Effects of long-term retinoic acid treatment on epidermal differentiation in vivo: specific modifications in the programme of terminal differentiation.

To investigate the effects of long-term all-trans-retinoic acid (RA) treatment on epidermal differentiation in vivo, rhino mice were treated topically with 0.005% RA, and their epidermis was analysed histologically and biochemically after 5, 13 and 26 weeks of treatment. Effects of RA were observed first in the living layers of the epidermis, and then in the non-viable stratum corneum. Five weeks of topical RA led to thickening of the spinous and granular compartments, induction of keratins K6, K16 and K17, and suppression of filaggrin expression. After 13 and 26 weeks of RA treatment, the number of anucleate cornified cell layers remained similar to controls, but additional changes in histology and protein expression were observed. The results showed that prolonged administration of topical RA induced epidermal hyperproliferation, but did not suppress differentiation, in contrast to results observed in keratinocyte cultures. However, the distinct histological and biochemical changes observed in the spinous, granular and cornified layers of RA-treated skin after 26 weeks of treatment, suggested that the progeny of RA-treated basal cells undergo a modified programme of terminal differentiation. Considering the present data together with results of previous in vivo studies, we propose that long-term topical RA treatment retards, or specifically modulates, the later stages in epidermal differentiation, or programmed cell death.