Keratinocyte differentiation in hyperproliferative epidermis: topical application of PPARalpha activators restores tissue homeostasis.
We recently showed that topically applied PPARalpha activators promote epidermal differentiation in intact adult mouse skin. In this study we determined the effect of clofibrate and Wy-14,643, activators of PPARalpha, on hyperproliferative epidermis in hairless mice, induced either by repeated barrier abrogation (subacute model) or by essential fatty acid deficiency (chronic model). The hyperproliferative epidermis was characterized by an increased number of proliferating cells expressing proliferating cell nuclear antigen. Topical treatment with PPARalpha activators resulted in a substantial decrease in epidermal hyperplasia in both the subacute and chronic models of hyperproliferation. Following topical treatment, proliferating cell nuclear antigen-expressing cells were restricted to the basal layer, similar to normal epidermis. In hyperproliferative epidermis there was decreased expression of involucrin, profilaggrin-filaggrin, and loricrin as assayed by in situ hybridization and immunohistochemistry. Following topical treatment with PPAR activators staining for these mRNAs and proteins increased towards normal levels. Finally, topically applied clofibrate also increased apoptosis. This study demonstrates that topical PPAR activators have profound effects on epidermal gene expression in hyperproliferative skin disorders. Treatment with PPARalpha activators normalizes cell proliferation and promotes epidermal differentiation, correcting the cutaneous pathology. This study identifies PPARalpha activators as potential skin therapeutic agents.
Kömüves
L G
LG
Departments of Dermatology, Medicine, and Pediatrics, University of California San Francisco School of Medicine, San Francisco, California, USA.
Hanley
K
K
Man
M Q
MQ
Elias
P M
PM
Williams
M L
ML
Feingold
K R
KR
D000287:Administration, Topical; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002994:Clofibrate / Q000494:pharmacology; D000078404:Epidermal Cells; D006706:Homeostasis / Q000187:drug effects; D000960:Hypolipidemic Agents / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology*; D008297:Male; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000008:administration & dosage; D012879:Skin Physiological Phenomena / Q000187:drug effects; D014157:Transcription Factors / Q000008:administration & dosage
D000960:Hypolipidemic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D002994:Clofibrate