1,25-DIHYDROXYVITAMIN D-3 INCREASES SECRETION OF INSULIN-LIKE GROWTH-FACTOR BINDING PROTEIN-4 (IGFBP-4) BY HUMAN OSTEOBLAST-LIKE CELLS IN-VITRO AND ELEVATES IGFBP-4 SERUM LEVELS IN-VIVO

Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) are thought to play an important role in the regulation of bone metabolism. In the present study, we investigated the effect of 1,25-dihydroxyvitamin D-3 [1,25-(OH)(2)D-3] on the expression and secretion of IGFBPs in human osteoblast-like osteosarcoma cells (MG63) and untransformed human bone-derived cells in vitro. Northern blot analysis revealed that 1,25-(OH)(2)D-3 (10(-8) mol/L) increased IGFBP-4 messenger RNA maximally 11-fold over control level in MG63 cells (after 24 h treatment) and 2.8-fold in human bone-derived cells (at 10(-10) mol/L). 1,25-(OH)(2)D-3 increased secretion of IGFBP-4 2- and 3-fold, respectively, in MG63 cells and in human bone-derived cells. In normal human bone-derived cells, 1,25-(OH)(2)D-3 also stimulated messenger RNA expression (3.9-fold) and the secretion of IGFBP-3 (2.2-fold). 1,25-(OH)(2)D-3 also increased IGFBP-4 expression in skin fibroblasts but not in hepatocellular carcinoma cells. Consistent with these in vitro findings, treatment of human subjects with high doses of oral 1,25-(OH)(2)D-3 (2-3 mu g/day) for psoriasis resulted in a significant increase in serum IGFBP-4 concentration compared with pretreatment levels. Our observations present direct evidence that 1,25-(OH)(2)D-3 plays an important role in the regulation of IGFBP secretion in vitro and in vivo.