CIRCULATING INSULIN-LIKE GROWTH-FACTOR BINDING-PROTEINS (IGFBP)-1 AND(IGFBP)-2 INDUCED IN VITAMIN-C-DEFICIENT OR FASTED GUINEA-PIGS INHIBIT IGF-I ACTION IN CULTURED-CELLS

Collagen gene expression and proteoglycan synthesis are decreased in v itamin C-deficient guinea pigs losing weight and in fasted guinea pigs receiving ascorbate. Sera from such guinea pigs contain an insulin-li ke growth factor (IGF)-I-reversible inhibitor of collagen, proteoglyca n and DNA synthesis and elevated levels of 29 and 35-kDa IGF binding p roteins (IGFBPs). We now have identified the induced proteins as IGFBP s 1 and 2 and investigated their role as inhibitors. Guinea pig sera w ere treated with antibodies to IGFBPs 1 and 2 and antibody-IGFBP compl exes were removed by passage through a Protein A-Sepharose column. Inh ibitor content of fasted and scorbutic sera, and Protein A pass-throug h fractions derived from them, was assessed by their level of stimulat ion of DNA and collagen synthesis in 3T3 cells, compared to analogousl y treated normal guinea pig serum. Removal of IGFBP-1 from scorbutic s erum reversed inhibition of collagen and DNA synthesis by more than ha lf but removal of IGFBP-2 was less effective. Removal of both IGFBPs r eversed inhibition almost completely. Similar results were obtained wi th fasted guinea pig serum. Conversely, purified rat IGFBPs 1 and 2 in hibited DNA and collagen synthesis in cells cultured in normal guinea pig serum or IGF-I-stimulated DNA synthesis, with IGFBP-1 being more p otent. Thus, IGFBP-1 and, to a lesser extent IGFBP-2, cause inhibition of IGF-I action by sera from fasted and scorbutic guinea pigs and may inhibit collagen gene expression in vivo.