title: Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts.
abstract: Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor alpha (ERalpha) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERalpha in differentiated osteoclasts (ERalpha(DeltaOc/DeltaOc)) and found that ERalpha(DeltaOc/DeltaOc) females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ERalpha(DeltaOc/DeltaOc) mice. The expression of ERalpha was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.
authors.affiliation: Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Imai
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Shingo
authors.initials: S
authors.lastname: Sato
authors.forename: Kazusane
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Katsuhide
authors.initials: K
authors.lastname: Igarashi
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Harada
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Azuma
authors.forename: Andree
authors.initials: A
authors.lastname: Krust
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
authors.forename: Shu
authors.initials: S
authors.lastname: Takeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takayanagi
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Jun
authors.initials: J
authors.lastname: Kanno
authors.forename: Kunio
authors.initials: K
authors.lastname: Takaoka
authors.forename: T John
authors.initials: TJ
authors.lastname: Martin
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
mesh_terms: D000818:Animals; D017209:Apoptosis; D015519:Bone Density; D001851:Bone Diseases, Metabolic / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D016723:Bone Remodeling / Q000187:drug effects; D056657:Cathepsin K; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D019426:Integrases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010052:Ovariectomy; D010641:Phenotype; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D019014:fas Receptor / Q000378:metabolism*