j. Cosmet. Sci., 50, 185-202 (May/June 1999) Preprints of the 1999 Annual Scientific Seminar (Friday's Program) May 6-7, 1999 Chicago Hilton & Towers Chicago, IL 185

186 JOURNAL OF COSMETIC SCIENCE ROLE OF NUCLEAR HORMONE RECEPTORS IN REGULATING EPIDERMAL DIFFERENTIATION Kenneth Feingold Department of Veterans Affairs Medical Center Nuclear hormone receptors are transcription factors that regulate many cellular functions including cell differentiation and proliferation. Nuclear hormone receptors which heterodimerize with RXR, such as PAR, the vitamin D receptor, and the thyroid hormone receptor have been shown to regulate keratinocyte proliferation and differentiation. In transgenic mice that overexpress either an PAR or RXR dominant negative mutant, epidermal differentiation is abnormal. Peroxisome Proliferator Activated Receptors (PPARs) heterodimerize with RXR. PPARc• is activated by many chemicals including the lipid lowering drug clofibrate and by a variety of fatty acids. We have previously shown that PPARc• activators stimulate epidermal development in fetal skin explants and in utero resulting in the accelerated appearance of mature lameliar membranes in the extracellular spaces of the stratum corneum, a multilayered stratum corneum, and a competent barrier forming earlier in gestation (Hanley et al, JCl 100:705, 1997). Additionally, there is an increase in the activity of 13 glucocerebrosidase and steroid sulfatase, two enzymes required for a normal stratum corneum, and the increased expression of profilaggrin and Ioricrin, two proteins essential for the formation of cornecytes (Hanley et al JCl 100:705, 1997, Komuves et al. J.I.D. 111:429, 1998). Moreover, in cultured human keratinocytes, PPARc• activators increased cornified envelope formation 3-fold, increased involucrin and transglutaminase protein and mRNA levels 2-10 fold, and inhibited DNA synthesis. The aim of the present study was to determine the role of PPAR(• activation in adult epidermis. Topical treatment of several strains of adult mice with PPAR activators resulted in decreased epidermal thickness, coupled with increased expression of involucrin, profilaggrin/filaggrin, and Ioricrin (detected by in situ hybridization and immunohistochmistry). Moreover, topically applied PPAR activators increased apoptosis (as measured by TUNEL assay) while decreasing cell proliferation (detected by BrdU incorporation). Topical treatment with PPAR activators did not disturb baseline epidermal permeability barrier, but resulted in an accelerated recovery of barrier function following acute barrier abrogation by either tape stripping or detergent treatment. To determine whether these effects were due to specific PPAR(• activation, we analyzed keratinocyte gene expression in PPARc• knockout mice, which display focal parakeratosis, suggestive of impaired differentiation. Compared with the wild-type epidermis, involucrin, profilaggrin/filaggrin, and Ioricrin expression (detected by in situ hybridization and immunohistochemistry) were decreased in PPAR-c• knockout mice. Moreover, topical clofibrate treatment did not increase epidermal differentiation in PPAR-c• knockout mice. This study shows that PPAR-c• activation promotes keratinocyte gene expression, enhancing epidermal differentiation and inhibiting proliferation in intact adult skin. Moreover, endogenous activation of PPAR-c• may play a role in the regulation of normal keratinocyte differentiation.