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

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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.