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Excessive retinoic acid impaired proliferation and differentiation of human fetal palatal chondrocytes (hFPCs).

Chondrocyte proliferation and differentiation is a fundamental process during hard palatogenesis. Excessive retinoic acid (RA), the biologically most active metabolite of vitamin A, has been reported to adversely affect chondrogenesis. The aim of this study was to investigate the mechanisms underlying RA-induced chondrocyte differentiation by using human fetal palatal chondrocytes (hFPCs) aging about 9 weeks of amenorrhea. RA treatment inhibited proliferation and induced apoptosis in hFPCs. Alkaline phosphatase activity assay, quantitative alcian blue staining, and real-time PCR analysis revealed that RA treatment stimulated hFPCs to undergo maturation and terminal differentiation, as demonstrated by decreased chondrogenic markers and increased osteogenic markers. Further studies demonstrated that RA treatment increased Wnt/β-catenin signaling, as demonstrated by Wnt/β-catenin target gene expression analysis and a luciferase-based β-catenin-activated reporter assay. To address the role of Wnt/β-catenin signaling, we treated hFPCs with Dickkopf-related protein 1, an extracellular inhibitor of Wnt/β-catenin signaling, and the observed all-trans retinoic acid-mediated increases in nuclear accumulation of β-catenin, alkaline phosphatase activity, and type I collagen mRNA were attenuated, suggesting that RA modulated Wnt signaling at ligand-receptor level. In summary, excessive all-trans retinoic acid inhibited proliferation and promoted ossification of hFPCs by upregulation of Wnt/β-catenin signaling.