Estrogens Attenuate Oxidative Stress and the Differentiation and Apoptosis of Osteoblasts by DNA-Binding-Independent Actions of the ERα
Abstract
Estrogens diminish oxidative stress in bone and bone marrow, attenuate the generation of osteoblasts, and decrease the prevalence of mature osteoblast apoptosis. We have searched for the molecular mechanism of these effects using as tools a mouse model bearing an estrogen receptor α (ERα) knock‐in mutation that prevents binding to DNA (ERαNERKI/−) and several osteoblast progenitor cell models expressing the wild‐type ERα or the ERαNERKI/−. We report that the ability of estrogens to diminish the generation of reactive oxygen species, stimulate the activity of glutathione reductase, and decrease the phosphorylation of p66shc, as well as osteoblastogenesis and osteoblast number and apoptosis, were fully preserved in ERαNERKI/− mice, indicating that the DNA‐binding function of the ERα is dispensable for all these effects. Consistent with the attenuation of osteoblastogenesis in this animal model, 17β‐estradiol attenuated bone morphogenetic protein 2 (BMP‐2)–induced gene transcription and osteoblast commitment and differentiation in murine and human osteoblastic cell lines. Moreover, 17β‐estradiol attenuated BMP‐2‐induced differentiation of primary cultures of calvaria‐ or bone marrow–derived osteoblastic cells from ERαNERKI/− mice as effectively as in cells from wild‐type littermates. The inhibitory effect of the hormone on BMP‐2 signaling resulted from an ERα‐mediated activation of ERKs and the phosphorylation of Smad1 at the linker region of the protein, which leads to…
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