Intrinsic Sex Differences in the Early Growth Hormone Responsiveness of Sex-Specific Genes in Mouse Liver

摘要

The following abstracts from Molecular Endocrinology have been selected by the editors of JCEM as being particularly relevant to readers interested in translational science. Estrogens attenuate osteoclastogenesis and stimulate osteoclast apoptosis, but the molecular mechanism and contribution of these effects to the overall antiosteoporotic efficacy of estrogens remain controversial. We selectively deleted the estrogen receptor (ER)a from the monocyte/macrophage cell lineage in mice (ERary.m ’-) and found a 2-fold increase in osteoclast pro- genitors in the marrow and the number of osteoclasts in cancellous bone, along with a decrease in cancellous bone mass. After loss of estrogens these mice failed to exhibit the expected increase in osteoclast progenitors, the number of osteoclasts in bone, and further loss of cancellous bone. However, they lost cortical bone indistinguishably from their littermate controls. Mature osteoclasts from ERaiycm ’~ were resistant to the proapoptotic effect of 17B-estradiol. In any case, the effects of estrogens on osteoclasts were unhindered in mice bearing an ERa knock-in mutation that prevented binding to DNA. Moreover, a polymeric form of estrogen that is not capable of stimulating the nuclear-initiated actions of ERa was as effective as 17B-estradiol in inducing osteoclast apoptosis in cells with the wild-type ERa. We conclude that estrogens attenuate osteoclast generation and lifespan via cell autonomous effects mediated by DNA-binding-independent actions of ERa. Elimination of these effects is sufficient for loss of bone in the cancellous compartment in which complete perforation of trabeculae by osteoclastic resorption precludes subse- quent refilling of the cavities by the bone-forming osteoblasts. However, additional effects of estrogens on osteoblasts, osteocytes, and perhaps other cell types are required for their protective effects on the cortical compartment, which constitutes 80% of the skeleton.