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We recently found that estrogen receptor (ER) antagonists prevent high-dose estrogen from inducing the formation of new cancellous bone within the medullary cavity of mouse long bones. In the present investigation, we studied the role of specific ER subtypes in this response by examining whether this is impaired in female ERbeta(-/-) mice previously generated by targeted gene deletion. Vehicle or 17beta-estradiol (E(2)) (range 4-4,000 microg. kg(-1). day(-1)) was administered to intact female ERbeta(-/-) mice and wild-type littermates by subcutaneous injection for 28 days. The osteogenic response was subsequently assessed by histomorphometry performed on longitudinal and cross sections of the tibia. E(2) was found to cause an equivalent increase in cancellous bone formation in ERbeta(-/-) mice and littermate controls, as assessed at the proximal and distal regions of the proximal tibial metaphysis. E(2) also resulted in a similar increase in endosteal mineral apposition rate in these two genotypes, as assessed at the tibial diaphysis. In contrast, cortical area in ERbeta(-/-) mice was found to be greater than that in wild types irrespective of E(2) treatment, as was tibial bone mineral density as measured by dual-energy X-ray absorptiometry, consistent with previous reports of increased cortical bone mass in these animals. We conclude that, although ERbeta acts as a negative modulator of cortical modeling, this isoform does not appear to contribute to high-dose estrogen's ability to induce new cancellous bone formation in mouse long bones.

High-dose estrogen both stimulates new medullary bone formation and suppresses hematopoiesis in mouse long bones. To determine whether the latter response is a direct consequence of the former, we compared the time course of estrogen's effects on osteogenesis and hematopoietic bone marrow. Flow cytometry was employed to measure hematopoietic subpopulations in bone marrow from femurs of female mice killed at different times after commencing 0.5 mg estradiol/wk to each animal. Estrogen markedly reduced the number of leucocytes (CD11a positive), which had already diminished by 75% after 4 days and had virtually disappeared by 18 days. Specific populations showed a similar pattern of decline after estrogen, including B lymphocytes, monocytes, and endothelial cells. In contrast, the osteogenic precursor population showed a marked increase after estrogen treatment, as assessed by assaying alkaline phosphatase-positive colony-forming units (fibroblastic) ex vivo. However, this rise did not reach significance until 8 days after estrogen administration, suggesting that it follows rather than precedes estrogen's effects on hematopoiesis. We conclude that estrogen does not suppress hematopoiesis in mouse long bones as a direct consequence of its effects on osteogenesis.