help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow A correction has been published
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Harris, H. A.
Right arrow Articles by Keith, J. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Harris, H. A.
Right arrow Articles by Keith, J. C., Jr.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Endocrinology Vol. 144, No. 10 4241-4249
Copyright © 2003 by The Endocrine Society

Evaluation of an Estrogen Receptor-ß Agonist in Animal Models of Human Disease

Heather A. Harris, Leo M. Albert, Yelena Leathurby, Michael S. Malamas, Richard E. Mewshaw, Chris P. Miller, Yogendra P. Kharode, James Marzolf, Barry S. Komm, Richard C. Winneker, Donald E. Frail, Ruth A. Henderson, Yuan Zhu and James C. Keith, Jr.

Women’s Health Research Institute (H.A.H., Y.P.K., J.M., B.S.K., R.C.W., D.E.F., R.A.H., Y.Z.) and Chemistry and Screening Sciences (R.E.M., C.P.M.), Wyeth Research, Collegeville, Pennsylvania 19426; Cardiovascular and Metabolic Diseases, Wyeth Research (L.M.A., Y.L., J.C.K.), Cambridge, Massachusetts 02140; and Chemistry and Screening Sciences, Wyeth Research (M.S.M.), Monmouth Junction, New Jersey 08852

Address all correspondence and requests for reprints to: Heather A. Harris, Ph.D., Women’s Health Research Institute, RN 3256, 500 Arcola Road, Collegeville, Pennsylvania 19426. E-mail: harrish{at}wyeth.com.

The discovery of a second estrogen receptor (ER), called ERß, in 1996 sparked intense interest within the scientific community to discover its role in mediating estrogen action. However, despite more than 6 yr of research into the function of this receptor, its physiological role in mediating estrogen action remains unclear and controversial. We have developed a series of highly selective agonists for ERß and have characterized their activity in several clinically relevant rodent models of human disease. The activity of one such compound, ERB-041, is reported here. We conclude from these studies that ERß does not mediate the bone-sparing activity of estrogen on the rat skeleton and that it does not affect ovulation or ovariectomy-induced weight gain. In addition, these compounds are nonuterotrophic and nonmammotrophic. However, ERB-041 has a dramatic beneficial effect in the HLA-B27 transgenic rat model of inflammatory bowel disease and the Lewis rat adjuvant-induced arthritis model. Daily oral doses as low as 1 mg/kg reverse the chronic diarrhea of HLA-B27 transgenic rats and dramatically improve histological disease scores in the colon. The same dosing regimen in the therapeutic adjuvant-induced arthritis model reduces joint scores from 12 (maximal inflammation) to 1 over a period of 10 d. Synovitis and Mankin (articular cartilage) histological scores are also significantly lowered (50–75%). These data suggest that one function of ERß may be to modulate the immune response, and that ERß-selective ligands may be therapeutically useful agents to treat chronic intestinal and joint inflammation.




This article has been cited by other articles:


Home page
 Cancer Prevention ResearchHome page
M. L. Slattery and F.A. Fitzpatrick
Convergence of Hormones, Inflammation, and Energy-Related Factors: A Novel Pathway of Cancer Etiology
Cancer Prevention Research, November 1, 2009; 2(11): 922 - 930.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
T. Yokota, K. Oritani, K. P. Garrett, T. Kouro, M. Nishida, I. Takahashi, M. Ichii, Y. Satoh, P. W. Kincade, and Y. Kanakura
Soluble Frizzled-Related Protein 1 Is Estrogen Inducible in Bone Marrow Stromal Cells and Suppresses the Earliest Events in Lymphopoiesis
J. Immunol., November 1, 2008; 181(9): 6061 - 6072.
[Abstract] [Full Text] [PDF]

