Estrogen Deficiency and Tobacco Smoke Exposure Promote Matrix Metalloproteinase-13 Activation in Skin of Aging B6 Mice
ABSTRACT Estrogen deficiency may contribute to extracellular matrix turnover in skin. This has led previous authors to postulate that aged skin heals less efficiently when compared to younger skin. Also, cigarette smokers have been shown to heal less efficiently than nonsmokers. Matrix metalloproteinase (MMP)-13, an enzyme that participates in the degradation of the extracellular matrix, has been implicated in physiologic aging and wound healing. This study investigates the effects of smoke exposure and estrogen deficiency on MMP-13 in young and aged female mouse skin. Young and aged female C57Bl/6J mice were ovariectomized. They were then randomly administered either 17β-estradiol (E2) or placebo pellets. Half the animals in each age group were further randomized to exposure to cigarette smoke for a period of 6 months. Smoking and estrogen deficiency increased MMP-13 protein and activity in aged skin. The tissue inhibitors of metalloproteinases, which inhibit MMPs, activity was unchanged across all groups. E2 replacement decreased the actual level of MMP-13 protein and activity. We also found an increased collagen content and decreased ER receptor protein level in aged, smoke-exposed female mice. Our experimental data show that tobacco smoke exposure and estrogen deficiency are additive risk factors for promoting increased activity of MMP-13 in aged skin. These findings suggest that MMP-13 functions as a mediator of smoke-induced skin injury in susceptible, aged experimental female mice.
SourceAvailable from: Bertrand Czarny[Show abstract] [Hide abstract]
ABSTRACT: Matrix metalloproteinases like MMP-13 cleave and remodel the extracellular matrix and thereby play a crucial role in tumor progression in vivo. Using a highly selective inhibitor to block MMP-13 protein activity, we demonstrate a striking inhibitory effect on invasive tumor growth and vascularization in murine skin squamous cell carcinoma (SCC). Therapy outcome critically depends on animal age in C57Bl/6 mice and was successful in old female but not in young female mice. Treatment success was recovered by ovariectomy in young and abolished by 17ß-estradiol supplementation in old mice, suggesting a hormone dependent inhibitor effect. Responsiveness of the tumorigenic keratinocytes BDVII and fibroblasts to 17ß-estradiol was confirmed in vitro, where MMP-13 inhibitor treatment led to a reduction of cell invasion and VEGF release. This correlated well with a less invasive and vascularized tumor in treated mice in vivo. 17ß-estradiol supplementation also reduced invasion and VEGF release in vitro with no additional reduction upon MMP-13 inhibitor treatment. This suggests that low 17ß-estradiol levels in old mice in vivo lead to enhanced MMP-13 levels and VEGF release, allowing a more effective inhibitor treatment compared to young mice.In this study, we present a strong link between lower estrogen levels in old female mice, an elevated MMP-13 level, which results in a more effective MMP-13 inhibitor treatment in fibroblasts and SCC cells in vitro and in vivo. © 2014 Wiley Periodicals, Inc.International Journal of Cancer 12/2014; 135(12). DOI:10.1002/ijc.28866 · 5.01 Impact Factor
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ABSTRACT: The role that estrogens play in the aging lung is poorly understood. Remodeling of the aging lung with thickening of the alveolar walls and reduction in the number of peripheral airways is well recognized. The present study was designed to address whether estrogen deficiency would affect age-associated changes in the lungs of female C57Bl/6J mice. Lungs isolated from old mice (24 month old, estrogen deficient) demonstrated decreased lung volume and decreased alveolar surface area. There was no difference in alveolar number in the lungs of old and young (6 month old, estrogen replete) mice. Estrogen replacement restored lung volume, alveolar surface area, and alveolar wall thickness to that of a young mouse. ERα protein expression increased without a change in ERβ protein expression in the lung tissue isolated from old mice. In the lungs of old mice, the number of apoptotic cells was increased as well as the activation of matrix metalloproteinases (MMP)-2 and extracellular signal-regulated kinase (ERK). Young mice had the highest serum 17β-estradiol (E2) levels that decreased with age resulting in a decreased ratio of E2 to testosterone in old mice. Our data suggest that in the aging female mouse lung, estrogen deficiency and an increase of ERα expression lead to the development of an emphysematous phenotype. Estrogen replacement partially prevents these age-associated changes in the lung architecture by restoration of interalveolar septa. Understanding the role of estrogens in the remodeling of the lung during aging may facilitate interventions and therapies for aging-related lung disease in women.Endocrinology 11/2013; 155(2). DOI:10.1210/en.2013-1345 · 4.64 Impact Factor
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ABSTRACT: Skin aging various considerably between individuals and depends on intrinsic factors such as age, oestrogen deficiency during menopause, and on extrinsic factors such as exposure to UV light and tobacco addiction. The clinical and histological characteristics of these different types of aging are described as well as the principle highly complex mechanisms that are involved. Treatment for skin aging has become the main reason why patients consult in cosmetic dermatology. For this reason, dermatologist should know how to analyse this condition and offer suitable therapeutic care that takes into account the aging of the subcutaneous tissue.Annales de Dermatologie et de Vénéréologie 10/2009; 136. DOI:10.1016/S0151-9638(09)72530-X · 0.67 Impact Factor