Ontogeny of somatomedin during development in the mouse: Serum concentrations, molecular forms, binding proteins, and tissue receptors

Abstract

The purpose of this study was to assess the ontogeny of serum concentrations and molecular forms of somatomedin during fetal and postnatal development and to define the changes in serum binding proteins for somatomedin-C during various stages of development. The finding that fetal, placental, and decidual mouse tissues possess receptors for somatomedin suggests a role for somatomedin in fetal growth and possibly in the maintenance of pregnancy. Serum somatomedin-C was measured using a highly specific, heterologous radioimmunoassay (RIA) and a less specific membrane binding assay (MBA) which is more sensitive to the influence of somatomedins other than somatomedin-C. The assays were validated for mouse serum by showing that serum concentrations were reduced in genetically growth hormone-deficient mice and in hypophysectomized mice and were increased by growth hormone therapy. As in the human, the RIA measures only a portion of the somatomedin-C present in mouse serum. This “covering up” of somatomedin is attributed to the presence of serum binding proteins and is corrected by treatment of serum samples with acid. By both RIA and MBA, serum somatomedin concentrations are low in fetal and newborn mice, begin to rise in the fourth postnatal week, and reach adult values by 7 weeks of age. The chromatographic pattern of adult mouse serum on Sephacryl 200 is similar to that observed with human sera: The immunoreactive material elutes at apparent molecular weights of 140,000 and 30,000–40,000. The elution profile of 125I-labeled somatomedin-C bound to components of serum is nearly identical to the pattern of endogenous activity. As with human serum, somatomedin-C in acidified mouse serum elutes at a lower molecular weight, coincident with insulin and purified somatomedin-C. Maternal serum somatomedin declines in the last half of gestation at the time when placental lactogen levels rise. Along with the absolute decline in somatomedin content is the appearance of unsaturated sites on somatomedin binding proteins. These findings are unexpected and unexplained since somatomedin rises late in pregnancy in humans and several lines of evidence suggest that placental lactogen has the capacity to stimulate somatomedin production. We previously have presented evidence that explants of multiple fetal mouse tissues synthesize somatomedin-C. The present study shows that the immunoreactive somatomedin-C in fetal mouse serum shares identical characteristics with those reported previously for media obtained from mouse liver explants. It seems possible that somatomedin's actions are exerted primarily at or near its site of production and that circulatory levels do not reflect the importance of somatomedin-C on fetal growth. While elucidation of the dramatic developmental changes in serum content and molecular forms of somatomedin-C and in somatomedin binding proteins may be essential to clarifying the role of somatomedin on fetal growth, proof that somatomedin stimulates fetal growth will depend in large part on studies of its biological actions on fetal tissues.