At the Cutting EdgeExtracellular matrix integrity: A possible mechanism for differential clinical effects among selective estrogen receptor modulators and estrogens?
Introduction
Estrogen exerts a broad spectrum of effects in many different tissues via interaction with and activation of estrogen receptors (ER's). ERs are ligand-activated transcription factors with six structural domains of overlapping function. In the absence of ligand, ER exists as a monomeric, latent form and can be found in either the cytosol or the nucleus. Upon estrogen binding, a conformational change is induced in the receptor that favors ER dimerization and recruitment of co-factors that form a transcriptional complex. This ligand-bound complex is then translocated into the nucleus where it can bind either directly to a specific upstream element in the promoter region of estrogen-responsive genes, termed the estrogen response elements (ERE), or indirectly to other upstream promotor elements via complexes with other proteins, ultimately causing a change in gene expression that leads to a change in cell function. More recently, a controversial proposal of possible non-nuclear receptors for estrogen associated with the cell membrane has been described that may mediate some of the rapid, non-genomic effects of estrogens (Hisamoto and Bender, 2005, Sak and Everaus, 2004).
Selective ER modulators (SERMs) are a structurally diverse family of molecules that bind with high affinity to and modulate the activity of ER's, but can act as ER agonists, partial agonists, or antagonists in a tissue-dependent manner (McDonnell, 2004). Included in this family of molecules are triphenylethylene compounds such as tamoxifen, toremifene, clomiphene, idoxifene, and droloxifene; benzothiophenes such as raloxifene and arzoxifene; the centchroman-related (benzopyran) compound levormeloxifene; the tetrahydronaphthalene lasofoxifene; and the indole bazedoxifene. SERMs currently in clinical use include tamoxifen for the prevention and treatment of breast cancer, toremifene for the treatment of breast cancer, clomiphene for the induction of ovulation, and raloxifene for the prevention and treatment of postmenopausal osteoporosis.
The development of multiple SERMs and their subsequent preclinical and clinical characterization has demonstrated that the pharmacology of these ER ligands is complex. It is now apparent that in addition to structural diversity, the SERMs produce different conformations of the SERM-bound ER complex which in turn can induce different effects not only between tissues, but also within the same cell type or target tissue. Heat map analyses of global gene expression in bone cells (Kian et al., 2004) and human breast cancer cells (Frasor et al., 2004, Levenson et al., 2002) have revealed substantial differences in gene expression changes induced by structurally distinct SERMs. These results support the general concept that different SERMs can evoke heterogeneous effects on gene expression, and ultimately cell function, within the same tissue. However, our understanding of how different SERM-induced gene expression profiles contribute to variant clinical outcomes remains very limited. This article reviews recent evidence suggesting that differential effects of ER ligands on factors involved in extracellular matrix (ECM) integrity and collagen turnover may play a role in at least some of the diverse clinical effects of these molecules.
Section snippets
Diversity of estrogen and SERM effects on genitourinary tissue
The genitourinary system has proven to be important in differentiating clinical effects among estrogens and SERMs. This diversity of effects was first evident with respect to varying degrees of stimulation of the uterine endometrium, but more recently has become evident with other genitourinary effects related to pelvic organ prolapse and urinary incontinence (Goldstein and Nanavati, 2002, Silfen et al., 1999, Warming et al., 2003).
Differential effects of ER ligands on rat uterine gene expression
The molecular mechanism for how estrogen and different ER ligands may exert diverse effects on uterine physiology and pathophysiology with prolonged treatment was addressed in a recent microarray analysis of gene expression in ovariectomized rats (Helvering et al., 2005). Global gene expression of uterine tissue was compared between ovary-intact rats, ovariectomized rats, and ovariectomized rats treated for 5 weeks with maximally bone efficacious doses of 17α-ethinyl estradiol (0.1 mg/kg/day) or
Differential effects among estrogens and SERMs on ECM turnover: potential implications in other tissues
Estrogen effects on MMP expression or activity also have been reported in a variety of non-gynecological cell types and tissues in vitro and on circulating levels of MMPs in humans. In most cases, estrogen seems to up-regulate MMP activity or expression, including MMP-9 in mesangial cells (Potier et al., 2001), MMP-2 in vascular smooth muscle cells (Wingrove et al., 1998), intact arteries (Zhang et al., 2000), and retinal pigment epithelial cells (Marin-Castano et al., 2003), and MMP-9 in the
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