Regulation of bone growth via ligand-specific activation of estrogen receptor alpha

Estrogens are well known for their capacity to promote bone maturation and at high doses to induce growth plate closure and thereby stop further growth. High-dose estrogen treatment has therefore been used to limit growth in extremely tall girls. However, recent data suggest that this treatment may have severe side effects, including increased risk of cancer and reduced fertility. We hypothesized that estrogenic effects in bone are mediated via ERa signaling. Twelve-week-old ovariectomized female C57BL/6 mice were subcutaneously injected for 4 weeks with E2 or selective ER alpha (PPT) or ER alpha (DPN) agonists. After killing, tibia and femur lengths were measured, and growth plate morphology was analyzed. E2- and PPT-treated mice had shorter tibiae and femur bones when compared to vehicle-treated controls, whereas animals treated with DPN had similar bone lengths compared to controls. Growth plate height and hypertrophic zone height were reduced in animals treated with E2 or PPT but not in those treated with DPN, supporting that the effect was mediated via ER alpha. Moreover, PCNA staining revealed suppressed proliferation of chondrocytes in the tibia growth plate in PPT-or E2-treated mice compared to controls. Our data show that estrogenic effects on bone growth and growth plate maturation are mainly mediated via ER alpha. Our findings may have direct implications for the development of new and more selective treatment modalities of extreme tall stature using selective estrogen receptor modulators that may have low side effects than high-dose E2 treatment.