VWC2 Increases Bone Formation Through Inhibiting Activin Signaling.
VWC2 Increases Bone Formation Through Inhibiting Activin Signaling.
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DOI：
10.1007/s00223-018-0462-9
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发表时间：
2018-12
影响因子：
4.2
通讯作者：
Mochida Y
中科院分区：
文献类型：
--
作者：
Almehmadi A;Ohyama Y;Kaku M;Alamoudi A;Husein D;Katafuchi M;Mishina Y;Mochida Y
通过生物信息学方法，我们鉴定了一种新的半胱氨酸结蛋白成员，VWC2（含有 2 的冯维勒布兰德因子 C 结构域），以前称为 Brorin。由于 Brorin 被认为具有骨形态发生蛋白 (BMP) 拮抗剂的作用，因此我们研究了 Brorin/VWC2 与几种 BMP 的结合；然而，所测试的 BMP 均未与 VWC2 结合。相反，激活素的 βA 亚基被发现是转化生长因子 (TGF)-β 超家族成员之间的结合伴侣。在这里，我们发现 Vwc2 基因表达在成骨细胞分化早期暂时上调，VWC2 蛋白存在于骨基质中，并定位于成骨细胞/骨细胞。在 MC3T3-E1 成骨细胞系和原代成骨细胞中，外源 VWC2 存在时，激活素 A 诱导的 Smad2 磷酸化受到抑制。研究了VWC2对用激活素A处理的离体颅骨器官培养物的影响，并且用VWC2恢复了由激活素A降低的骨形态测量参数。当我们进一步研究VWC2抑制激活素A对骨形成影响的生物学机制时，我们发现激活素A对成骨细胞生长、分化和矿化的影响被VWC2逆转。综上所述，VWC2 是一种新型分泌蛋白，通过抑制 Activin-Smad2 信号通路促进骨形成。
By a bioinformatics approach, we have identified a novel cysteine knot protein member, VWC2 (von Willebrand factor C domain containing 2) previously known as Brorin. Since Brorin has been proposed to function as a bone morphogenetic protein (BMP) antagonist, we investigated the binding of Brorin/VWC2 to several BMPs; however, none of the BMPs tested were bound to VWC2. Instead, the βA subunit of activin was found as a binding partner among transforming growth factor (TGF)-β superfamily members. Here, we show that Vwc2 gene expression is temporally upregulated early in osteoblast differentiation, VWC2 protein is present in bone matrix, and localized at osteoblasts/osteocytes. Activin A-induced Smad2 phosphorylation was inhibited in the presence of exogenous VWC2 in MC3T3-E1 osteoblast cell line and primary osteoblasts. The effect of VWC2 on ex vivo cranial bone organ cultures treated with activin A was investigated, and bone morphometric parameters decreased by activin A were restored with VWC2. When we further investigated the biological mechanism how VWC2 inhibited the effects of activin A on bone formation, we found that the effects of activin A on osteoblast cell growth, differentiation, and mineralization were reversed by VWC2. Taken together, a novel secretory protein, VWC2 promotes bone formation by inhibiting Activin-Smad2 signaling pathway.
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影响因子：
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通讯作者：
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