C/EBPα regulates osteoclast lineage commitment
C/EBPα regulates osteoclast lineage commitment
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DOI：
10.1073/pnas.1211383110
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发表时间：
2013-04-30
影响因子：
11.1
通讯作者：
Li, Yi-Ping
中科院分区：
文献类型：
--
作者：
Chen, Wei;Zhu, Guochun;Li, Yi-Ping
尽管最近从Finkel-Biskis-Jinkins骨肉瘤癌基因（c-fos）的靶向缺失的影响中获得了一些见解，但脾病灶形成病毒（SFFV）前病毒整合1 1）、小眼症相关转录因子、NF-κ B和活化细胞胞质核因子1（NFATc 1）转录因子基因，从单核细胞/巨噬细胞指定破骨细胞（OC）谱系定型的转录因子的潜在机制仍不清楚。为了表征转录因子调节OC谱系定型的机制，我们绘制了组织蛋白酶K（Ctsk）启动子中的关键顺式调节元件，该元件在OC中特异性表达，并发现CCAAT/增强子结合蛋白α（C/EBP α）是关键的顺式调节元件结合蛋白。我们的研究结果表明C/EBP α在前OC和OC中高度表达。巨噬细胞集落刺激因子和NF-κ B配体的受体激活剂的组合存在显著诱导高C/EBP α表达。此外，C/EBP α（-/-）新生小鼠表现出破骨细胞生成受损和严重的骨硬化表型，但单核细胞/巨噬细胞发育不受影响。C/EBP α（-/-）小鼠骨髓细胞破骨细胞生成受损可通过c-fos过表达来挽救在不存在NF-κ B配体受体激活剂的情况下，小鼠骨髓细胞和单核细胞/巨噬细胞中C/EBP α的异位表达诱导NF-κ B、c-fos、Nfatc 1和Ctsk受体激活剂的表达，并将单核细胞/巨噬细胞重编程为OC样细胞。我们的研究结果表明，C/EBP α直接上调c-fos表达。与C/EBP α（+/+）对照相比，C/EBP α（+/-）小鼠表现出骨密度增加。这些发现确立了C/EBP α作为OC谱系定型的关键转录调节因子，为过度骨吸收疾病（如骨质疏松症和关节炎）提供了独特的治疗靶点。
Despite recent insights gained from the effects of targeted deletion of the Finkel-Biskis-Jinkins osteosarcoma oncogene (c-fos), Spleen focus-forming virus (SFFV) proviral integration 1 (PU.1), microphthalmia- associated transcription factor, NF-kappa B, and nuclear factor of activated cells cytoplasmic 1 (NFATc1) transcription factor genes, the mechanism underlying transcription factors specifying osteoclast (OC) lineage commitment from monocyte/macrophage remains unclear. To characterize the mechanism by which transcription factors regulate OC lineage commitment, we mapped the critical cis-regulatory element in the promoter of cathepsin K (Ctsk), which is expressed specifically in OCs, and found that CCAAT/enhancer binding protein alpha (C/EBP alpha) is the critical cis-regulatory element binding protein. Our results indicate that C/EBP alpha is highly expressed in pre-OCs and OCs. The combined presence of macrophage colony-stimulating factor and receptor activator of NF-kappa B ligand significantly induces high C/EBP alpha expression. Furthermore, C/EBP alpha(-/-) newborn mice exhibited impaired osteoclastogenesis, and a severe osteopetrotic phenotype, but unaffected monocyte/macrophage development. Impaired osteoclastogenesis of C/EBP alpha(-/-) mouse bone marrow cells can be rescued by c-fos overexpression. Ectopic expression of C/EBP alpha in mouse bone marrow cells and monocyte/ macrophage cells, in the absence of receptor activator of NF-kappa B ligand, induces expression of receptor activator of NF-kappa B, c-fos, Nfatc1, and Ctsk, and it reprograms monocyte/ macrophage cells to OC-like cells. Our results demonstrate that C/EBP alpha directly up-regulates c-fos expression. C/EBP alpha(+/-) mice exhibit an increase in bone density compared with C/EBP alpha(+/+) controls. These discoveries establish C/EBP alpha as the key transcriptional regulator of OC lineage commitment, providing a unique therapeutic target for diseases of excessive bone resorption, such as osteoporosis and arthritis.