Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis
Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis
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DOI：
10.1038/nm.2653
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发表时间：
2012-03-01
期刊：
影响因子：
82.9
通讯作者：
Takahashi, Naoyuki
中科院分区：
文献类型：
--
作者：
Maeda, Kazuhiro;Kobayashi, Yasuhiro;Takahashi, Naoyuki
信号分子Wnt通过依赖于β连环蛋白和非依赖于连环蛋白的非正则途径来调节骨骼的动态平衡。在关节炎和骨质疏松症中，规范的Wnt信号受损会导致骨丢失；然而，目前还不清楚非规范的Wnt信号如何调节骨吸收。WNT5A通过受体酪氨酸激酶样孤儿受体(ROR)蛋白激活非规范的Wnt信号。我们发现Wnt5a-Ror2信号在成骨细胞系细胞和破骨细胞前体之间促进了破骨细胞的形成。成骨细胞系细胞表达WNT5a，而破骨细胞前体细胞表达Ror2。缺乏Wnt5a或Ror2的小鼠，以及那些缺乏破骨细胞前体特异性Ror2或成骨细胞特异性Wnt5a的小鼠，显示出破骨细胞生成受损。Wnt5A-Ror2通过激活JNK和在RANK基因启动子上募集c-Jun来增强破骨细胞前体细胞核因子-kappaB受体激活物(RANK)的表达，从而增强RANKL诱导的破骨细胞分化。一种可溶性形式的Ror2作为Wnt5a的诱饵受体，在小鼠关节炎模型中消除了骨破坏。我们的结果表明，Wnt5a-Ror2通路在生理和病理环境中对破骨细胞的形成至关重要，并代表了包括关节炎在内的骨骼疾病的治疗靶点。
The signaling molecule Wnt regulates bone homeostasis through beta-catenin-dependent canonical and beta-catenin-independent noncanonical pathways. Impairment of canonical Wnt signaling causes bone loss in arthritis and osteoporosis; however, it is unclear how noncanonical Wnt signaling regulates bone resorption. Wnt5a activates noncanonical Wnt signaling through receptor tyrosine kinase-like orphan receptor (Ror) proteins. We showed that Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhanced osteoclastogenesis. Osteoblast-lineage cells expressed Wnt5a, whereas osteoclast precursors expressed Ror2. Mice deficient in either Wnt5a or Ror2, and those with either osteoclast precursor-specific Ror2 deficiency or osteoblast-lineage cell-specific Wnt5a deficiency showed impaired osteoclastogenesis. Wnt5a-Ror2 signals enhanced receptor activator of nuclear factor-kappa B (RANK) expression in osteoclast precursors by activating JNK and recruiting c-Jun on the promoter of the gene encoding RANK, thereby enhancing RANK ligand (RANKL)-induced osteoclastogenesis. A soluble form of Ror2 acted as a decoy receptor of Wnt5a and abrogated bone destruction in mouse arthritis models. Our results suggest that the Wnt5a-Ror2 pathway is crucial for osteoclastogenesis in physiological and pathological environments and represents a therapeutic target for bone diseases, including arthritis.