Organ Messenger Ribonucleic Acid and Plasma Proteome Changes in the Adjuvant-Induced Arthritis Model: Responses to Disease Induction and Therapy with the Estrogen Receptor-β Selective Agonist ERB-041

Follettie, Maximillian T.; Pinard, Marc; Keith, James C.; Wang, Lili; Chelsky, Daniel; Hayward, Clive; Kearney, Paul; Thibault, P; Paramithiotis, Eustache; Dorner, Andrew J.; Harris, Heather A.

doi:10.1210/en.2005-0600

Cited by 43 publications

(32 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data, however, do not rule out any impact on airway smooth muscle hypertrophy/hyperplasia as suggested by others (Hughes et al, 2002). Indeed, considerable data have been published regarding the positive effects of ER␤ agonists in certain models of inflammatory disease (Harris et al, 2003Cristofaro et al, 2006;Follettie et al, 2006). However, a recent review indicated that ER␤ agonists are ineffective in a range of inflammatory models including collagen-induced arthritis (Harris, 2006).…”

Section: Discussioncontrasting

confidence: 69%

Estrogen Receptor β: Expression Profile and Possible Anti-Inflammatory Role in Disease

Catley

Birrell²,

Hardaker³

et al. 2008

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Estrogen receptor (ER) ␤ agonists have been demonstrated to possess anti-inflammatory properties in inflammatory disease models. The objective of this study was to determine whether ER␤ agonists affect in vitro and in vivo preclinical models of asthma. mRNA expression assays were validated in human and rodent tissue panels. These assays were then used to measure expression in human cells and our characterized rat model of allergic asthma. ERB-041 [7-ethenyl-2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-5-ol], an ER␤ agonist, was profiled on cytokine release from interleukin-1␤-stimulated human airway smooth muscle (HASM) cells and in the rodent asthma model. Although ER␤ expression was demonstrated at the gene and protein level in HASM cells, the agonist failed to have an impact on the inflammatory response. Similarly, in vivo, we observed temporal modulation of ER␤ expression after antigen challenge. However, the agonist failed to have an impact on the model endpoints such as airway inflammation, even though plasma levels reflected linear compound exposure and was associated with an increase in receptor activation after drug administration. In these modeling systems of airway inflammation, an ER␤ agonist was ineffective. Although ER␤ agonists are anti-inflammatory in certain models, this novel study would suggest that they would not be clinically useful in the treatment of asthma.

show abstract

Section: Discussioncontrasting

confidence: 69%

Estrogen Receptor β: Expression Profile and Possible Anti-Inflammatory Role in Disease

Catley

Birrell²,

Hardaker³

et al. 2008

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…Thus, MIP-1 protein is a key player in the pathogenesis of several diseases (72). Earlier publications and preclinical studies from Wyeth clearly indicated the anti-inflammatory effects of ER-␤ ligands (58). As obesity is an inflammatory disease (9), induction of MIP-1 was not surprising considering the level of fat mass and body weight increase in vehicle-treated high-fat dietfed animals.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Receptor-β-selective Ligands Alleviate High-fat Diet- and Ovariectomy-induced Obesity in Mice

