Studies of the functions of TGFBI in bone homeostasis and cancer development

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The extracellular matrix (ECM) is a major part of the body’s connective tissues like bone and cartilage. Thus several mutations affecting proteins of the ECM are linked to human diseases. For example Osteogenesis imperfecta is characterized by a reduced bone mineral density and biomechanical instability. Additionally the ECM has pivotal functions in diverse types of cancer, since interactions of cancer cells with the ECM influence migration, proliferation, survival and apoptosis of cancer cells. I plan to analyze the functions of the ECM protein TGFBI (or βIg-h3), a putative target gene of the AP- 1 transcription factor FOS in bone-forming osteoblasts and myocytes. By characterizing the phenotype of mice with osteoblast-specific loss of function of Tgfbi and mice that inducibly overexpress Tgfbi in osteoblasts, the physiological role of TGFBI in bone homeostasis will be investigated. Fos overexpression under the control of the H2 promoter results in the development of osteosarcoma (OS) in mice. Therefore the role of Tgfbi as a target gene of Fos will be genetically adressed in this context. Human OS cell lines and human tumor biopsies will be used to elucidate the function of FOS and TGFBI and to validate the data obtained in mouse models.Since Fos can also function as a tumor suppressor in specific cellular contexts, the second aim of the project is to investigate the function of Tgfbi as a potential tumor suppressor gene in a Fos-dependent mouse model of Rhabdomyosarcoma (RMS). The goal will be first to establish an improved model of RMS in mice by deleting Fos and p53 specifically in muscle cells and to investigate the relevance of TGFBI in this setting and in human RMS. I plan to perform in vitro analyses of human RMS cells after stable knock-down or over-expression of FOS and TGFBI. Human patient material will also be analyzed.