title: Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival.
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.
authors.affiliation: Division of Molecular and Cellular Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Krum
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Miranda-Carboni
authors.forename: Peter V
authors.initials: PV
authors.lastname: Hauschka
authors.forename: Jason S
authors.initials: JS
authors.lastname: Carroll
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Lane
authors.forename: Leonard P
authors.initials: LP
authors.lastname: Freedman
authors.forename: Myles
authors.initials: M
authors.lastname: Brown
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D018920:Coculture Techniques; D004967:Estrogens / Q000502:physiology*; D053222:Fas Ligand Protein / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D019014:fas Receptor / Q000502:physiology
chemical_list: D004967:Estrogens; D053222:Fas Ligand Protein; C491899:Fas protein, mouse; D019014:fas Receptor