H. Jiang et al., MODULATION OF LIMB BUD CHONDROGENESIS BY RETINOIC ACID AND RETINOIC ACID RECEPTORS, The International journal of developmental biology, 39(4), 1995, pp. 617-627
An excess of retinoic acid (RA) in the mouse embryo in utero produces
hypochondrogenesis and severe limb bone deformities. Since one of the
RA receptors - RAR-beta 2, is specifically induced in the limb bud cel
ls upon treatment of embryos with teratogenic doses of RA, we investig
ated if this receptor played a role in teratogenesis by regulating the
process of chondrogenesis. In micromass cultures of mouse limb bud me
senchymal cells, we found that a downregulation of RAR-beta 2 as well
as several other RAR isoforms by supplementation of the culture medium
with specific antisense oligodeoxynucleotides stimulated chondrogenes
is: cartilage nodule number, sulfated proteoglycans, and synthesis of
collagen type IIB were all enhanced in a dose-dependent manner. Howeve
r, only the antisense RAR-beta 2 probe efficiently prevented the stron
g inhibitory effects of exogenous RA on chondrogenesis in these cells.
The data suggest that the RAR-RA complexes play a role in position-de
pendent patterning of the limb skeleton in normal development and that
, in particular, RAR-beta 2 serves to prevent the mesenchymal cells fr
om expressing their chondrogenic bias. Our results further strengthen
the argument that RA-dependent elevation in RAR-beta 2 levels plays a
unique role in RA-induced teratogenesis.