The impact of the transcription factor c-Jun on bone mass via the regulation of osteoprogenitor cells

骨质疏松症等骨量减少的疾病不仅给患者及其家庭带来了沉重的负担，而且对人口老龄化的现代卫生保健系统提出了挑战。转录因子c-Jun属于AP1家族，参与纤维化和恶性疾病。在我们的实验中，我们观察到c-Jun诱导异位移植成人骨的新生长，并且c-Jun使不同亚群的骨祖细胞在肾包膜下建立异位骨。我们发现c-Jun破坏生长板的规则结构，主要是未成熟的骨骼细胞表达c-Jun。面部纯化的骨祖细胞的基因表达研究显示，骨骼干细胞中的刺猬信号增加。骨质疏松模型显示，c-Jun诱导骨祖细胞在股骨原位移植后急剧扩增，钻孔骨折模型显示c-Jun诱导可显著加速骨折愈合。延长奖学金将允许我进行以下实验：首先，使用我们改进的细胞培养技术进一步表征c-Jun影响骨祖细胞的信号通路。其次，在系列移植模型中测试c-Jun是否介导了分化程度更高的骨祖细胞自我更新能力的增强。第三，我们将受益于我们改进的细胞培养技术来控制c-Jun在体外和体内是否诱导人间充质干细胞成骨分化。第四，我们将研究一次性诱导c-Jun是否加速骨折愈合。总之，本研究旨在提高我们对骨祖细胞如何调节整体骨量的理解，并开发利用致癌基因治疗骨质疏松症和骨折的新方法。

Diseases with a decreased bone mass such as osteoporosis cause not only a high burden to patients and their families but also challenge modern health care system with aging populations. The transcription factor c-Jun belongs to the AP1 family and contributes to fibrotic and malignant diseases. In our experiments we observed that c-Jun induces new growth of ectopically transplanted adult bones and that c-Jun causes different subsets of osteoprogenitors to build ectopic bone under the renal capsule. We showed that c-Jun disrupts the regular architecture of the growth plate and that mainly immature skeletal cells express c-Jun. Gene expression studies in facs purified osteoprogenitors showed increased hedgehog signaling in skeletal stem cells. An osteoporosis model revealed that c-Jun leads to a dramatic expansion of thy osteoprogenitors after orthotopic transplantation into the femur and a drilling facture model shows that c-Jun induction significantly accelerates fracture healing. Extending the fellowship will allow me the following experiments: First, to use our improved cell cultures techniques to further characterize signaling pathways through which c-Jun effects osteoprogenitors. Second, to test in a serial transplantation model if c-Jun mediates increased self-renewal capacity to more differentiated osteoprogenitors. Third, we will benefit from our improved cell culture techniques to control whether c-Jun induces the osteogenic differentiation of human mesenchymal stem cells in vitro and in vivo. Fourth, we will investigate if the onetime induction of c-Jun accelerates fracture healing. In conclusion, this proposal aims at improving our understanding about how osteoprogenitors regulate the overall skeletal mass and developing novel approaches to take advantage of an oncogene to treat osteoporosis and fractures.