INSULIN-LIKE GROWTH FACTOR-II AND TRANSFORMING GROWTH FACTOR-BETA-1 REGULATE INSULIN-LIKE GROWTH FACTOR-I SECRETION IN MOUSE BONE-CELLS

Bone cells in culture produce and respond to growth factors, suggesting that local as well as systemic factors regulate bone volume. Previous studies have shown that IGF-I is the major mitogen produced by mouse bone cells and that its production is regulated by systemic agents such as PTH and estrogen. Because IGF-II and transforming growth factor beta-1 have been shown, respectively, to increase and decrease MC3T3-E1 cell proliferation, we tested the hypothesis that these two growth factors modulate the production of IGF-1 in this cell line. In order to eliminate artifacts owing to IGF binding proteins, conditioned media samples were pretreated with IGF-II before measurement of IGF-I by RIA. After 24 h treatment at a density of 2.5 x 10(4) cells/cm2, IGF-II (10-mu-g/l) induced a 2.2-fold increase compared with untreated control (9.5 +/- 1.5) vs 4.2 +/- 0.44 pg/mu-g protein, p < 0.001), whereas transforming growth factor beta-1 (1-mu-g/l) caused a 66% decrease in IGF-I production (1.5 +/- 0.3 vs 4.2 +/- 0.44 pg/mu-g protein, p < 0.001). Both IGF-II and transforming growth factor beta-1 regulated IGF-I production in a dose-, time- and cell density-dependent manner. The lowest effective doses for IGF-II and transforming growth factor beta-1 were 1 and 0.01-mu-g/l, respectively. These results support a role for IGF-II and transforming growth factor beta-1 as potent modulators of IGF-I secretion in mouse bone cells. Furthermore, regulation of IGF-I production in bone cells by IGF-II and transforming growth factor beta-1 in an autocrine/paracrine manner could represent a component part of the mechanism whereby the skeleton locally adapts in reponse to external stimuli.