Yepuru

Eswaraka

Kearbey

et al. 2010

Journal of Biological Chemistry

115

112

View full text Add to dashboard Cite

Obesity is an epidemic problem affecting millions of people in the Western hemisphere and costs the United States economy more than $200 billion annually. Currently, there are no effective treatments to combat obesity. Recent studies have implicated the constitutive activity of estrogen receptor (ER) ␤ as an important regulator of metabolic diseases. However, the potential of ER-␤-selective ligands to offset obesity is not clear. We evaluated the pharmacological effect of ER-␤-selective ligands (␤-LGNDs) in animal models of high-fat diet-and ovariectomyinduced obesity. Ligand binding, transactivation, and uterotrophic studies with ␤-LGNDs demonstrated selectivity for ER-␤ over ER-␣. Animals fed a high-fat diet showed a significant increase in body weight, and this weight gain was attenuated by ␤-LGNDs. High-fat diet-mediated increases in serum cholesterol, leptin, glucose, and fat accumulation in organs were also reduced by ␤-LGNDs. In addition, MRI scanning indicated that ␤-LGNDs altered body composition by reducing fat mass and increasing lean body mass. Organ weights and gene expression analyses demonstrated that adipose tissue is the center of action for ␤-LGNDs, and the reduction in body weight is likely due to increased energy expenditure. In vitro and in vivo mechanistic studies indicated that the anti-obesity effects of ␤-LGNDs were due to indirect peroxisome proliferator-activated receptor ␥ antagonistic actions requiring the ligand binding domain of ER-␤ and through abrogation of the ability of PGC-1 to coactivate peroxisome proliferator-activated receptor ␥. In conclusion, these studies indicate that ligand-activated ER-␤ is a potential therapeutic target to combat obesity and obesity-related metabolic diseases.Obesity is an epidemic disease affecting over 400 million people globally (1). Two-thirds of adults and children in the United States are either overweight or obese, making it a serious health risk and economic burden to society (2). Obesity is not a standalone disease, as its emergence leads to various complications, including type 2 diabetes mellitus (T2DM), 3 hypertension, atherosclerosis, and other cardiovascular diseases, osteoporosis, and clinical depression (3, 4). The United States Food and Drug Administration required an anti-obesity drug to reduce the body weight by 5% and/or better results than placebo in 12 months, indicating that even a marginal reduction in body weight will cause a significant improvement in the welfare of these patients (5). Despite the exponentially growing global obesity pharmaceutical market, only two Food and Drug Administration-approved drugs are available for this indication: 1) amphetamines and sibutramine that act on the hypothalamus to control appetite stimulation in the central nervous system, and 2) Orlistat, which is a lipase inhibitor that blocks gastrointestinal absorption of fat and decreases energy uptake (6). Despite mediocre performance, these drugs are commonly associated with side effects such as tachycardia, hypertension, fecal incontinence, ...

show abstract

“…At present, no overall conclusion can be made about whether all ER␤ ligands will be diabetogenic. The ER␤ ligands developed by various pharmaceutical companies all appear to have tissue selectivity, and they may not all influence ER␤ in skeletal muscle (19,20). However, it might be a good precautionary measure to examine effects on GLUT4 early in the development of ER␤ agonists that are being developed to target disease.…”

Section: Discussionmentioning

confidence: 99%

Muscle GLUT4 regulation by estrogen receptors ERβ and ERα

Barros

Machado

Warner

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

235

184

View full text Add to dashboard Cite

Estrogen is known to influence glucose homeostasis with dominant effects in the liver, but the role of estrogen receptors in muscle glucose metabolism is unknown. In the present study, we investigated the expression of the two estrogen receptors, ERα and ERβ, and their influence on regulation of the glucose transporter, GLUT4, and its associated structural protein, caveolin-1, in mouse gastrocnemius muscle. Immunohistochemical analysis revealed that ERα and ERβ are coexpressed in the nuclei of most muscle cells, and that their levels were not affected by absence of estradiol [in aromatase-knockout (ArKO) mice]. GLUT4 expression on the muscle cell membrane was not affected by loss of ERβ but was extremely reduced in ERα -/- mice and elevated in ArKO mice. RT-PCR confirmed a parallel reduction in GLUT4 mRNA levels in ERα -/- mice. Upon treatment of ArKO mice with the ERβ agonist 2,3-bis(4-hydroxyphenyl)propionitrile, GLUT4 expression was reduced. By immunofluorescence and Western blotting, caveolin-1 expression was higher in ArKO mice and lower in ERβ -/- and ERα -/- mice than in WT littermates. GLUT4 and caveolin-1 were colocalized in WT and ArKO mice but not in ERβ -/- and ERα -/- mice. These results reveal that ERα is a positive regulator of GLUT4 expression, whereas ERβ has a suppressive role. Both ERβ and ERα are necessary for optimal caveolin-1 expression. Taken together, these results indicate that colocalization of caveolin-1 and GLUT4 is not an absolute requirement for muscle glucose metabolism but that reduction in GLUT4 could be contributing to the insulin resistance observed in ERα -/- mice.

show abstract

Organ Messenger Ribonucleic Acid and Plasma Proteome Changes in the Adjuvant-Induced Arthritis Model: Responses to Disease Induction and Therapy with the Estrogen Receptor-β Selective Agonist ERB-041

Cited by 43 publications

References 57 publications

Estrogen Receptor β: Expression Profile and Possible Anti-Inflammatory Role in Disease

Estrogen Receptor β: Expression Profile and Possible Anti-Inflammatory Role in Disease

Estrogen Receptor-β-selective Ligands Alleviate High-fat Diet- and Ovariectomy-induced Obesity in Mice

Muscle GLUT4 regulation by estrogen receptors ERβ and ERα

Contact Info

Product

Resources

About