EFFECTS OF ELEVATED CIRCULATING IGF-1 ON THE EXTRACELLULAR-MATRIX IN HIGH-GROWTH C57BL 6J MICE/

Collagen biosynthesis was analyzed in C57BL/6J mice homozygous for the high-growth locus. Plasma levels of insulin-like growth factor-1 (IGF -1) were significantly elevated in high-growth mice at all ages studie d (3 wk-6 mo); IGF-binding proteins were also elevated. Skin biopsies were obtained from mice aged 3, 6, and 9 wk under halothane anesthesia . Mice were killed at 6 mo of age. Collagen, expressed per weight of t issue, was significantly increased in all tissues from high-growth mic e, as was collagen crosslinking, expressed as moles of cross-link per mole of collagen. Expression of types I and III collagen, lysyl oxidas e, and lysyl hydroxylase was increased in all tissues analyzed. There was a preferential increase in type III expression relative to type I expression. Rate and extent of accumulation of collagen in granulation tissue were measured in polyvinyl alcohol sponges implanted subcutane ously; collagen accumulation was significantly greater in the high-gro wth mice. These results suggest that 1) elevated circulating IGF-1 may increase collagen deposition both in normal tissue as well as in gran ulation tissue by increasing collagen gene expression, 2) IGF-1 may in crease collagen cross-linking by stimulating expression of lysyl oxida se, and 3) the preferential increase in dihydroxylated cross-links obs erved in high-growth mice may be due to the stimulation of lysyl hydro xylase expression by IGF-1. In summary, elevated levels of IGF-1 appea r to affect collagen both quantitatively and qualitatively, primarily through their effects on gene expression of collagen and of those enzy mes responsible for posttranslational modifications of collagen.