INHIBITION OF THE CHONDROCYTE PHENOTYPE BY RETINOIC ACID INVOLVES UP-REGULATION 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 al so been implicated in the premature closure of the cartilage growth pl ate following vitamin A intoxication or administration of retinoids fo r dermatologic conditions. Previous studies of the mechanism of action of retinoids in non-chondrogenic cells have concluded that retinoic a cid is a negative regulater of AP-1 responsive metalloprotease genes. We show that inhibition of expression of the cartilage phenotype by re tinoic acid in epiphyseal chondrocytes is associated with positive reg ulation 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 e xpression of cartilage matrix proteins and metalloproteases in this cu lture system, no appreciable changes in the expression of TGF-beta iso forms were evident in response to retinoic acid treatment. The present investigation demonstrates that regulation of AP-1 responsive genes b y retinoic acid can be either positive or negative, depending on the t arget cell type, and illuminates new mechanisms by which retinoic acid and other retinoids may exert control during development and growth o f the limb. (C) 1994 Wiley-Liss, Inc.*