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

Abstract

In prostanoid biosynthesis, the first two steps are catalyzed by cyclooxygenases (COX). In mice and humans, deregulated expression of COX-2, but not of COX-1, is characteristic of epithelial tumors, including squamous cell carcinomas 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 interfollicular epidermis and the pilosebaceous appendage of transgenic mouse skin. COX-2 overexpression in the expected locations, resulting in increased prostaglandin levels in epidermis and plasma, correlated with a pronounced skin phenotype. Heterozygous transgenic mice exhibited a reduced hair follicle density. Moreover, postnatally hair follicle morphogenesis and thinning of interfollicular dorsal epidermis were delayed. Adult transgenics showed a body-sitedependent sparse coat of greasy hair, the latter caused by sebaceous gland hyperplasia and increased epicutaneous sebum levels. In tail skin, hyperplasia of scale epidermis reflecting an increased number of viable and cornified cell layers was observed. Hyperplasia was a result of a disturbed program of epidermal differentiation rather than an increased proliferation rate, as reflected by the strong suppression of keratin 10, involucrin, and loricrin expression in suprabasal cells. Further pathological signs were loss of cell polarity, mainly of basal keratinocytes, epidermal invaginations into the dermis, and formation of horn perls. Invaginating hyperplastic lobes were surrounded by CD31-positive vessels. These results demonstrate a causal relationship between transgenic COX-2 expression in basal keratinocytes and epidermal hyperplasia as well as dysplastic features at discrete body sites.

UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

“…Our data also demonstrate that differentiated cells are more sensitive to UVB-induced upregulation of COX-2 mRNA and protein, a finding consistent with previous studies showing that UVB-induced COX-2 expression in mouse skin occurs primarily in the suprabasal, differentiated keratinocytes (Athar et al, 2001). At the present time, the mechanisms underlying the increased sensitivity of differentiated cells to UVB are not known although it should be noted that abnormal differentiation occurs in mouse epidermis following overexpression of COX-2 (Neufang et al, 2001). Differentiation related changes in mRNA expression for enzymes regulating arachidonic acid release and other prostanoid synthases and receptors were not observed following UVB treatment (see further below) indicating that this response was selective for COX-2.…”

Eryngium foetidum Suppresses Inflammatory Mediators Produced by Macrophages

“…Many studies have demonstrated that transgenic mice that overexpressed COX-2 in mammary glands, skin, and stomach are prone to develop tumours in these organs (Neufang et al, 2001;Muller-Decker et al, 2002;Oshima et al, 2004). In contrast, COX-2 knock-out mice are more resistant to tumorigenesis in various organs (Oshima et al, 1996;Tiano et al, 2002;Howe et al, 2005).…”

Hedgehog Signaling Regulates Sebaceous Gland Development

“…In addition, it will be important to explore the relationship between the Hedgehog pathway and other molecules implicated in sebocyte development, including c-Myc, 36,37 PPAR␥, 51,52 and COX-2. 53 Hair follicles and sebaceous glands both undergo cyclic changes after birth, 54 and Shh plays a major role in regulating proliferation of follicle epithelium during times of active growth. 17 Thus, in addition to its involvement in the initiation of sebaceous gland formation, the Hedgehog pathway is also likely to play a role in postnatal function of sebaceous glands.…”