RETINOIC ACID REGULATES THE EXPRESSION OF INSULIN-LIKE GROWTH-FACTOR-I AND GROWTH-FACTOR-II IN OSTEOBLASTS

Insulin-like growth factors (IGF) I and II are the most abundant growt h factors secreted by skeletal cells, and retinoic acid has many impor tant actions on cell differentiation and osteoblastic function. Some o f these actions may be mediated by changes in the expression of ICF I and II since IGFs are known to enhance the differentiated function of the osteoblast. We examined the effects of all-trans-retinoic acid on ICF I and IGF II expression in cultures of osteoblast-enriched cells f rom 22 day fetal rat calvariae (Ob cells). Retinoic acid caused a tran sient increase in IGF I and IGF II mRNA levels after 6 h, but after 24 and 48 h of treatment a dose-dependent decrease was observed. Cyclohe ximide prevented the inhibitory effect of retinoic acid. Retinoic acid treatment for 48 h decreased IGF I polypeptide levels in the culture medium. In contrast, 48 h exposure to retinoic acid increased IGF II p olypeptide levels, possibly due to increased levels of IGF binding pro tein-6. The decay of IGF I and II mRNA in transcriptionally arrested O b cells was similar in control and retinoic acid-treated cells. After 2 h, retinoic acid increased the rates of ICF I and II transcription, as determined by a nuclear run-on assay and heterogeneous nuclear RNA levels, but after 24 h retinoic acid was inhibitory. Retinoic acid had opposite effects to IGFs in osteoblasts and inhibited DNA and collage n synthesis. In conclusion, following a small transient increase, reti noic acid causes a pronounced decrease in ICF I and IGF II mRNA expres sion in Ob cells. However, treatment with retinoic acid causes a decre ase in IGF I and an increase in ICF ii polypeptide levels. These chang es in the IGF/IGFBP axis may be relevant to the mechanism of action of retinoic acid in bone. (C) 1997 Wiley-Liss, Inc.