Evaluation of an estrogen receptor-beta agonist in animal models of human disease.

Abstract

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

• Authors: 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, James C Keith Jr
• Journal: Endocrinology (Endocrinology) Vol. 144 Issue 10 Pg. 4241-9 (Oct 2003) ISSN: 0013-7227 [Print] United States
• PMID: 14500559 (Publication Type: Journal Article)

Chemical References

• ERB 041
• Estrogen Receptor beta
• HLA-B27 Antigen
• Oxazoles
• Receptors, Estrogen
• beta 2-Microglobulin

Topics

• Animals
• Animals, Genetically Modified
• Arthritis, Experimental (drug therapy)
• Bone Density (drug effects)
• Bone Diseases, Metabolic (drug therapy)
• Cell Line
• Disease Models, Animal
• Estrogen Receptor beta
• Female
• HLA-B27 Antigen (immunology)
• Humans
• Inflammatory Bowel Diseases (drug therapy, immunology)
• Mammary Glands, Animal (drug effects)
• Mice
• Ovariectomy
• Oxazoles (metabolism, pharmacology, therapeutic use)
• Rats
• Rats, Inbred Lew
• Rats, Sprague-Dawley
• Receptors, Estrogen (agonists, metabolism)
• Uterus (drug effects)
• Weight Gain (drug effects)
• beta 2-Microglobulin (immunology)