title: IL-17 mediates estrogen-deficient osteoporosis in an Act1-dependent manner.
abstract: Estrogen-deficient osteoporosis may be an inflammatory disorder and we therefore asked if IL-17 participates in its pathogenesis. Deletion of the principal IL-17 receptor (IL-17RA) protects mice from ovariectomy (OVX)-induced bone loss. Further supporting a central role of IL-17 in its pathogenesis, OVX-induced osteoporosis is prevented by a blocking antibody targeting the cytokine. IL-17 promotes osteoclastogenesis by stimulating RANK ligand (RANKL) expression by osteoblastic cells, mediated by the IL-17RA SEFIR/TILL domain. Estrogen deprivation, however does not enhance IL-17RA mRNA expression by osteoblasts or in bone, but augments that of Act1, an IL-17RA-interacting protein and signaling mediator. Similar to IL-17RA(-/-) mice, those lacking Act1 are protected from OVX-induced bone loss. Also mirroring IL-17RA-deficiency, absence of Act1 in osteoblasts, but not osteoclasts, impairs osteoclastogenesis via dampened RANKL expression. Transduction of WT Act1 into Act1(-/-) osteoblasts substantially rescues their osteoclastogenic capacity. The same construct, however, lacking its E3 ligase U-box or its SEFIR domain, which interacts with its counterpart in IL-17RA, fails to do so. Estrogen deprivation, therefore, promotes RANKL expression and bone resorption in association with upregulation of the IL-17 effector, Act1, supporting the concept that post-menopausal osteoporosis is a disorder of innate immunity.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: DeSelm
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Takahata
authors.forename: Julia
authors.initials: J
authors.lastname: Warren
authors.forename: Jean C
authors.initials: JC
authors.lastname: Chappel
authors.forename: Taimur
authors.initials: T
authors.lastname: Khan
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
authors.forename: Caini
authors.initials: C
authors.lastname: Liu
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Youngmi Faith
authors.initials: YF
authors.lastname: Kim
authors.forename: Wei
authors.initials: W
authors.lastname: Zou
authors.forename: Steven L
authors.initials: SL
authors.lastname: Teitelbaum
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism*; D010052:Ovariectomy; D053245:RANK Ligand / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020381:Interleukin-17; D053245:RANK Ligand; D053722:Receptors, Interleukin-17; C515963:Traf3ip2 protein, mouse