Abnormal differentiation of epidermis in transgenic mice constitutively expressing cyclooxygenase-2 in skin

In prostanoid biosynthesis, the first two steps are catalyzed by cyclooxyge nases (COX). In mice and humans, deregulated expression of COX-2. but not o f COX-1, is characteristic of epithelial tumors, including squamous cell ca rcinomas of skin. To explore the function of COX-2 in epidermis, a keratin 5 promoter was used to direct COX-2 expression to the basal cells of interf ollicular epidermis and the pilosebaceous appendage of transgenic mouse ski n. COX-2 overexpression in the expected locations, resulting in increased p rostaglandin levels in epidermis and plasma, correlated with a pronounced s kin phenotype. Heterozygous transgenic mice exhibited a reduced hair follic le density. Moreover, postnatally hair follicle morphogenesis and thinning of interfollicular dorsal epidermis were delayed. Adult transgenics showed a body-site-dependent sparse coat of greasy hair, the latter caused by seba ceous gland hyperplasia and increased epicutaneous sebum levels. In tail sk in, hyperplasia of scale epidermis reflecting an increased number of viable and cornified cell layers was observed. Hyperplasia was a result of a dist urbed program of epidermal differentiation rather than an increased prolife ration rate, as reflected by the strong suppression of keratin 10, involucr in, and loricrin expression in suprabasal cells. Further pathological signs were loss of cell polarity, mainly of basal keratinocytes, epidermal invag inations into the dermis, and formation of horn perls. Invaginating hyperpl astic lobes were surrounded by CD31-positive vessels. These results demonst rate a causal relationship between transgenic COX-2 expression in basal ker atinocytes and Epidermal hyperplasia as well as dysplastic features at disc rete body sites.