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骨質疏松癥是主要困擾老人特別是老年女性的一種常見病。德國馬克斯·德爾布呂克分子醫學中心的研究人員最近發現了導致骨質疏松癥的基因機理，為治療這種病提供了新思路。 骨質疏松是正常骨生長和骨吸收之間的平衡失調，即骨吸收過度時產生的。通常這種平衡由成骨細胞和破骨細胞這兩種功能相反的細胞協同作用維持。馬克斯·德爾布呂克分子醫學中心14日發表新聞公報說，其研究人員最近發現，人體中一種特殊轉錄因子在維護骨生長和骨吸收平衡方面起著非常重要的作用。 公報介紹說，這種轉錄因子又分為轉錄活化因子和轉錄抑制因子兩種不同形態。其中，轉錄活化因子能激活一個名為“MafB”的基因，從而抑制破骨細胞的形成。相反，轉錄抑制因子則能抑制“MafB”基因，從而有利于破骨細胞的擴散和活動。研究人員推測，轉錄活化因子和轉錄抑制因子的比例失調是導致骨質疏松癥的一個原因。 研究人員認為，借助上述發現，通過研發調節轉錄活化因子和轉錄抑制因子產生的藥物，應該能達到維護骨生長和骨吸收平衡的目的，從而有效治療骨質疏松癥。 推薦原始出處： 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. (責任編輯：Doctor001) |
