhibit (if amino-terminal forms predomi nate) IGF-I-stimulated chondrocyte proliferation.