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Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival. EMBO J

Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
The EMBO Journal (Impact Factor: 10.75). 03/2008; 27(3):535-45. DOI: 10.1038/sj.emboj.7601984
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ABSTRACT Estrogen deficiency in menopause is a major cause of osteoporosis in women. Estrogen acts to maintain the appropriate ratio between bone-forming osteoblasts and bone-resorbing osteoclasts in part through the induction of osteoclast apoptosis. Recent studies have suggested a role for Fas ligand (FasL) in estrogen-induced osteoclast apoptosis by an autocrine mechanism involving osteoclasts alone. In contrast, we describe a paracrine mechanism in which estrogen affects osteoclast survival through the upregulation of FasL in osteoblasts (and not osteoclasts) leading to the apoptosis of pre-osteoclasts. We have characterized a cell-type-specific hormone-inducible enhancer located 86 kb downstream of the FasL gene as the target of estrogen receptor-alpha induction of FasL expression in osteoblasts. In addition, tamoxifen and raloxifene, two selective estrogen receptor modulators that have protective effects in bone, induce apoptosis in pre-osteoclasts by the same osteoblast-dependent mechanism. These results demonstrate that estrogen protects bone by inducing a paracrine signal originating in osteoblasts leading to the death of pre-osteoclasts and offer an important new target for the prevention and treatment of osteoporosis.

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Available from: Myles Brown, Dec 13, 2014
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    • "Subjects with conditions suspected of affecting any biases were excluded from the study. Subjects were also excluded if they had been receiving corticoid, estrogen, androgen, T3 (triiodothyronine)-T4 (thyroxine) therapy or diphenylhydantoin, vitamin D, bisphosphonate, calcitonin, fluoride, thiazide diuretics, or barbiturates for more than 6 months, as all these drugs affect any biases.33,34,35,36,37,38) Since it was impossible to obtain a population-based register for technical and legal reasons, the selection of control subjects meeting the inclusion/exclusion criteria was made from volunteers (students, hospital workers, patients' relatives, etc.) attending the hospital. "
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    • "Previous studies have revealed that 17-β estradiol increases osteoprotegrin mRNA and protein levels in human osteoblastic cells in a dose- and time-dependent manner.10 Alternatively, a paracrine mechanism was found in which oestrogen affects osteoclast survival via upregulation of the Fas ligand in osteoblasts, leading to the apoptosis of osteoclast precursors.11 "
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