The role of retinoic acid receptors in oral epithelial differentiation

Abstract

Retinoic acid (RA) is important for regulation of epithelial differentiation. RA exerts its effects via nuclear retinoic acid receptors (RARs), which act as transcription factors for numerous genes. Three RAR subtypes have, so far, been identified and research suggests that each subtype has specific functions in the cell. Within the oral cavity epithelial differentiation exhibits regional variation from the noncornified lining mucosa to the cornified masticatory mucosa. It was hypothesized, that RA influences oral epithelial differentiation and that this regulation is mediated by a region specific expression of the RARs. The goal was to investigate the effects of RA on oral epithelial differentiation and the role of retinoic acid receptor (RARs) in this process by finding an association between specific patterns of RAR expression and specific patterns of oral epithelial differentiation. Oral epithelial cells were grown in an organotypic culture system in various RA concentrations and with different types of fibroblasts. Keratinocyte differentiation was analyzed by histology and immunohistochemistry and/or immunoblotting, and expression of the RARs was detected by RT-PCR experiments. Using this approach, it was shown that RA exerts major regulatory effects on oral epithelial differentiation by inhibiting epithelial cornification. This regulation is modified by the underlying fibroblasts. Examination of the RAR expression in the cultured epithelia revealed that RAR$\beta$ expression is inversely associated with the degree of epithelial cornification. In contrast, RAR$\alpha$ and RAR$\gamma$ expression do not vary appreciably with a change in epithelial differentiation in vitro. Similar RAR expression patterns were found in situ when comparing oral epithelia from a cornified and a noncornified region. These results are consistent with the hypothesis that RAR$\beta$ plays a major role in the RA-sensitive regulation of oral epithelial differentiation. However, preliminary experiments with a RAR$\beta$ specific agonist indicated that the increase in RAR$\beta$ expression may be a secondary phenomenon as a result of the switch from a cornified to a noncornified pattern of oral epithelial differentiation. Continued use of the organotypic culture model and the new approach of using RAR subtype specific retinoids will shed new light on the functions of RARs in oral epithelia.