Evidence for a role for insulin-like growth factor binding proteins in glucocorticoid inhibition of normal human osteoblast-like cell proliferation

Department of Medicine, Loma Linda University, CA, USA.

Glucocorticoids (GCs) inhibit bone formation in vivo and inhibit osteoblast proliferation and collagen synthesis in vitro. These effects may be mediated by alterations in the insulin-like growth factor (IGF) system. In the present study of normal human osteoblast-like (HOB) cells, we tested the hypothesis that dexamethasone (Dex) inhibits IGF anabolic activity in bone by altering expression of IGF binding proteins (IGFBPs), particularly by decreasing expression of IGFBP-5 and IGFBP-3 (which enhance IGF activity) and increasing expression of IGFBP-4 (which inhibits IGF actions). Dexamethasone treatment caused a dose-dependent inhibition of HOB cell proliferation (69 +/- 4% of control at 10(-8) mol/l Dex) in seven separate experiments. Dexamethasone decreased IGFBP-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 control in three HOB preparations). Dexamethasone decreased secretion of 29-31-kD IGFBP-5 and 38-42-kD IGFBP-3 proteins, determined by Western ligand blot and IGFBP-5 immunoblot, and induced a dose-dependent decrease in IGFBP-3 and IGFBP-5 secretion determined by specific radioimmunoassays. The effects of Dex on IGFBP-4 mRNA and on secretion of 25-kD IGFBP-4 levels were inconsistent between different cell preparations. Results suggest that GC inhibition of IGFBP-5 and IGFBP-3 production could decrease IGF activities and contribute to GC inhibition of bone formation.

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