Endocrinology, Vol 133, 1525-1531, Copyright © 1993 by Endocrine Society

ARTICLES

Insulin-like growth factor-I (IGF-I) enhanced proteolysis of IGF- binding protein-4 in conditioned medium from primary cultures of human decidua: independence from IGF receptor binding

SE Myers, PT Cheung, S Handwerger and SD Chernausek
Division of Endocrinology and the Perinatal Research Institute, Children's Hospital Medical Center, Cincinnati, Ohio 45229.

Previous studies demonstrated that human decidual cells release insulin- like growth factor-binding protein (IGFBP)-1, IGFBP-2, and a 24- kilodalton (kDa) IGFBP in culture. The accumulation of 24-kDa IGFBP, as assessed by ligand blot analysis, decreased when the cells were exposed to IGF-I, but the mechanism was not explored. In the present study, we observed that the IGF-I-mediated decrease in IGFBP-4 accumulation could be explained by increased IGFBP-4 proteolysis. Analysis by IGFBP-4 immunoblotting demonstrated a decline in 24-kDa IGFBP-4 accompanied by a marked increase in a 17- to 18.5-kDa IGFBP-4 fragment(s). In addition, when medium from IGF-I-treated cells was incubated with rat IGFBP-4, the decrease in IGFBP-4 was inhibited by chelators of divalent cations and inhibitors of serine proteases. IGF-I enhancement of IGFBP- 4 proteolysis occurs independent of the type I IGF receptor. [Leu24,1- 62]IGF-I, an analog with reduced receptor affinity, mimicked the effect of native IGF-I in cell culture. Additionally, alpha-IR3, a monoclonal antibody to the type I IGF receptor, did not block the effect of IGF-I. When IGF-I was incubated with medium from control cells, there was a marked decrease in 24-kDa IGFBP-4 levels and a concomitant increase in levels of a 17- to 18.5-kDa fragment(s), suggesting that IGFBP-4 complexed with IGF-I is more susceptible to proteolysis than IGFBP-4 alone. Together, these findings suggest a novel mechanism for regulation of IGF-I action in the decidua.

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