Retinoic acid stimulates the transcription of insulin-like growth factor binding protein-6 in skeletal cells

Publisher Website
Google Scholar
Abstract
Retinoic acid has important actions on cell differentiation and osteoblastic function, and some of these actions may be mediated by changes in the insulin-like growth factor (IGF) axis. Skeletal cells synthesize IGF I and II and the six known IGF binding proteins (IGFBP). IGFBP-6 binds IGF II with high affinity and prevents IGF II-mediated effects. In fibroblasts, IGFBP-6 levels are regulated by retinoic acid, and we postulated that retinoic acid may regulate IGF II in bone by altering IGFBP-6 synthesis. We examined the effect of retinoic acid on IGFBP-6 expression in cultures of osteoblast-enriched cells from 22-day fetal rat calvariae (Ob cells). Retinoic acid caused a time- and dose-dependent increase in IGFBP-6 mRNA levels, as determined by Northern blot analysis. The effect was maximal after 48 h of treatment and observed with retinoic acid at concentrations of 10 nM to 1 μM. Retinoic acid increased IGFBP-6 polypeptide levels in the culture medium, as determined by Western immunoblot analysis. Cycloheximide at 3.6 μM slightly decreased IGFBP-6 transcripts but did not prevent the stimulatory effect of retinoic acid. The decay of IGFBP-6 mRNA in transcriptionally arrested Ob cells was similar in control and retinoic acid-treated cells, and retinoic acid increased the rates of IGFBP-6 transcription, as determined by nuclear run on assays. In conclusion, retinoic acid enhances IGFBP-6 expression in Ob cells by transcriptional mechanisms. Since IGFBP-6 prevents the effects of IGF II, increased synthesis of IGFBP-6 could mediate selected actions of retinoic acid in bone.