Inhibition of proliferation of chondrocytes by specific receptors in response to retinoids.

All-trans retinoic acid inhibited the proliferation of chondrocytes derived from rat xiphoid cartilage when added to the culture medium at 10(-10)-10(-8) M. Proliferation of mouse clonal osteoblastic cells was also inhibited to a significant extent by all-trans retinoic acid. However, no such inhibitory effects on rat smooth muscle cells and human fibroblasts were observed. Flow cytometric analyses of chondrocytes labeled with propidium iodide revealed that all-trans retinoic acid arrested chondrocytes at the G1 phase of the cell cycle. Since 9-cis retinoic acid, which is synthesized enzymatically from all-trans retinoic acid, also inhibited the proliferation of chondrocytes, we investigated the subtypes of retinoic acid receptors in chondrocytes. Northern blot analysis revealed high levels of mRNA for retinoid X receptor alpha (RXR alpha), moderate levels of mRNA for retinoic acid receptor gamma (RAR gamma), and low levels of mRNA for RAR alpha and RXR beta. The mRNA for RAR beta and RXR gamma were not detected. These results suggest that retinoids are associated with the inhibition of proliferation of chondrocytes via both families of nuclear receptors, namely, RARs and RXRs.