Home page
 Ann Rheum DisHome page
M Hegen, J C Keith Jr, M Collins, and C L Nickerson-Nutter
Utility of animal models for identification of potential therapeutics for rheumatoid arthritis
Ann Rheum Dis, November 1, 2008; 67(11): 1505 - 1515.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. C. Catley, M. A. Birrell, E. L. Hardaker, J. de Alba, S. Farrow, S. Haj-Yahia, and M. G. Belvisi
Estrogen Receptor {beta}: Expression Profile and Possible Anti-Inflammatory Role in Disease
J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 83 - 88.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
O. Bukulmez, D. B. Hardy, B. R. Carr, R. A. Word, and C. R. Mendelson
Inflammatory Status Influences Aromatase and Steroid Receptor Expression in Endometriosis
Endocrinology, March 1, 2008; 149(3): 1190 - 1204.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
A. Cvoro, D. Tatomer, M.-K. Tee, T. Zogovic, H. A. Harris, and D. C. Leitman
Selective Estrogen Receptor- Agonists Repress Transcription of Proinflammatory Genes
J. Immunol., January 1, 2008; 180(1): 630 - 636.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
S. Savolainen, T. Pakarainen, I. Huhtaniemi, M. Poutanen, and S. Makela
Delay of Postnatal Maturation Sensitizes the Mouse Prostate to Testosterone-Induced Pronounced Hyperplasia: Protective Role of Estrogen Receptor-{beta}
Am. J. Pathol., September 1, 2007; 171(3): 1013 - 1022.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
R. H. Straub
The Complex Role of Estrogens in Inflammation
Endocr. Rev., August 1, 2007; 28(5): 521 - 574.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
J. A. Arreguin-Arevalo, T. L. Davis, and T. M. Nett
Differential Modulation of Gonadotropin Secretion by Selective Estrogen Receptor 1 and Estrogen Receptor 2 Agonists in Ovariectomized Ewes
Biol Reprod, August 1, 2007; 77(2): 320 - 328.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
D. Xing, W. Feng, A. P. Miller, N. M. Weathington, Y.-F. Chen, L. Novak, J. E. Blalock, and S. Oparil
Estrogen modulates TNF-{alpha}-induced inflammatory responses in rat aortic smooth muscle cells through estrogen receptor-beta activation
Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2607 - H2612.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
A. Cvoro, S. Paruthiyil, J. O. Jones, C. Tzagarakis-Foster, N. J. Clegg, D. Tatomer, R. T. Medina, M. Tagliaferri, F. Schaufele, T. S. Scanlan, et al.
Selective Activation of Estrogen Receptor-{beta} Transcriptional Pathways by an Herbal Extract
Endocrinology, February 1, 2007; 148(2): 538 - 547.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
H. Grans, M. Nilsson, K. Dahlman-Wright, and B. Evengard
Reduced levels of oestrogen receptor {beta} mRNA in Swedish patients with chronic fatigue syndrome
J. Clin. Pathol., February 1, 2007; 60(2): 195 - 198.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
H. A. Harris
Estrogen Receptor-{beta}: Recent Lessons from in Vivo Studies
Mol. Endocrinol., January 1, 2007; 21(1): 1 - 13.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
J. L. Turgeon, M. C. Carr, P. M. Maki, M. E. Mendelsohn, and P. M. Wise
Complex Actions of Sex Steroids in Adipose Tissue, the Cardiovascular System, and Brain: Insights from Basic Science and Clinical Studies
Endocr. Rev., October 1, 2006; 27(6): 575 - 605.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
C. Bolego, E. Vegeto, C. Pinna, A. Maggi, and A. Cignarella
Selective Agonists of Estrogen Receptor Isoforms: New Perspectives for Cardiovascular Disease
Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2192 - 2199.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. W. Hsieh, S. S. Rajan, S. K. Sharma, Y. Guo, E. R. DeSombre, M. Mrksich, and G. L. Greene
Identification of Ligands with Bicyclic Scaffolds Provides Insights into Mechanisms of Estrogen Receptor Subtype Selectivity
J. Biol. Chem., June 30, 2006; 281(26): 17909 - 17919.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
O. Wada-Hiraike, O. Imamov, H. Hiraike, K. Hultenby, T. Schwend, Y. Omoto, M. Warner, and J.-A. Gustafsson
Role of estrogen receptor beta in colonic epithelium
PNAS, February 21, 2006; 103(8): 2959 - 2964.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. T. Follettie, M. Pinard, J. C. Keith Jr., L. Wang, D. Chelsky, C. Hayward, P. Kearney, P. Thibault, E. Paramithiotis, A. J. Dorner, et al.
