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

• Published in: Endocrinology (Philadelphia) Vol. 144; no. 10; pp. 4241 - 4249
• Main Authors: Harris, Heather A., Albert, Leo M., Leathurby, Yelena, Malamas, Michael S., Mewshaw, Richard E., Miller, Chris P., Kharode, Yogendra P., Marzolf, James, Komm, Barry S., Winneker, Richard C., Frail, Donald E., Henderson, Ruth A., Zhu, Yuan, Keith, James C.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Oxford University Press 01.10.2003; Endocrine Society
• Subjects: Agonists; Animal diseases; Animal models; Animals; Animals, Genetically Modified; Arthritis; Arthritis, Experimental - drug therapy; beta 2-Microglobulin - immunology; Biological and medical sciences; Bone Density - drug effects; Bone Diseases, Metabolic - drug therapy; Cartilage (articular); Cell Line; Diarrhea; Disease Models, Animal; Estrogen Receptor beta; Estrogen receptors; Estrogens; Female; Fundamental and applied biological sciences. Psychology; Histocompatibility antigen HLA; HLA-B27 Antigen - immunology; Humans; Immune response; Inflammatory bowel diseases; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - immunology; Joints (anatomy); Mammary Glands, Animal - drug effects; Mice; Ovariectomy; Ovulation; Oxazoles - metabolism; Oxazoles - pharmacology; Oxazoles - therapeutic use; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Receptors; Receptors, Estrogen - agonists; Receptors, Estrogen - metabolism; Skeleton; Synovitis; Uterus - drug effects; Vertebrates: endocrinology; Weight Gain - drug effects; Human; Estrogen receptor β; Animal model; Agonist
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2003-0550

The discovery of a second estrogen receptor (ER), called ERβ, 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 ERβ 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 ERβ 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 ERβ may be to modulate the immune response, and that ERβ-selective ligands may be therapeutically useful agents to treat chronic intestinal and joint inflammation.