title: Role of direct estrogen receptor signaling in wear particle-induced osteolysis.
abstract: Estrogen withdrawal following surgical ovariectomy was recently shown to mitigate particle-induced osteolysis in the murine calvarial model. Currently, we hypothesize that estrogen receptors (ERs) were involved in this paradoxical phenomenon. To test this hypothesis, we first evaluated polyethylene (PE) particle-induced osteolysis in the murine calvarial model, using wild type (WT) C57BL6J female mice, ERα deficient (ERαKO) mice, and WT mice either treated with 17β-estradiol (E2) or with the ER pan-antagonist ICI 182,780. According to micro-CT and histomorphometry, we showed that bone resorption was consistently altered in both ERαKO and ICI 182,780 treated mice as compared to WT and E2 groups. Then, we demonstrated that ER disruption consistently decreased both PE and polymethylmethacrylate (PMMA) particle-induced production of TNF-α by murine macrophages in vitro. Similar results were obtained following ER blockade using ICI 182,780 in RAW 264.7 and WT macrophages. ER disruption and pre treatment with ICI 182,780 resulted in a consistent down-regulation of particle-induced TNF-α mRNA expression relative to WT macrophages or untreated RAW cells. These results indicate that the response to wear particles involves estrogen receptors in female mice, as part of macrophage activation. Estrogen receptors may be considered as a future therapeutic target for particle-induced osteolysis.
authors.affiliation: Department of Orthopaedic Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA. chrnich@gmail.com
authors.forename: Christophe
authors.initials: C
authors.lastname: Nich
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Rao
authors.forename: Roberto D
authors.initials: RD
authors.lastname: Valladares
authors.forename: Chenguang
authors.initials: C
authors.lastname: Li
authors.forename: Jane E
authors.initials: JE
authors.lastname: Christman
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Antonios
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yao
authors.forename: Stefan
authors.initials: S
authors.lastname: Zwingenberger
authors.forename: Hervé
authors.initials: H
authors.lastname: Petite
authors.forename: Moussa
authors.initials: M
authors.lastname: Hamadouche
authors.forename: Stuart B
authors.initials: SB
authors.lastname: Goodman
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000077267:Fulvestrant; D017353:Gene Deletion; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010014:Osteolysis / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D020959:Polyethylene / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D016207:Cytokines; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000077267:Fulvestrant; D004958:Estradiol; D020959:Polyethylene