Estrogen is critical for skeletal homeostasis and regulates bone remodeling, in part, by modulating the expression of receptor activator of NF-κB ligand (RANKL), an essential cytokine for bone resorption by osteoclasts. RANKL can be produced by a variety of hematopoietic (e.g. T and B-cell) and mesenchymal (osteoblast lineage, chondrocyte) cell types. The cellular mechanisms by which estrogen acts on bone are still a matter of controversy. By using murine reconstitution models that allow for selective deletion of estrogen receptor-alpha (ERα) or selective inhibition of RANKL in hematopoietic vs. mesenchymal cells, in conjunction with in situ expression profiling in bone cells, we identified bone lining cells as important gatekeepers of estrogen-controlled bone resorption. Our data indicate that the increase in bone resorption observed in states of estrogen deficiency in mice is mainly caused by lack of ERα-mediated suppression of RANKL expression in bone lining cells.Estrogen is an important regulator of bone mass. The role of estrogen for bone homeostasis in humans is illustrated by the fact that estrogen deficiency is one of the major causes of postmenopausal osteoporosis 1 . Estrogen acts through two receptors, estrogen receptor-alpha (ERα) and -beta (ERβ), with ERα being more important for the regulation of bone metabolism 2 . Estrogen receptors are widely expressed in a variety of cells in bone and bone marrow. However, the actual target cell responsible for mediating the effects of estrogen on bone is still a matter of debate 3 . One of the most important downstream mediators of the action of estrogen on bone is the osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) system. RANKL is an essential cytokine for osteoclast differentiation, activation, and survival 4, 5 . RANKL is produced by a variety of cells such as cells of the stromal cell lineage, activated T lymphocytes, but also B lymphocytes 5 . OPG is a soluble decoy receptor for RANKL which binds RANKL, and thereby inhibits osteoclastogenesis 6 . RANKL acts through the receptor RANK which is expressed in the cell membrane of osteoclasts and osteoclast precursor cells 7 . RANKL, RANK, and OPG are essential, non-redundant factors for osteoclast biology. Osteoclasts are entirely absent in RANK or RANKL deficient mice, leading to osteopetrosis, whereas OPG-deficient mice exhibit excessive bone resorption and severe osteoporosis 5,7,8 . RANKL exists in two biologically active forms, a membrane-bound form and a soluble form. Membrane-bound RANKL can be shed by matrix metalloproteinase 14 or by a disintegrin and metalloproteinase (ADAM) 10 9 resulting in soluble RANKL. In addition, soluble RANKL is produced by immune cells as a primary secreted form 5 . It is well established that sex steroids regulate the RANKL-OPG axis in osteoblast-like cells in vitro 10,11 . There is good evidence that OPG is regulated directly by sex hormones, whereas the sex steroid-mediated regulation of RANKL appears to be mainly indirect [10][11][12][13] . In vivo, o...

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