IL-17 mediates estrogen-deficient osteoporosis in an Act1-dependent manner.
IL-17 mediates estrogen-deficient osteoporosis in an Act1-dependent manner.
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DOI：
10.1002/jcb.24165
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发表时间：
2012-09
影响因子：
4
通讯作者：
Teitelbaum, Steven L.
中科院分区：
文献类型：
--
作者：
DeSelm, Carl J.;Takahata, Yoshifumi;Warren, Julia;Chappel, Jean C.;Khan, Taimur;Li, Xiaoxia;Liu, Caini;Choi, Yongwon;Kim, Youngmi Faith;Zou, Wei;Teitelbaum, Steven L.
雌激素缺乏性骨质疏松症可能是一种炎症性疾病，因此我们询问IL-17是否参与其发病机制。主要IL-17受体（IL-17 RA）的缺失保护小鼠免受卵巢切除术（OVX）诱导的骨丢失。进一步支持IL-17在其发病机制中的中心作用，通过靶向细胞因子的阻断抗体预防OVX诱导的骨质疏松症。IL-17通过刺激成骨细胞表达RANK配体（RANKL）促进破骨细胞生成，由IL-17 RA SEFIR/TILL结构域介导。然而，雌激素剥夺并不增强成骨细胞或骨中IL-17 RA mRNA的表达，而是增强了Act 1（一种IL-17 RA相互作用蛋白和信号介质）的表达。与IL-17 RA −/−小鼠类似，缺乏Act 1的小鼠受到保护，免受OVX诱导的骨质流失。也反映了IL-17 RA缺乏，成骨细胞中缺乏Act 1，但破骨细胞中没有，通过抑制RANKL表达损害破骨细胞生成。WT Act 1转导入Act 1 −/−成骨细胞实质上挽救了它们的破骨细胞生成能力。然而，缺乏其E3连接酶U盒或其SEFIR结构域（其与IL-17 RA中的对应物相互作用）的相同构建体不能这样做。因此，雌激素剥夺促进RANKL表达和骨吸收，与IL-17效应物Act 1的上调相关，支持绝经后骨质疏松症是先天免疫紊乱的概念。
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 IL17RA-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 upregualtion of the IL-17 effector, Act1, supporting the concept that post-menopausal osteoporosis is a disorder of innate immunity.
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影响因子：
4.9
作者：
Adamopoulos IE;Chao CC;Geissler R;Laface D;Blumenschein W;Iwakura Y;McClanahan T;Bowman EP
通讯作者：
Bowman EP
影响因子：
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4.8
作者：
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