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骨质疏松症是主要困扰老人特别是老年女性的一种常见病。德国马克斯·德尔布吕克分子医学中心的研究人员最近发现了导致骨质疏松症的基因机理，为治疗这种病提供了新思路。 骨质疏松是正常骨生长和骨吸收之间的平衡失调，即骨吸收过度时产生的。通常这种平衡由成骨细胞和破骨细胞这两种功能相反的细胞协同作用维持。马克斯·德尔布吕克分子医学中心14日发表新闻公报说，其研究人员最近发现，人体中一种特殊转录因子在维护骨生长和骨吸收平衡方面起着非常重要的作用。 公报介绍说，这种转录因子又分为转录活化因子和转录抑制因子两种不同形态。其中，转录活化因子能激活一个名为“MafB”的基因，从而抑制破骨细胞的形成。相反，转录抑制因子则能抑制“MafB”基因，从而有利于破骨细胞的扩散和活动。研究人员推测，转录活化因子和转录抑制因子的比例失调是导致骨质疏松症的一个原因。 研究人员认为，借助上述发现，通过研发调节转录活化因子和转录抑制因子产生的药物，应该能达到维护骨生长和骨吸收平衡的目的，从而有效治疗骨质疏松症。 推荐原始出处： The EMBO Journal advance online publication 14 May 2009; doi:10.1038/emboj.2009.127 Transcription factor C/EBP isoform ratio regulates osteoclastogenesis through MafB Jeske J Smink1,a, Valérie Bégay1,a, Ton Schoenmaker2, Esta Sterneck3, Teun J de Vries2 and Achim Leutz1 1 Max Delbrueck Center for Molecular Medicine, Berlin, Germany 2 Departments of Periodontology and Oral Cell Biology, Academic Centre of Dentistry Amsterdam, Universiteit van Amsterdam and Vrije Universiteit, Amsterdam, The Netherlands 3 National Cancer Institute, Center for Cancer Research, Frederick, MD, USA Disequilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts is central to many bone diseases. Here, we show that dysregulated expression of translationally controlled isoforms of CCAAT/enhancer-binding protein β (C/EBPβ) differentially affect bone mass. Alternative translation initiation that is controlled by the mammalian target of rapamycin (mTOR) pathway generates long transactivating (LAP*, LAP) and a short repressive (LIP) isoforms from a single C/EBPβ transcript. Rapamycin, an inhibitor of mTOR signalling increases the ratio of LAP over LIP and inhibits osteoclastogenesis in wild type (WT) but not in C/EBPβ null (c/ebp-/-) or in LIP knock-in (L/L) osteoclast precursors. C/EBPβ mutant mouse strains exhibit increased bone resorption and attenuated expression of MafB, a negative regulator of osteoclastogenesis. Ectopic expression of LAP and LIP in monocytes differentially affect the MafB promoter activity, MafB gene expression and dramatically affect osteoclastogenesis. These data show that mTOR regulates osteoclast formation by modulating the C/EBPβ isoform ratio, which in turn affects osteoclastogenesis by regulating MafB expression. (责任编辑：Doctor001) |
