Abstract
Estrogen regulation of the male skeleton was first clearly demonstrated in patients with aromatase deficiency or a mutation in the ERα gene. Estrogen action on the skeleton is thought to occur mainly through the action of the nuclear receptors ERα and ERβ. Recently, in vitro studies have shown that the G protein–coupled receptor GPR30 is a functional estrogen receptor (ER). GPR30-deficient mouse models have been generated to study the in vivo function of this protein; however, its in vivo role in the male skeleton remains underexplored. We have characterized size, body composition, and bone mass in adult male Gpr30 knockout (KO) mice and their wild-type (WT) littermates. Gpr30 KO mice weighed more and had greater nasal-anal length (p < .001). Both lean mass and percent body fat were increased in the KO mice. Femur length was greater in Gpr30 KO mice, as was whole-body, spine, and femoral areal bone mineral density (p < .01). Gpr30 KO mice showed increased trabecular bone volume (p < .01) and cortical thickness (p < .001). Mineralized surface was increased in Gpr30 KO mice (p < .05). Bromodeoxyuridine (BrdU) labeling showed greater proliferation in the growth plate of Gpr30 KO mice (p < .05). Under osteogenic culture conditions, Gpr30 KO femoral bone marrow cells produced fewer alkaline phosphatase–positive colonies in early differentiating osteoblast cultures but showed increased mineralized nodule deposition in mature osteoblast cultures. Serum insulin-like growth factor 1 (IGF-1) levels were not different. These data suggest that in male mice, GPR30 action contributes to regulation of bone mass, size, and microarchitecture by a mechanism that does not require changes in circulating IGF-1. © 2011 American Society for Bone and Mineral Research.
Highlights
Bone is a dynamic compartmentalized organ composed of mineralized, stromal, and hematopoietic marrow compartments
In 2005, two groups showed that 17b-estradiol binds to and signals through it, leading to the designation of GPR30 as GPER1 in International Union of Pharmacology nomenclature.[12,13] GPR30 is a Gs-coupled sevenpass transmembrane protein originally cloned by multiple groups in the late 1990s.(14–18) In vitro it has been found to be activated by estrogen and G1, a GPR30-specific agonist,(19) and to induce cAMP elevation, intracellular calcium mobilization, and transactivation of epidermal growth factor receptors (EGFRs).(20–24) These signaling events may originate from GPR30 localized to the plasma membrane[21,22,24] or within an intracellular membrane compartment.[23,25] Initial human tissue expression analysis of Received in original form March 2, 2010; revised form June 22, 2010; accepted August 2, 2010
Expression has been shown in connective tissues such as cartilage and bone.[26,27] Expression in the human growth plate cartilage declines as puberty progresses.[26]. In bone, GPR30 has been found to be expressed in osteoblasts, osteocytes, and osteoclasts.[27]. In immortalized rat calvarial preosteoblasts, Runx2, a critical regulator of osteoblast cell differentiation, was shown to upregulate Gpr30 gene expression
Summary
Bone is a dynamic compartmentalized organ composed of mineralized, stromal, and hematopoietic marrow compartments. Expression has been shown in connective tissues such as cartilage and bone.[26,27] Expression in the human growth plate cartilage declines as puberty progresses.[26] In bone, GPR30 has been found to be expressed in osteoblasts, osteocytes, and osteoclasts.[27] In immortalized rat calvarial preosteoblasts, Runx, a critical regulator of osteoblast cell differentiation, was shown to upregulate Gpr gene expression This resulted in increased cellular proliferation in these osteoblast progenitors.[28] Combined, the results of this study and the expression analysis strongly suggest a role for GPR30 in skeletal metabolism
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