Mechanisms of Osteoprotective Actions of Estrogens

Abstract

Estrogens are primary sex hormones controlling female reproductive development and functions. Skeletal abnormalities in males with estrogen signaling impairments suggest that estrogens are critical for bone health in both sexes. The biological effects of estrogens are mediated by the action of estrogen receptors (ERα and ERβ). Lasting effects of estrogens are mediated by the ER genomic signaling pathway, in which ERs function as DNA-binding transcriptional factors acting in cooperation with various epigenetic cofactors to modulate the target gene expression through chromatin reconfiguration. Rapid biological responses to estrogen stimuli are mediated by the plasma membrane-associated ERs through activation of nongenomic intracellular signaling pathways. The estrogen signaling may cross-talk with signaling pathways of other biological regulators through ER interactions with their cytoplasmic or nuclear signal transducers. Major insights into estrogen regulation of bone physiology were obtained in studies on mice with genetically manipulated ER genes and in clinical observations of individuals with hereditary estrogen signaling abnormalities. In the osteoclasts, ERα mediates osteoprotective estrogen actions in cancellous bones, while the osteoblastic ERα supports cortical bone accrual. In the cartilage, estrogens induce epiphyseal closure in pubertal females. Treatment with estrogens and related compounds prevents development of osteoporosis and counteracting symptoms in postmenopausal women.