Ameloblastin modulates osteoclastogenesis through the integrin/ERK pathway.
Ameloblastin modulates osteoclastogenesis through the integrin/ERK pathway.
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DOI：
10.1016/j.bone.2013.01.041
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发表时间：
2013-05
期刊：
影响因子：
4.1
通讯作者：
Luan, Xianghong
中科院分区：
文献类型：
--
作者：
Lu, Xuanyu;Ito, Yoshihiro;Atsawasuwan, Phimon;Dangaria, Smit;Yan, Xiulin;Wu, Tuojiang;Evans, Carla A.;Luan, Xianghong
细胞外基质的蛋白质通常具有多种功能，以促进从信号传导到结构支持的复杂任务。在这里，我们集中在骨骼和牙齿中表达的基质蛋白之一，基质粘附蛋白成釉蛋白（AMBN）的功能。转基因小鼠下颌骨中AMBN水平升高5倍，发生牙根牙骨质吸收、分层和牙槽骨厚度减少。AMBN功能的获得也导致出生后42天小鼠颌骨的松质骨体积和骨量显著减少。在破骨细胞生成的体外模型中，AMBN调节骨髓来源的单核细胞（BMMCs）的破骨细胞分化，并显著增加破骨细胞数量和吸收陷窝。此外，AMBN增加了一倍以上的BMMC粘附，加速细胞铺展，并促进足体带和肌动蛋白环的形成。这些作用与ERK 1/2和AKT磷酸化水平升高以及破骨细胞活化相关基因的高表达有关。阻断整合素α2β1和ERK 1/2通路可减轻AMBN对破骨细胞分化的影响。总之，我们的数据表明，AMBN通过调节细胞粘附和肌动蛋白细胞骨架聚合，启动整合素依赖性细胞外基质信号级联反应和增强破骨细胞生成来增加破骨细胞数量和分化以及矿化组织吸收。
Proteins of the extracellular matrix often have multiple functions to facilitate complex tasks ranging from signaling to structural support. Here we have focused on the function of one of the matrix proteins expressed in bones and teeth, the matrix adhesion protein ameloblastin (AMBN). Transgenic mice with 5-fold elevated AMBN levels in mandibles suffered from root cementum resorption, delamination, and reduced alveolar bone thickness. AMBN gain of function also resulted in a significant reduction in trabecular bone volume and bone mass dentistry in 42 days postnatal mouse jaws. In an in vitro model of osteoclastogenesis, AMBN modulated osteoclast differentiation from bone marrow derived monocytes (BMMCs), and dramatically increased osteoclast numbers and resorption pits. Furthermore, AMBN more than doubled BMMC adhesion, accelerated cell spreading, and promoted podosome belt and actin ring formation. These effects were associated with elevated ERK1/2 and AKT phosphorylation as well as higher expression of osteoclast activation related genes. Blocking integrin α2β1 and ERK 1/2 pathways alleviated the effects of AMBN on osteoclast differentiation. Together, our data indicate that AMBN increases osteoclast number and differentiation as well as mineralized tissue resorption by regulating cell adhesion and actin cytoskeleton polymerization, initiating integrin-dependent extracellular matrix signaling cascades and enhancing osteoclastogenesis.
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