Unraveling estrogen action in osteoporosis.
A decrease in estrogen levels at menopause leads to a rapid loss of bone mineral density and an increase in fracture risk. For over ten years it has been known that the beneficial effects of estrogen are due in part to the ability of estrogen to suppress osteoclastogenic cytokine production in T-cells and osteoblasts. In addition to suppressing these cytokines, estrogen has been shown to induce the apoptotic death of osteoclasts. A variety of different mechanisms have been suggested to explain the estrogen regulation of osteoclast survival. One hypothesis is that estrogen, via rapid non-genomic signaling, induces apoptosis without the need for direct binding of estrogen receptor alpha (ERalpha) to DNA. A second hypothesis proposes that estrogen-stimulation of ERalpha in osteoclasts induces the expression Fas Ligand which in turn leads to cell death via an autocrine mechanism. In contrast, recent work from our lab has led to a genomic model of estrogen action in which estrogen acts to induce ERalpha binding to transcriptional enhancers in the Fas Ligand gene leading to its upregulation in osteoblasts which through a paracrine mechanism induces apoptosis in osteoclasts. Here we will focus on these differing models of the mechanism of estrogen-mediated osteoclast apoptosis.
Krum
Susan A
SA
Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachussets, USA.
Brown
Myles
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015519:Bone Density; D016207:Cytokines / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010006:Osteoblasts / Q000502:physiology; D010010:Osteoclasts / Q000378:metabolism*; D010024:Osteoporosis / Q000378:metabolism*
D016207:Cytokines; D047628:Estrogen Receptor alpha; D004967:Estrogens; D053222:Fas Ligand Protein