Estrogen Receptor-β Inhibits Skeletal Growth and Has the Capacity to Mediate Growth Plate Fusion in Female Mice

Abstract

To determine the long-term role of ERβ in the regulation of longitudinal bone growth, appendicular and axial skeletal growth was followed and compared in female ERβ^−/−, ERα^−/−, and ERα^−/−β^−/− mice. Our results show that ERβ inhibits appendicular and axial skeletal growth and has the capacity to induce fusion of the growth plates. Introduction: Estrogen affects skeletal growth and promotes growth plate fusion in humans. In rodents, the growth plates do not fuse after sexual maturation, but prolonged treatment with supraphysiological levels of estradiol has the capacity to fuse the growth plates. It should be emphasized that the estrogen receptor (ER)α^−/− and the ERα^−/−β^−/−, but not the ERβ^−/−, mouse models have clearly increased serum levels of estradiol. Materials and Methods: The skeletal growth was monitored by X-ray and dynamic histomorphometry, and the growth plates were analyzed by quantitative histology, calcein double labeling, bromodeoxyuridine (BrdU) incorporation, and TUNEL assay in 4- and 18-month-old female ERβ^−/−, ERα^−/−, and ERα^−/−β^−/− mice. Results: Young adult (4-month-old) ERβ^−/− mice demonstrated an increased axial- and appendicular-skeletal growth, supporting the notion that ERβ inhibits skeletal growth in young adult female mice. Interestingly, the growth plates were consistently fused in the appendicular skeleton of 18-month-old female ERα^−/− mice. This fusion of growth plates, caused by a prolonged exposure to supraphysiological levels of estradiol in female ERα^−/− mice, must be mediated through ERβ because old ERα^−/−β^−/− mice displayed unchanged, unfused growth plates. Conclusions: Our results confirm that ERβ is a physiological inhibitor of appendicular- and axial-skeletal growth in young adult female mice. Furthermore, we made the novel observation that ERβ, after prolonged supraphysiological estradiol exposure, has the capacity to mediate growth plate fusion in old female mice.