Inhibition of the chondrocyte phenotype by retinoic acid involves upregulation of metalloprotease genes independent of TGF-beta.

Retinoic acid has been identified as a key morphogen governing pattern formation in the developing cartilaginous skeleton. Retinoids have also been implicated in the premature closure of the cartilage growth plate following vitamin A intoxication or administration of retinoids for dermatologic conditions. Previous studies of the mechanism of action of retinoids in non-chondrogenic cells have concluded that retinoic acid is a negative regulator of AP-1 responsive metalloprotease genes. We show that inhibition of expression of the cartilage phenotype by retinoic acid in epiphyseal chondrocytes is associated with positive regulation of AP-1 responsive metalloprotease genes, as well as induction of gene expression for the two components of the transcription factor AP-1, c-fos and c-jun. Despite the similar effects of TGF-beta 1 on expression of cartilage matrix proteins and metalloproteases in this culture system, no appreciable changes in the expression of TGF-beta isoforms were evident in response to retinoic acid treatment. The present investigation demonstrates that regulation of AP-1 responsive genes by retinoic acid can be either positive or negative, depending on the target cell type, and illuminates new mechanisms by which retinoic acid and other retinoids may exert control during development and growth of the limb.