GLUCOSYLCERAMIDES STIMULATE MITOGENESIS IN AGED MURINE EPIDERMIS

Glucosylceramides (GlcCer) and ceramides (Cer) appear to have opposite effects on epidermal growth and differentiation. Whereas Cer inhibit mitosis and induce terminal differentiation and apoptosis in cultured keratinocytes, GlcCer is mitogenic in young murine epidermis, Using a recently described murine model of chronologic senescence we explored whether GlcCer is mitogenic in aged epidermis. Epidermal GlcCer conten t increases following topical applications of either conduritol-B epox ide (CBE), an inhibitor of GlcCer hydrolysis, or exogenous GlcCer in a penetration-enhancing vehicle. During chronologic aging in the hairle ss mouse, baseline epidermal DNA synthesis rates remain normal until 1 8 mo, but decline significantly at 24 mo, Topical CBE stimulates a 1.5 - to 1.9-fold increase in epidermal DNA synthesis in all age groups (i .e., 1-2, 18, and 24 mo), Although the CBE induced increase in [H-3]th ymidine incorporation in 24 mo old animals is significant (p < 0.01), it is not sufficient to reach the absolute levels reached in similarly treated, younger mouse epidermis. Moreover, topical GlcCer induced mi togenesis is both dose dependent and hexose specific in young (1-2 mo old) animals, and remains effective in aged (less than or equal to 24 mo old) animals, Furthermore, the CBE induced increase in DNA synthesi s in aged epidermis is sufficient to produce epidermal hyperplasia. Fi nally, although an increased GlcCer:Cer ratio can alter stratum corneu m barrier function and membrane structure, neither stratum corneum fun ction nor extracellular membrane structure change under these experime ntal conditions, and therefore the mitogenic effects of increased epid ermal GlcCer cannot be attributed to effects on the stratum corneum, T hese results show that: (i) elevations in endogenous GlcCer are mitoge nic for aged as well as young murine epidermis; (ii) topical GlcCer is also mitogenic when delivered in an enhancing vehicle; and (iii) desp ite the putative importance of epidermal DNA synthesis for barrier hom eostasis, these mitogenic alterations do not alter stratum corneum fun ction.