Retinoic acid regulates the expression of insulin-like growth factors I and II in osteoblasts.

Insulin-like growth factors (IGF) I and II are the most abundant growth factors secreted by skeletal cells, and retinoic acid has many important action on cell differentiation and osteoblastic function. Some of these actions may be mediated by changes in the expression of IGF I and II since IGFs are known to enhance the differentiated function of the osteoblast. We examined the effects of all-transretinoic acid on IGF I and IGF II expression in cultures of osteoblast-enriched cells from 22 day fetal rat calvariae (Ob cells). Retinoic acid caused a transient 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. Cycloheximide 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 polypeptide levels, possible due to increased levels of IGF binding protein-6. The decay of IGF I and II mRNA in transcriptionally arrested Ob cells was similar in control and retinoic acid-treated cells. After 2 h, retinoic acid increased the rates of IGF 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 collagen synthesis. In conclusion, following a small transient increase, retinoic acid causes a pronounced decrease in IGF I and IGF II mRNA expression in Ob cells. However, treatment with retinoic acid causes a decrease in IGF I and an increase in IGF II polypeptide levels. These changes in the IGF/IGFBP axis may be relevant to the mechanism of action of retinoic acid in bone.