Changes in cell characteristics due to retinoic acid; specifically, a decrease in the expression of claudin-1 and increase in claudin-4 within tight junctions in stratified oral keratinocytes

J Periodontal Res. 2010 Apr;45(2):207-15. doi: 10.1111/j.1600-0765.2009.01219.x. Epub 2009 Sep 23.


Background and objective: It has been reported that retinoic acid disintegrates the desmosome formation of squamous epithelium, resulting in inhibition of stratification. In contrast, it is not known whether retinoic acid influences the integration of tight junctions. Therefore, our objective of this study is to disclose effects of retinoic acid on the formation and maintenance of tight junction.

Material and methods: In the present study, the alteration of expression of tight junction constituent proteins and keratin peptides in immortalized oral mucosal epithelial cells (GE1) induced by 1 microm retinoic acid was analyzed by immunofluorescence, electron microscopy and reverse transcription-polymerase chain reaction (RT-PCR).

Results: The stratifying GE1 cells expressed claudin-1, claudin-4, claudin-5, occludin and zonula occludens 1 in the control culture. The RT-PCR showed that retinoic acid significantly reduced the expression of claudin-1 mRNA, whereas it dramatically enhanced expression of claudin-4 mRNA. Immunofluorescence showed that claudin-1 was present at cell-to-cell contact sites in the flattened uppermost layers of the control culture. In the culture with retinoic acid, the flattened uppermost cells were absent and there claudin-1 was less present, but claudin-4 was prominently present in all layers. Claudin-5 was present in a variety of patterns, regardless of the presence of retinoic acid. Along with the change of claudin species, the expressions of keratin 7, keratin 8 and keratin 18, as markers for the simple epithelium, were clearly stimulated by retinoic acid.

Conclusion: Retinoic acid changed the expression of tight junction constituent molecules, such as claudin-1 and claudin-4, in oral keratinocytes. These findings suggest that long-term application of retinoids in clinical therapy should be carefully performed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Claudin-1
  • Claudin-4
  • Claudin-5
  • Cytoplasm / drug effects
  • Cytoplasm / ultrastructure
  • Epithelial Cells / drug effects
  • Intercellular Junctions / drug effects
  • Intercellular Junctions / ultrastructure
  • Keratin-18 / drug effects
  • Keratin-7 / drug effects
  • Keratin-8 / drug effects
  • Keratinocytes / drug effects*
  • Keratinocytes / ultrastructure
  • Keratins / drug effects
  • Membrane Proteins / drug effects*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mouth Mucosa / cytology
  • Mouth Mucosa / drug effects*
  • Occludin
  • Phosphoproteins / drug effects
  • Tight Junctions / drug effects*
  • Tretinoin / pharmacology*
  • Zonula Occludens-1 Protein


  • Claudin-1
  • Claudin-4
  • Claudin-5
  • Cldn1 protein, mouse
  • Cldn4 protein, mouse
  • Cldn5 protein, mouse
  • Keratin-18
  • Keratin-7
  • Keratin-8
  • Krt7 protein, mouse
  • Krt8 protein, mouse
  • Membrane Proteins
  • Occludin
  • Ocln protein, mouse
  • Phosphoproteins
  • Tjp1 protein, mouse
  • Zonula Occludens-1 Protein
  • Tretinoin
  • Keratins