Chevalley T, Strong D D, Mohan S, Baylink D, Linkhart T A
Department of Medicine, Loma Linda University, CA, USA.
Eur J Endocrinol. 1996 May;134(5):591-601. doi: 10.1530/eje.0.1340591.
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.
糖皮质激素（GCs）在体内抑制骨形成，在体外抑制成骨细胞增殖和胶原蛋白合成。这些作用可能是由胰岛素样生长因子（IGF）系统的改变介导的。在本项针对正常人成骨样（HOB）细胞的研究中，我们检验了以下假设：地塞米松（Dex）通过改变IGF结合蛋白（IGFBPs）的表达来抑制骨中IGF的合成代谢活性，特别是通过降低IGFBP - 5和IGFBP - 3（增强IGF活性）的表达以及增加IGFBP - 4（抑制IGF作用）的表达。在七项独立实验中，地塞米松处理导致HOB细胞增殖呈剂量依赖性抑制（在10^(-8) mol/l地塞米松时为对照的69±4%）。地塞米松将IGFBP - 5 mRNA水平降至对照的20 - 30%（10^(-8)和10^(-7) mol/l处理24小时）。在六份HOB制剂中，10^(-8) mol/l地塞米松均降低了IGFBP - 5 mRNA水平（为对照的35±7%），且这种作用具有时间依赖性。地塞米松还降低了IGFBP - 3 mRNA水平（在三份HOB制剂中为对照的74±9%）。通过Western配体印迹和IGFBP - 5免疫印迹测定，地塞米松降低了29 - 31-kD IGFBP - 5和38 - 42-kD IGFBP - 3蛋白的分泌，通过特异性放射免疫测定确定，地塞米松诱导IGFBP - 3和IGFBP - 5分泌呈剂量依赖性降低。地塞米松对IGFBP - 4 mRNA以及25-kD IGFBP - 4水平分泌的影响在不同细胞制剂之间不一致。结果表明，GC对IGFBP - 5和IGFBP - 3产生的抑制作用可能会降低IGF活性，并导致GC对骨形成的抑制。
