B. Gabbitas et E. Canalis, RETINOIC ACID REGULATES THE EXPRESSION OF INSULIN-LIKE GROWTH-FACTOR-I AND GROWTH-FACTOR-II IN OSTEOBLASTS, Journal of cellular physiology, 172(2), 1997, pp. 253-264
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.