title: Intact IGF-binding protein-4 and -5 and their respective fragments isolated from chronic renal failure serum differentially modulate IGF-I actions in cultured growth plate chondrocytes.
abstract: 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 proteins (IGFBP). Elevated levels of immunoreactive IGFBP-4 in CRF serum are inversely correlated with the standardized heights of these children, whereas levels of IGFBP-5, which circulates mainly as proteolyzed fragments, are positively correlated with growth parameters. To delineate the respective effects of these IGFBP on growth cartilage, the biologic effects of intact and 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 carboxy-terminal fragments IGFBP-5(144-252) and IGFBP-4(136-237) and the amino-terminal fragment IGFBP-4(1-122) were purified to homogeneity from CRF hemofiltrates. Intact IGFBP-4 and, to a lesser extent, IGFBP-4(1-122) inhibited IGF-I-induced cell proliferation. In contrast, intact IGFBP-5 was stimulatory in the absence or presence of exogenous IGF-I, 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 demonstrated that intact IGFBP-4 prevented the binding of (125)I-IGF-I to chondrocytes, whereas intact IGFBP-5 enhanced ligand binding and was able to bind 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-inhibitory binding proteins in the growth cartilage. IGFBP-5, however, can either stimulate (if it remains intact) or inhibit (if amino-terminal forms predominate) IGF-I-stimulated chondrocyte proliferation.
authors.affiliation: Division of Pediatric Nephrology, University Children's Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kiepe
authors.affiliation: Department of Medicine, Veterans Affairs Medical Center and University of Washington, Seattle, Washington.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Andress
authors.affiliation: J. L. Pettis Veterans Administration Medical Center and Loma Linda University, Loma Linda, California.
authors.forename: Subburaman
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Lower Saxony Institute for Peptide Research, Hannover, Germany.
authors.forename: Ludger
authors.initials: L
authors.lastname: Ständker
authors.affiliation: Division of Pediatric Nephrology, University Children's Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Ulinski
authors.affiliation: Division of Pediatric Nephrology, University Children's Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Himmele
authors.affiliation: Division of Pediatric Nephrology, University Children's Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Otto
authors.initials: O
authors.lastname: Mehls
authors.affiliation: Division of Pediatric Nephrology, University Children's Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tönshoff
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006132:Growth Plate / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000302:isolation & purification* / Q000378:metabolism / Q000494:pharmacology*; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000302:isolation & purification* / Q000378:metabolism / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D007676:Kidney Failure, Chronic / Q000097:blood*; D010446:Peptide Fragments / Q000302:isolation & purification; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics
chemical_list: D018974:Insulin-Like Growth Factor Binding Protein 4; D018975:Insulin-Like Growth Factor Binding Protein 5; D010446:Peptide Fragments; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1