Control of rat tail skin temperature regulation by estrogen receptor-beta selective ligand

Opas, Evan E.; Scafonas, Angela; Nantermet, Pascale V.; Wilkening, Robert R.; Birzin, Elizabeth T.; Wilkinson, Hilary; Colwell, Lawrence F.; Schaeffer, James M.; Towler, Dwight A.; Rodan, Gideon A.; Schmidt, Azriel

doi:10.1016/j.maturitas.2009.07.007

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Volume 64, Issue 1 , Pages 46-51, 20 September 2009

Control of rat tail skin temperature regulation by estrogen receptor-beta selective ligand

Evan E. Opas
- Department of Molecular Endocrinology and Bone Biology, WP26A-1000, Merck Research Laboratories, West Point, PA 19486, USA
- Current address: Inflammation and Pulmonary Diseases, Johnson & Johnson PRD, Welsh and McKean Roads, Spring House, PA 19477, USA.
Angela Scafonas
- Department of Molecular Endocrinology and Bone Biology, WP26A-1000, Merck Research Laboratories, West Point, PA 19486, USA
Pascale V. Nantermet
- Department of Molecular Endocrinology and Bone Biology, WP26A-1000, Merck Research Laboratories, West Point, PA 19486, USA
Robert R. Wilkening
- Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Elizabeth T. Birzin
- Department of Atherosclerosis and Endocrinology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Hilary Wilkinson
- Department of Molecular Endocrinology and Bone Biology, WP26A-1000, Merck Research Laboratories, West Point, PA 19486, USA
Lawrence F. Colwell
- Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
- Current address: 234 Matawan Ave., Matawan, NJ 07747, USA.
James M. Schaeffer
- Department of Atherosclerosis and Endocrinology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
Dwight A. Towler
- Department of Molecular Endocrinology and Bone Biology, WP26A-1000, Merck Research Laboratories, West Point, PA 19486, USA
- Current address: Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, USA.
Gideon A. Rodan
- Department of Molecular Endocrinology and Bone Biology, WP26A-1000, Merck Research Laboratories, West Point, PA 19486, USA
- Deceased.
Azriel Schmidt
- Department of Molecular Endocrinology and Bone Biology, WP26A-1000, Merck Research Laboratories, West Point, PA 19486, USA
- Corresponding author. Tel.: +1 215 652 3498; fax: +1 215 652 4328.

Received 4 March 2009; received in revised form 8 July 2009; accepted 16 July 2009. published online 06 August 2009.

Abstract

Objective

To test the role of ERβ in the control of estrogen-dependent thermoregulation in rats.

Methods

Test the ability of an ERβ-selective ligand to suppress the elevation in basal rat tail skin temperature (TST) caused by ovariectomy (OVX).

Results

ERβ-19 is a tetrahydrofluorenone ERβ-selective ligand that displaces 0.1nM estradiol from ERβ with an IC50 of 1.8nM compared to an IC50 of 141nM for ERα. Like estradiol, it acts as an agonist on ERβ-mediated transactivation and transrepression with 25- and 60-fold selectivity, respectively, over ERα-controlled transcription. Administration of estradiol to estrogen-depleted rats suppresses the ovariectomy-induced elevation of TST. Similar treatment of OVX rats with ERβ-19 also results in suppression of elevated TST. However, in contrast to estradiol, ERβ-19 does not suppress body weight, does not increase uterine weight, nor does it stimulate uterocalin biomarker expression which is under the control of ERα. Thus, the ERβ-19 suppression of rat TST is mediated by ERβ without eliciting the activity of ERα.