The role of specific retinoid receptors in sebocyte growth and differentiation in culture

Retinoic acid derivatives (retinoids) exert their pleiotropic effects on ce ll development through specific nuclear receptors, the retinoic acid recept ors and retinoid X receptors, Despite recent progress in understanding the cellular and molecular mechanisms of retinoid activity, it is unknown which of the retinoid receptor pathways are involved in the specific processes o f sebocyte growth and development. In this study, we investigated the roles of specific retinoid receptors in sebocyte growth and differentiation, by testing the effects of selective retinoic acid receptor and retinoid X rece ptor ligands at concentrations between 10(-10) M and 10(-6) M in a primary rat preputial cell monolayer culture system. Cell growth was determined by number of cells and colonies, and cell differentiation by analysis of lipid -forming colonies. All-trans retinoic acid and selective retinoic acid rece ptor agonists (CD271 = adapalene, an RAR-beta,gamma agonist; CD2043 = retin oic acid receptor pan-agonist; and CD336 = Am580, an RAR-alpha agonist) cau sed significant decreases in numbers of cells, colonies, and lipid-forming colonies, but with an exception at high doses of all-tuans retinoic acid (1 0(-6) M), with which only a small number of colonies grew but they became t wice as differentiated as controls (42.2 +/- 4.0% vs 22.6 +/- 2.7%, mean +/ - SEM, lipid-forming colonies, p < 0.01). Furthermore, the RAR-beta,gamma a ntagonist CD2665 antagonized the suppressive effects of all-trans retinoic acid, adapalene, and CD2043 on both cell growth and differentiation, In con trast, the retinoid X receptor agonist CD2809 increased cell growth slightl y and lipid-forming colonies dramatically in a clear dose-related manner to a maximum of 73.7%+/- 6.7% at 10(-6) M (p < 0.001). Our data suggest that retinoic acid receptors and retinoid X receptors differ in their roles in s ebocyte growth and differentiation (i) retinoic acid receptors, especially the beta and/or gamma subtypes, mediate both the antiproliferative and anti differentiative effects of retinoids; (ii) retinoid X receptors mediate pro minent differentiative and weak proliferative effects; (iii) the antiprolif erative and antidifferentiative effects of all-trans retinoic acid are prob ably mediated by retinoic acid receptors, whereas its differentiative effec t at high dose may be mediated by retinoid X receptors via all-trans retino ic acid metabolism to 9-cis retinoic acid, the natural ligand of retinoid X receptors.