Pharmacological inhibition of tankyrase induces bone loss in mice by increasing osteoclastogenesis.
Pharmacological inhibition of tankyrase induces bone loss in mice by increasing osteoclastogenesis.
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DOI：
10.1016/j.bone.2017.10.017
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发表时间：
2018-01
期刊：
影响因子：
4.1
通讯作者：
Morita Y
中科院分区：
文献类型：
--
作者：
Fujita S;Mukai T;Mito T;Kodama S;Nagasu A;Kittaka M;Sone T;Ueki Y;Morita Y
Tankyrase是一种多聚(ADP-核糖)聚合酶，可导致泛素化和目标蛋白的降解。由于tankyrase抑制剂抑制了Axin蛋白的降解，Axin蛋白是典型的Wnt途径的负调控因子，因此它们有效地起到了Wnt抑制剂的作用。小分子Tankyrase抑制剂正在作为癌症和纤维化疾病的候选药物进行研究，在这些疾病中，Wnt通路被异常激活。据报道，tankyrase还能降解接头蛋白SH3BP2(SH3结构域结合蛋白2)。我们先前已经证明SH3BP2功能获得突变增强了核因子-κB配体受体激活物(RANKL)诱导的小鼠骨髓来源巨噬细胞的破骨细胞生成。尽管Tankyrase和SH3BP2之间的相互作用已有报道，但目前尚不清楚Tankyrase的抑制是否以及如何影响骨细胞和骨量。在这里，我们已经证明了tankyrase抑制剂(IWR-1、XAV939和G007-LK)通过积累SH3BP2、随后的SYK磷酸化和NFATc1的核转位，增强了RANKL诱导的小鼠骨髓基质细胞和人外周血单核细胞中破骨细胞的形成和功能。Tankyrase抑制剂还促进成骨细胞的分化和成熟，表现为成骨细胞相关基因的表达增加，同时SH3BP2蛋白积累，ABL、TAZ和Runx2的核转位增加。最重要的是，对小鼠Tankyrase的药物抑制显著减少了胫骨和腰椎的骨体积，并伴随着破骨细胞数量的增加。我们的发现揭示了Tankyrase抑制在骨细胞中的作用，并突出了该抑制物对骨的潜在不利影响。
Tankyrase is a poly(ADP-ribose) polymerase that leads to ubiquitination and degradation of target proteins. Since tankyrase inhibitors suppress the degradation of AXIN protein, a negative regulator of the canonical Wnt pathway, they effectively act as Wnt inhibitors. Small molecule tankyrase inhibitors are being investigated as drug candidates for cancer and fibrotic diseases, in which the Wnt pathways are aberrantly activated. Tankyrase is also reported to degrade the adaptor protein SH3BP2 (SH3 domain-binding protein 2). We have previously shown that SH3BP2 gain-of-function mutation enhances receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis in murine bone marrow-derived macrophages (BMMs). Although the interaction between tankyrase and SH3BP2 has been reported, it is not clear whether and how the inhibition of tankyrase affects bone cells and bone mass. Here, we have demonstrated that tankyrase inhibitors (IWR-1, XAV939, and G007-LK) enhanced RANKL-induced osteoclast formation and function in murine BMMs and human peripheral blood mononuclear cells through the accumulation of SH3BP2, subsequent phosphorylation of SYK, and nuclear translocation of NFATc1. Tankyrase inhibitors also enhanced osteoblast differentiation and maturation, represented by increased expression of osteoblast-associated genes accompanied by the accumulation of SH3BP2 protein and enhanced nuclear translocation of ABL, TAZ, and Runx2 in primary osteoblasts. Most importantly, pharmacological inhibition of tankyrase in mice significantly decreased tibia and lumbar vertebrae bone volumes in association with increased numbers of osteoclasts. Our findings uncover the role of tankyrase inhibition in bone cells and highlight the potential adverse effects of the inhibitor on bone.
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影响因子：
--
作者：
Ju YI;Sone T;Ohnaru K;Choi HJ;Choi KA;Fukunaga M
通讯作者：
Fukunaga M
影响因子：
3.7
作者：
Papadaki ME;Lietman SA;Levine MA;Olsen BR;Kaban LB;Reichenberger EJ
通讯作者：
Reichenberger EJ
DOI：
10.1007/978-1-61779-415-5_2
发表时间：
2012-01-01
期刊：
BONE RESEARCH PROTOCOLS, SECOND EDITION
影响因子：
--
作者：
Bakker, Astrid D.;Klein-Nulend, Jenneke
通讯作者：
Klein-Nulend, Jenneke
影响因子：
3.7
作者：
Mukai T;Gallant R;Ishida S;Yoshitaka T;Kittaka M;Nishida K;Fox DA;Morita Y;Ueki Y
通讯作者：
Ueki Y
影响因子：
15.9
作者：
Levaot, Noam;Simoncic, Paul D.;Rottapel, Robert
通讯作者：
Rottapel, Robert