Organ Messenger Ribonucleic Acid and Plasma Proteome Changes in the Adjuvant-Induced Arthritis Model: Responses to Disease Induction and Therapy with the Estrogen Receptor-{beta} Selective Agonist ERB-041
Endocrinology, February 1, 2006; 147(2): 714 - 723.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
F. Chen, K. Knecht, E. Birzin, J. Fisher, H. Wilkinson, M. Mojena, C. T. Moreno, A. Schmidt, S.-i. Harada, L. P. Freedman, et al.
Direct Agonist/Antagonist Functions of Dehydroepiandrosterone
Endocrinology, November 1, 2005; 146(11): 4568 - 4576.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
G. D. Barish, M. Downes, W. A. Alaynick, R. T. Yu, C. B. Ocampo, A. L. Bookout, D. J. Mangelsdorf, and R. M. Evans
A Nuclear Receptor Atlas: Macrophage Activation
Mol. Endocrinol., October 1, 2005; 19(10): 2466 - 2477.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
M M. Elloso, K. Phiel, R. A Henderson, H. A Harris, and S. J Adelman
Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands
J. Endocrinol., May 1, 2005; 185(2): 243 - 252.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
K. F. Koehler, L. A. Helguero, L.-A. Haldosen, M. Warner, and J.-A. Gustafsson
Reflections on the Discovery and Significance of Estrogen Receptor {beta}
Endocr. Rev., May 1, 2005; 26(3): 465 - 478.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
H. A. Harris, K. L. Bruner-Tran, X. Zhang, K. G. Osteen, and C. R. Lyttle
A selective estrogen receptor-{beta} agonist causes lesion regression in an experimentally induced model of endometriosis
Hum. Reprod., April 1, 2005; 20(4): 936 - 941.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
C. J. Fabian and B. F. Kimler
Selective Estrogen-Receptor Modulators for Primary Prevention of Breast Cancer
J. Clin. Oncol., March 10, 2005; 23(8): 1644 - 1655.
[Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
C. C. Chadwick, S. Chippari, E. Matelan, L. Borges-Marcucci, A. M. Eckert, J. C. Keith Jr., L. M. Albert, Y. Leathurby, H. A. Harris, R. A. Bhat, et al.
Identification of pathway-selective estrogen receptor ligands that inhibit NF-{kappa}B transcriptional activity
PNAS, February 15, 2005; 102(7): 2543 - 2548.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
D. P. McDonnell
The Molecular Pharmacology of Estrogen Receptor Modulators: Implications for the Treatment of Breast Cancer
Clin. Cancer Res., January 15, 2005; 11(2): 871s - 877s.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
A. S. Lovegrove, J. Sun, K. A. Gould, D. B. Lubahn, K. S. Korach, and P. H. Lane
Estrogen receptor {alpha}-mediated events promote sex-specific diabetic glomerular hypertrophy
Am J Physiol Renal Physiol, September 1, 2004; 287(3): F586 - F591.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
A. Hillisch, O. Peters, D. Kosemund, G. Muller, A. Walter, B. Schneider, G. Reddersen, W. Elger, and K.-H. Fritzemeier
Dissecting Physiological Roles of Estrogen Receptor {alpha} and {beta} with Potent Selective Ligands from Structure-Based Design
Mol. Endocrinol., July 1, 2004; 18(7): 1599 - 1609.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. B. Hawkins and P. Thomas
The Unusual Binding Properties of the Third Distinct Teleost Estrogen Receptor Subtype ER{beta}a Are Accompanied by Highly Conserved Amino Acid Changes in the Ligand Binding Domain
Endocrinology, June 1, 2004; 145(6): 2968 - 2977.
[Abstract] [Full Text] [PDF]

Home page
 ScienceHome page
J. L. Turgeon, D. P. McDonnell, K. A. Martin, and P. M. Wise
Hormone Therapy: Physiological Complexity Belies Therapeutic Simplicity
Science, May 28, 2004; 304(5675): 1269 - 1273.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
C. Hegele-Hartung, P. Siebel, O. Peters, D. Kosemund, G. Muller, A. Hillisch, A. Walter, J. Kraetzschmar, and K.-H. Fritzemeier
Impact of isotype-selective estrogen receptor agonists on ovarian function
PNAS, April 6, 2004; 101(14): 5129 - 5134.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
D. P. McDonnell
Mining the Complexities of the Estrogen Signaling Pathways for Novel Therapeutics
Endocrinology, October 1, 2003; 144(10): 4237 - 4240.
[Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2003 by The Endocrine Society