EVIDENCE FOR A ROLE FOR INSULIN-LIKE GROWTH-FACTOR BINDING-PROTEINS IN GLUCOCORTICOID INHIBITION OF NORMAL HUMAN OSTEOBLAST-LIKE CELL-PROLIFERATION

Glucocorticoids (GCs) inhibit bone formation in vivo and inhibit osteo blast proliferation and collagen synthesis in vitro. These effects may be mediated by alterations in the insulin-like growth factor (IGF) sy stem. In the present study of normal human osteoblast-like (HOB) cells , we tested the hypothesis that dexamethasone (Dex) inhibits IGF anabo lic activity in bone by altering expression of IGF binding proteins (I GFBPs), particularly by decreasing expression of IGFBP-5 and IGFBP-3 ( which enhance IGF activity) and increasing expression of IGFBP-4 (whic h inhibits IGF actions). Dexamethasone treatment caused a dose-depende nt inhibition of HOB cell proliferation (69 +/- 4% of control at 10(-8 ) mol/l Dex) in seven separate experiments. Dexamethasone decreased IG FBP-5 mRNA levels to 20-30% of control (10(-8) and 10(-7) mol/l for 24 h). In six of six HOB preparations, 10(-8) mol/l Dex decreased IGFBP-5 mRNA levels (35 +/- 7% of control) and this effect was time dependent . Dexamethasone also decreased IGFBP-3 mRNA levels (74 +/- 9% of contr ol in three HOB preparations). Dexamethasone decreased secretion of 29 -31-kD IGFBP-5 and 38-42-kD IGFBP-3 proteins, determined by Western li gand blot and IGFBP-5 immunoblot, and induced a dose-dependent decreas e in IGFBP-3 and IGFBP-5 secretion determined by specific radioimmunoa ssays. The effects of Dex on IGFBP-4 mRNA and on secretion of 25-kD IG FBP-4 levels were inconsistent between different cell preparations. Re sults suggest that GC inhibition of IGFBP-5 and IGFBP-3 production cou ld decrease IGF activities and contribute to GC inhibition of bone for mation.