Estradiol induces proliferation of keratinocytes via receptor‐ mediated mechanisms

Abstract

In this study, we investigated the effects of estradiol on the proliferation of neonatal keratinocytes, the expression of estrogen receptor isoforms, and the signaling mechanisms by which estradiol mediates cell growth. We demonstrate that estradiol binds neonatal keratinocytes with high affinity (Kd=5.2nM) and limited capacity (Bmax of 14.2fmol/mg of protein), confirming the presence of estrogen binding sites. Using specific antibodies, we demonstrate that keratinocytes express both estrogen receptor (ER)-alpha and ER-beta. At physiological concentrations, estradiol up-regulates the level of ER-alpha receptors in keratinocytes and induces keratinocyte proliferation. The proliferative effect of estradiol requires the availability of functional estrogen receptors, as it is abrogated by anti-estrogen administration. Estradiol effect on keratinocyte proliferation is most likely mediated in part by activation of a nongenomic, membrane-associated, signaling pathway involving activation of the extracellular signal regulated kinases 1 and 2 and in part by the genomic signaling pathway through activation of nuclear receptors.

Effect of estrogens on skin aging and the potential role of SERMs

“…This is further supported by another group who demonstrated that incubation of cultured human epidermal keratinocytes with estradiol increased phosphorylation levels of ERK1 and ERK2 kinases within 15 minutes (Verdier-Sevrain et al 2004).…”

“…Another study has demonstrated mRNA and protein for ERβ and not ERα is expressed in cultured human epidermal keratinocytes Watanabe 2003a, 2003b), while a different group have shown that both ERα and ERβ are expressed in cultured human neonatal foreskin keratinocytes (Verdier-Sevrain et al 2004). These differences may be due to differences in anatomical site, since the number of estrogen receptors has been shown to differ with anatomical site, with face skin homogenates having a greater number of receptors than breast or thigh skin (Hasselquist et al 1980).…”

“…Furthermore, the stimulation of proliferation and DNA synthesis of human epidermal keratinocytes by estrogens has been demonstrated in vitro (Urano et al 1995;Kanda and Watanabe 2004;Verdier-Sevrain et al 2004) and cultured human epidermal keratinocytes have high affi nity estrogen binding sites (Verdier-Sevrain et al 2004). Specifi c antibodies for the two distinct intracellular estrogen receptors (ERα and ERβ) have shown that epidermal keratinocytes from human scalp skin of both sexes predominately express ERβ in situ (Thornton et al 2003).…”

Delayed healing and induction of secretory leukocyte protease inhibitor in polycystic ovary syndrome rat skin wounds

“…Estrogen receptor β (ERβ) is strongly expressed in the human stratum basal and spinosum of the scalp epithelium (29) and the increase in ERα expression is induced by estrogen in keratinocytes (30). SLPI regulates the proliferation of human endometrial epithelial cells and is expressed strongly to promote the proliferation of carcinoma cells (16,17,31).…”

Coactivator-mediated estrogen response in human squamous cell carcinoma lines

“…Clinically, decreased estrogen levels associated with menopause correlate with epidermal thinning, and estrogen containing skin creams have been shown to increase epidermal thickness (Fuchs et al 2003, Hall & Phillips 2005. The E2 induces proliferation of neonatal keratinocytes in vitro, which express both ERa and ERb (Verdier-Sevrain et al 2004). ERb was expressed by many cell types in skin from the human scalp, while ERa was localized to the dermal papilla and sebocytes (Thornton et al 2003).…”