TGF-β Signaling Regulates Cementum Formation through Osterix Expression.
TGF-β Signaling Regulates Cementum Formation through Osterix Expression.
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DOI：
10.1038/srep26046
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发表时间：
2016-05-16
影响因子：
4.6
通讯作者：
Cho ES
中科院分区：
文献类型：
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作者：
Choi H;Ahn YH;Kim TH;Bae CH;Lee JC;You HK;Cho ES
TGF-β/BMPs在哺乳动物发育中具有广泛公认的作用，包括在骨和牙齿形成中。为了确定小鼠牙齿发育中TGF-β信号传导的自主需求的功能相关性，我们分析了骨钙素-Cre介导的Tgfbr 2（OCCreTgfbr 2fl/fl）条件性敲除小鼠，其缺乏分化成牙骨质细胞和牙骨质细胞的功能性TGF-β受体II（TβRII）。引人注目的是，OCCreTgfbr 2fl/fl突变小鼠表现出细胞牙骨质质量急剧减少，基质分泌和矿物质沉积率降低。为探讨TGF-β信号通路通过TβRII在牙骨质形成中作用的分子机制，我们利用OCCM-30细胞建立了TβRII表达降低的小鼠成牙骨质细胞模型。有趣的是，Osterix（Osx）的表达，细胞牙骨质形成的主要调节因子之一，在缺乏TβRII的OCCM-30细胞中大大减少。因此，在这些细胞中，功能性ALP活性和与牙骨质形成相关的基因的表达降低，并且细胞被Osx转导部分拯救。我们还发现TGF-β信号通过Smad依赖性途径直接调节Osx的表达。这些结果有力地表明，TGF-β信号作为Osx的上游调节因子之一在成牙骨质细胞分化和牙骨质形成中起着重要作用。
TGF-β/BMPs have widely recognized roles in mammalian development, including in bone and tooth formation. To define the functional relevance of the autonomous requirement for TGF-β signaling in mouse tooth development, we analyzed osteocalcin-Cre mediated Tgfbr2 (OCCreTgfbr2fl/fl) conditional knockout mice, which lacks functional TGF-β receptor II (TβRII) in differentiating cementoblasts and cementocytes. Strikingly, OCCreTgfbr2fl/fl mutant mice exhibited a sharp reduction in cellular cementum mass with reduced matrix secretion and mineral apposition rates. To explore the molecular mechanisms underlying the roles of TGF-β signaling through TβRII in cementogenesis, we established a mouse cementoblast model with decreased TβRII expression using OCCM-30 cells. Interestingly, the expression of osterix (Osx), one of the major regulators of cellular cementum formation, was largely decreased in OCCM-30 cells lacking TβRII. Consequently, in those cells, functional ALP activity and the expression of genes associated with cementogenesis were reduced and the cells were partially rescued by Osx transduction. We also found that TGF-β signaling directly regulates Osx expression through a Smad-dependent pathway. These findings strongly suggest that TGF-β signaling plays a major role as one of the upstream regulators of Osx in cementoblast differentiation and cementum formation.