Retinoic acid rapidly reduces cartilage matrix synthesis by altering gene transcription in chondrocytes

Abstract

Retinoic acid can alter the differentiation of a variety of cell types, including chondrocytes. This action may explain the high incidence of craniofacial and limb defects resulting from exposure to retinoic acid during development, and may be the basis for the compound's inhibition of a chondrosarcoma tumor in vivo. In order to understand the mechanism of action of retinoic acid, we studied the expression of chondrocyte-specific proteins as well as other proteins that indicate a shift in the differentiated phenotype of the cell following exposure to retinoic acid. After 48 hr of exposure to retinoic acid chondrocytes stopped synthesizing the chondrocyte-specific pro alpha 1 (II) chain of collagen II and a 370-kDa precursor protein of a cartilage-specific proteoglycan. Instead, the cells synthesized increased amounts of fibronectin and the pro alpha 1 chain of collagen III. These changes could be detected as early as 12 hr after treatment. In addition, the steady-state levels of specific mRNA transcripts coding for these differentiation markers correlated with their protein synthesis levels. Also, nuclear runoff experiments indicated that retinoic acid down regulated transcription of the collagen II gene, while stimulating collagen III gene transcription. These observations suggest that retinoic acid may alter the expression of the chondrocyte phenotype by selectively changing the normal pattern of gene expression.