The role of the G protein-coupled receptor GPR30 in the effects of estrogen in ovariectomized mice

1 Center for Bone Research, Institute of Medicine, Sahlgrenska Academy, Göteborg University, Göteborg; 2 Pediatric Endocrinology Unit, Department of Woman and Child Health, Karolinska Institutet, Stockholm; and 3 Unit of Drug Target Discovery, Department of Experimental Medical Science, Lund University, Lund, Sweden Submitted 13 August 2008 ; accepted in final form 12 December 2008 In vitro studies suggest that the membrane G protein-coupled receptor GPR30 is a functional estrogen receptor (ER). The aim of the present study was to determine the possible in vivo role of GPR30 as a functional ER primarily for the regulation of skeletal parameters, including bone mass and longitudinal bone growth, but also for some other well-known estrogen-regulated parameters, including uterine weight, thymus weight, and fat mass. Three-month-old ovariectomized (OVX) GPR30-deficient mice (GPR30 –/– ) and wild-type (WT) mice were treated with either vehicle or increasing doses of estradiol (E 2 ; 0, 30, 70, 160, or 830 ng·mouse –1 ·day –1 ). Body composition [bone mineral density (BMD), fat mass, and lean mass] was analyzed by dual-energy-X ray absorptiometry, while the cortical and trabecular bone compartments were analyzed by peripheral quantitative computerized tomography. Quantitative histological analyses were performed in the distal femur growth plate. Bone marrow cellularity and distribution were analyzed using a fluorescence-activated cell sorter. The estrogenic responses on most of the investigated parameters, including increase in bone mass (total body BMD, spine BMD, trabecular BMD, and cortical bone thickness), increase in uterine weight, thymic atrophy, fat mass reduction, and increase in bone marrow cellularity, were similar for all of the investigated E 2 doses in WT and GPR30 –/– mice. On the other hand, E 2 treatment reduced longitudinal bone growth, reflected by decreased femur length and distal femur growth plate height, in the WT mice but not in the GPR30 –/– mice compared with vehicle-treated mice. These in vivo findings demonstrate that GPR30 is not required for normal estrogenic responses on several major well-known estrogen-regulated parameters. In contrast, GPR30 is required for a normal estrogenic response in the growth plate. estrogen receptor; growth; bone Address for reprint requests and other correspondence: C. Ohlsson, Dept. of Internal Medicine. Sahlgrenska Univ. Hospital, SE-41345 Göteborg (e-mail Claes.Ohlsson{at}medic.gu.se )