Deletion of Menin in craniofacial osteogenic cells in mice elicits development of mandibular ossifying fibroma
Deletion of Menin in craniofacial osteogenic cells in mice elicits development of mandibular ossifying fibroma
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DOI：
10.1038/onc.2017.364
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发表时间：
2018-02
期刊：
影响因子：
8
通讯作者：
Sooyeon Lee;Peng Liu;R. Teinturier;J. Jakob;M. Tschaffon;A. Tasdogan;Rainer Wittig;S. Hoeller;D. Baumhoer;Lucien Frappart;Lucien Frappart;Sabine Vettorazzi;Philippe Bertolino;Chang X. Zhang;Jan Tuckermann
中科院分区：
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作者：
Sooyeon Lee;Peng Liu;R. Teinturier;J. Jakob;M. Tschaffon;A. Tasdogan;Rainer Wittig;S. Hoeller;D. Baumhoer;Lucien Frappart;Lucien Frappart;Sabine Vettorazzi;Philippe Bertolino;Chang X. Zhang;Jan Tuckermann
骨化纤维瘤 (OF) 是一种罕见的颅面骨良性肿瘤，如果不及时治疗，其尺寸可能会达到相当大的程度并导致毁容。尽管 OF 的临床病理学特征已明确，但其潜在病因仍很大程度上未知。我们的工作表明，Men1（一种负责 1 型多发性内分泌肿瘤的肿瘤抑制基因）对于 OF 的形成至关重要，并表明在成骨细胞中靶向破坏 Men1 (Men1 Runx2Cre) 的小鼠会在下颌骨中形成多灶性 OF，外显率达 100%。通过谱系追踪分析，我们证明 Men1 的缺失会阻止 OF 中基质骨祖细胞处于 osterix 阳性的前成骨细胞分化阶段。对从 OF（OF 衍生的 MSCs (OFMSCs)）中分离出的缺乏 Men1 的基质梭形细胞进行的分析显示，细胞周期蛋白依赖性激酶 (CDK) 抑制剂 Cdkn1a 的下调，与增殖率的增加一致。有趣的是，Men1 缺陷的 OFMSC 中 Men1 的重新表达恢复了 Cdkn1a 的表达并消除了细胞增殖，支持了 Men1 在 OF 中的肿瘤抑制作用。尽管我们的工作首次提供了 Men1 在 OF 发育中的证据，但它进一步提供了第一个 OF 基因小鼠模型，可用于更好地了解这些良性肿瘤的分子发病机制，并有可能开发新的治疗策略。
Ossifying fibroma (OF) is a rare benign tumor of the craniofacial bones that can reach considerable and disfiguring dimensions if left untreated. Although the clinicopathological characteristics of OF are well established, the underlying etiology has remained largely unknown. Our work indicates that Men1—a tumor suppressor gene responsible of Multiple endocrine neoplasia type 1—is critical for OF formation and shows that mice with targeted disruption of Men1 in osteoblasts (Men1 Runx2Cre) develop multifocal OF in the mandible with a 100% penetrance. Using lineage-tracing analysis, we demonstrate that loss of Men1 arrests stromal osteoprogenitors in OF at the osterix-positive pre-osteoblastic differentiation stage. Analysis of Men1-lacking stromal spindle cells isolated from OF (OF-derived MSCs (OFMSCs)) revealed a downregulation of the cyclin-dependent kinase (CDK) inhibitor Cdkn1a, consistent with an increased proliferation rate. Intriguingly, the re-expression of Men1 in Men1-deficient OFMSCs restored Cdkn1a expression and abrogated cellular proliferation supporting the tumor-suppressive role of Men1 in OF. Although our work presents the first evidence of Men1 in OF development, it further provides the first genetic mouse model of OF that can be used to better understand the molecular pathogenesis of these benign tumors and to potentially develop novel treatment strategies.